Global and National
Prevalence of Diabetes
Worldwide Perspective on Diabetes
An epidemic of diabetes and obesity is sweeping the globe, largely
because of marked shifts in dietary practices and physical activity. In
2000, 171 million persons on the planet were known to have diabetes,
and by 2030, this ﬁgure is expected to increase to 366 million. More
than 80% of people with diabetes worldwide live in low- and middle-
income countries. During the next 2 decades, the world population is
expected to increase by 37%, but the prevalence of diabetes will increase
by 114%. In India, sub-Saharan Africa, and Latin America, diabetes
prevalence is projected to increase by 150% to 160%.1
In the United States and other developed economies, the rise in
diabetes prevalence is projected to be higher than 50%. As shown in
Figure 46-1, in 2005, 20.8 million people (7% of the population) have
been diagnosed with some form of diabetes. Another 6.2 million with
diabetes are undiagnosed. Of women 20 years or older, 8.8% have
overt diabetes, but there is a strong predilection for this disease among
ethnic groups. Higher-than-expected rates of pregestational diabetes
in women of childbearing age have been reported for 13.3% of non-
Hispanic blacks, 9.5% of Hispanic and Latino Americans, and 12.8%
of Native Americans.2
Epidemiology of Diabetes in
Studies suggest that the prevalence of diabetes among women of child-
bearing age is increasing in the United States.3,4
tion among populations with high rates of type 2 diabetes and the
impact of changes in diet (i.e., increased calories and fat content) and
lifestyle (i.e., sedentary) have brought marked increases in the percent-
age of patients with preexisting diabetes who will become pregnant in
the future. A virtual epidemic of childhood obesity is occurring in the
United States, bringing with it a sharp rise in childhood and adolescent
diabetes. This trend will have a profound impact on obstetrics and
pediatrics in the next 2 decades and beyond.5
efforts to provide care to the populations experiencing rising rates of
pregestational diabetes will be necessary if a signiﬁcant increase in
maternal and newborn morbidity is to be avoided. When offspring of
diabetic mothers are compared with weight-matched controls, the risk
of serious birth injury is doubled, the likelihood of cesarean section is
tripled, and the incidence of newborn intensive care unit admission is
Before the 20th century, pregnancy in the diabetic woman por-
tended death of mother or child, or both. In the 21st century, centers
providing meticulous metabolic and obstetric surveillance report peri-
natal loss rates approaching but still higher than those seen in the
Nevertheless, major problems with fetal and
maternal management persist. Stillbirth rates have fallen dramatically
but remain threefold or fourfold greater than rates for the normogly-
cemic population. Congenital fetal anomalies, many of them life
threatening and debilitating, remain three to four times more common
in diabetic pregnancies than in nondiabetic pregnancies.9
and birth injury occur 10 times more frequently in diabetic fetuses.
Studies indicate that the magnitude of such risks is proportional to the
degree of maternal hyperglycemia.10,11
To a great extent, the excessive
fetal and neonatal morbidity of diabetes in pregnancy is preventable
or at least reducible by meticulous prenatal and intrapartum care. This
chapter reviews the pathophysiology of this complex group of disorders
and identiﬁes the obstetric interventions that can improve outcome.
Diagnostic and classiﬁcation criteria for diabetes were issued by the
American Diabetes Association (ADA) in 1997.12
These criteria were
further modiﬁed in 2003 regarding the diagnosis of impaired fasting
This nomenclature is useful because it categorizes patients
according to the underlying pathophysiology, although we recognize
that the criteria are not as mutually exclusive as once thought. The
classiﬁcation includes four clinical types:
1. Type 1 diabetes, formerly referred to as insulin-dependent or juve-
2. Type 2 diabetes, formerly referred to as non–insulin-dependent or
3. Other speciﬁc types of diabetes related to a variety of genetic-,
drug-, or chemical-induced diabetes
4. Gestational diabetes mellitus
An alternative classiﬁcation that is commonly used in obstetrics was
proposed by Priscilla White when she was at the Joslin Clinic in Boston
Diabetes in Pregnancy
Thomas R. Moore, MD, and Patrick Catalano, MD
955CHAPTER 46 Diabetes in Pregnancy
was formerly believed that type 2 diabetes was primarily a disorder of
older individuals (accounting for its being called adult-onset diabetes),
there has been a signiﬁcant increase in the prevalence of type 2 diabetes
since 1990. At the turn of the 21st century, an estimated 13.8 million
people had a diagnosis of diabetes, 5 million people had undiagnosed
diabetes, and 41 million people had prediabetes.17
Although it is not in the scope of this chapter to review the spec-
trum of possible causes of type 2 diabetes, the increase in obesity in
the general population is a contributing factor; it is estimated that
approximately two thirds of the population in the United States are
overweight or obese.18
Obesity, particularly central obesity, which is
estimated by waist circumference, is a well-described risk factor. This
increase in visceral obesity affects hepatic metabolic function and is a
rich source of cytokines and inﬂammatory factors, which are recog-
nized as contributing to increasing insulin resistance.
Criteria for the diagnosis of diabetes in nonpregnant adults are
shown in Table 46-2. Although the 75-g, 2-hour oral glucose tolerance
test (OGTT) is the most sensitive and speciﬁc diagnostic test for type
2 diabetes, because of the ease of administration and reproducibility,
the fasting glucose test is often used as a ﬁrst-line diagnostic test,19
particularly in the nongravid population. Because the onset of type 2
diabetes is usually insidious, hyperglycemia not sufﬁcient to make the
diagnostic criteria for type 2 diabetes is often categorized as impaired
fasting glucose (IFG) (100 mg/dL to 125 mg/dL) or, if the 75-g OGTT
is employed, as impaired glucose tolerance (IGT) (2-hour glucose level
of 140 mg/dL to 199 mg/dL). The IFG and IGT have been ofﬁcially
designated prediabetes, and prediabetic individuals are at high risk for
the development of type 2 diabetes.19
Gestational Diabetes Mellitus
Gestational diabetes mellitus (GDM) as deﬁned by the Fourth Inter-
national Workshop-Conference on Gestational Diabetes as “carbohy-
drate intolerance of various degrees of severity, with onset or ﬁrst
recognition during pregnancy.”20
This deﬁnition does not preclude the
possibility that glucose intolerance might have predated the pregnancy
or that medications might be needed for optimal glucose control. The
underlying pathophysiology of GDM in most instances is similar to
that observed for type 2 diabetes: an inability to maintain an adequate
insulin response because of the signiﬁcant decreases in insulin sensitiv-
ity with advancing gestation. About 2% to 13% of women diagnosed
as having GDM have detectable antibodies directed against speciﬁc
beta cell antigens.21,22
Some of these deﬁciencies are population depen-
dent. Other patients diagnosed with GDM have genetic variants that
have been identiﬁed as causes of diabetes in the general population,
including autosomal dominant (discussed later) and maternal or mito-
chondrial inheritance patterns.23,24
It is estimated that as many as 3% to 9% of the population of
pregnant women will be diagnosed with GDM.15
This translates into
approximately 135,000 cases of GDM per year in the United States
alone. This is not surprising, because in many respects, GDM is the
harbinger of type 2 diabetes for many women, based on the underlying
pathophysiology of GDM and the increase in obesity in women of
reproductive age. Similarly, there is an increase in the incidence of
GDM in women immigrating to the United States, presumably because
of changes in diet and lifestyle. Clinical recognition of GDM is impor-
tant because therapy can reduce pregnancy complications and poten-
tially reduce long-term sequelae in the offspring.
Genetic and Other Causes of Diabetes
The ADA’s fourth classiﬁcation of diabetes includes speciﬁc types of
diabetes attributed to “other causes.” These causes include genetic
defects in insulin action, diseases of the exocrine pancreas (e.g., cystic
ﬁbrosis), and drug- or chemical-induced diabetes, such as in the treat-
ment of human immunodeﬁciency virus (HIV) infection or after
One of the well-characterized genetic defects
is often included under the heading of maturity-onset diabetes of
the young (MODY) (i.e., the glucokinase [GK] mutation). In 1998,
Hattersley and colleagues25
described the various phenotypic per-
mutations associated with the mutations of the glucokinase gene.
Glucokinase phosphorylates glucose to glucose-6 phosphate in the
pancreas and liver. A heterozygous glucokinase mutation results in
hyperglycemia, usually with a mildly elevated fasting glucose and
abnormal OGTT result. This occurs because of a defect in the sensing
of glucose by the beta cell, resulting in decreased insulin release, and
to a lesser degree because of reduced hepatic glycogen synthesis. In
pregnancy, it is estimated that 3% of women with GDM and an ele-
vated fasting glucose level greater than 110 mg/dL have this mutation.
If the heterozygous mutation is present in the fetus, then the altered
glucose sensing by the fetal pancreas will result in a decrease in insulin
secretion. In the fetus, insulin is a primary stimulus for growth, and
any defect in fetal insulin secretion results in decreased fetal growth
and possible growth restriction. Depending on whether the mother or
fetus, or both, have a defect in the glucokinase gene, the phenotype of
the infant can vary from intrauterine growth restriction (IUGR)
through normal fetal growth and to macrosomia.
in Normal and Diabetic
There are signiﬁcant changes in maternal metabolism in normal preg-
nancy. These include changes in maternal nutrient metabolism (i.e.,
carbohydrate, lipid, and protein metabolism) and changes in factors
such as energy expenditure. The overall goal of these maternal meta-
bolic adaptations is to prepare the pregnant woman to meet the
increased energy needs of the mother and growth of the fetus in the
TABLE 46-2 CRITERIA FOR THE DIAGNOSIS
Symptoms of diabetes and a casual plasma glucose level
м200 mg/dL (11.1 mmol/L). Casual is deﬁned as any time of
day without regard to time since the last meal. The classic
symptoms of diabetes include polyuria, polydipsia, and
unexplained weight loss.
Fasting plasma glucose level м126 mg/dL (7.0 mmol/L). Fasting is
deﬁned as no caloric intake for at least 8 hours.
Two-hour plasma glucose м200 mg/dL (11.1 mmol/L) during an
oral glucose tolerance test. The test should be performed as
described by the World Health Organization, using a glucose
load containing the equivalent of 75-g anhydrous glucose
dissolved in water.
Adapted from American Diabetes Association: Clinical practice
recommendations: Standards of medical care for diabetes—2007.
Diabetes Care 30:S4-S41, 2007.
956 CHAPTER 46 Diabetes in Pregnancy
latter third of pregnancy, when approximately 70% of fetal growth
The alterations in maternal metabolism are relatively
uniform during pregnancy unless there are major perturbations such
as starvation conditions. The metabolic changes during pregnancy
therefore take place on the background of a woman’s pregestational
metabolic status. For example, if a woman is healthy and lean before
conception, there is an increased need to store adipose tissue in early
pregnancy to meet the increased energy demands of late gestation and
to develop insulin resistance in late gestation to provide nutrients for
the growing fetus. If a woman is obese before conception, there is little
need to gain additional adipose tissue, but there is the requirement to
provide nutrients for the fetus in late gestation.
Normal Glucose-Tolerant Pregnancy
Glucose homeostasis is primarily a balance between insulin resistance
and insulin secretion. The alterations in insulin resistance affect endog-
enous glucose production (primarily hepatic glucose metabolism) and
peripheral glucose metabolism, which takes place in skeletal muscle.
In the lean pregnant woman with normal glucose tolerance, there is a
signiﬁcant 30% increase in basal hepatic glucose production by the
third trimester of pregnancy (Fig. 46-2). This is associated with a sig-
niﬁcant increase in basal or fasting insulin concentrations.27
decrease in fasting glucose concentrations most likely is the result of
increasing plasma volumes in early gestation and increased fetoplacen-
tal use in late pregnancy. In the postprandial state, the increasing
insulin concentrations enhance glucose uptake into skeletal muscle
and adipose tissue, and they almost completely suppress hepatic
glucose production. Although this is the case in lean women, obese
women with normal glucose tolerance have a decreased ability for
insulin to completely suppress hepatic glucose production in late preg-
These data support the concept of decreased insulin sensitivity
in late gestation that is more severe in obese women compared with
Peripheral insulin resistance is deﬁned as the decreased ability of
insulin to affect glucose uptake primarily in skeletal muscle and to a
lesser degree in adipose tissue. Various methods are used to assess
insulin sensitivity in vivo, including mathematical models of fasting
glucose and insulin modeling (e.g., homeostasis model assessment
), the intravenous glucose tolerance test (i.e.,
Bergman minimal model),31
and what many consider to be the gold
standard: the hyperinsulinemic-euglycemic clamp.32
Most of these
measures have identiﬁed a signiﬁcant 50% to 60% decrease in insulin
sensitivity in late gestation.33
The changes in insulin sensitivity during
gestation are a reﬂection of a woman’s pregravid insulin sensitivity
status. Lean women usually have greater pregravid insulin sensitivity
compared with overweight or obese women. These differences mani-
fest before pregnancy, and when evaluated against the metabolic back-
ground of pregnancy, the relationships are similar in late pregnancy,
albeit reduced by approximately 50% to 60% (Fig. 46-3). The decreases
in insulin sensitivity in late pregnancy are accompanied by an increase
in insulin response. The increased insulin response to a glucose load
increases approximately threefold compared with pregravid measures
Alterations in glucose metabolism in women with diabetes have been
most extensively examined in women with GDM, although the altera-
tions in glucose metabolism in women with type 2 diabetes are most
likely very similar but with increased insulin resistance and further
decompensation of beta cell function. In lean and obese women with
GDM with mildly elevated fasting glucose levels, there is a similar
increase in basal endogenous glucose production, as was observed in
subjects with normal glucose tolerance, although fasting insulin con-
centrations, particularly in late gestation, are greater than observed in
normal glucose-tolerant women.28,34
However, during insulin infusion
during euglycemic clamps, the ability of insulin to suppress endoge-
nous glucose production is decreased (approximately 80% versus 95%)
in GDM compared with a matched control group. There is also a sig-
FIGURE 46-2 Alterations in glucose production. Longitudinal
changes in total basal endogenous (primarily hepatic) glucose
production (mean ± SD) from pregravid through early gestation (12
to 14 weeks) and late gestation (34 to 36 weeks). (Adapted from
Catalano PM, Tyzbir ED, Wolfe RR, et al: Longitudinal changes in
basal hepatic glucose production and suppression during insulin
infusion in normal pregnant women. Am J Obstet Gynecol 167:913-
FIGURE 46-3 Alterations in insulin resistance. Longitudinal
changes in glucose infusion rate (i.e., insulin sensitivity) in lean
women from pregravid through early (12 to 14 weeks) and late (34
to 36 weeks) pregnancy during hyperinsulinemic-euglycemic clamp
(mean ± SD). The asterisk indicates change over time from pregravid
status through late pregnancy (ANOVA). (Adapted from Catalano PM,
Tyzbir ED, Roman NM, et al: Longitudinal changes in insulin release
and insulin resistance in non-obese pregnant women. Am J Obstet
Gynecol 165:1667-1672, 1991.)
957CHAPTER 46 Diabetes in Pregnancy
niﬁcant decrease in insulin sensitivity in women who go on to develop
GDM, when estimated before conception or after delivery,35
with a matched control group. During pregnancy, the percent decrease
in insulin sensitivity is approximately the same as the percent change
in a matched control group (i.e., approximately 50% to 60%). The
decreased insulin sensitivity observed during pregnancy in the
woman who develops GDM is a function of her pregravid metabolic
status, and clinically, the increased glucose concentrations represent
the inability of pancreatic beta cells to normalize glucose levels
The relationship between insulin sensitivity and insulin response
has been characterized by Bergman and colleagues16
as a hyperbolic
curve or, when multiplied, as the disposition index. A curve that is
“shifted to the left” can be plotted for individuals who go on to develop
GDM (Fig. 46-6). Whether the insulin resistance precedes the beta
cell defect or they occur concomitantly is not known with certainty.
proposed that insulin resistance caused the beta
cell dysfunction in susceptible individuals. The increased risk of type
2 diabetes in women who formerly had GDM may be a function of
decreasing insulin sensitivity (i.e., worsening insulin resistance) exac-
erbated by increasing age, adiposity, and the inability of the beta cells
to fully compensate.
The data on the changes on glucose metabolism in women with
type 1 diabetes are not as well examined. Schmitz and coworkers37
evaluated the longitudinal changes in insulin sensitivity in women with
type 1 diabetes in early and late pregnancy and after delivery. There
was a 50% decrease in insulin sensitivity in late gestation. There was
no signiﬁcant difference in insulin sensitivity in these women in early
pregnancy or within 1 week of delivery compared with nonpregnant
women with type 1 diabetes. Based on the available data, women with
FIGURE 46-4 Increased insulin response. Changes in ﬁrst (A) and
second (B) phase pregravid through early (12 to 14 weeks) and late
(34 to 36 weeks) pregnancy insulin response during an intravenous
glucose tolerance test (mean ± SD). The asterisk indicates change
over time from pregravid status through late pregnancy (ANOVA).
(Adapted from Catalano PM, Tyzbir ED, Roman NM, et al:
Longitudinal changes in insulin release and insulin resistance in non-
obese pregnant women. Am J Obstet Gynecol 165:1667-1672, 1991.)
Early pregnancy Late pregnancy
FIGURE 46-5 Alterations in insulin sensitivity. Longitudinal
changes in insulin sensitivity during clamp 40 mU·m−2
infusion in obese women (mean ± SD). GDM, gestational diabetes
mellitus; Pg, difference between groups; Pt, individual longitudinal
changes with time. (Adapted from Catalano PM, Huston L, Amini SB,
Kalhan SC: Longitudinal changes in glucose metabolism during
pregnancy in obese women with normal glucose tolerance and
gestational diabetes. Am J Obstet Gynecol 180:903-916, 1999.)
Insulin sensitivity index (ISI)
3rd Trimester Postpartum
0.1 0.2 0.3 0.4
FIGURE 46-6 Insulin sensitivity and secretion relationships
in normal women and women with gestational diabetes
mellitus. Prehepatic insulin secretion was assessed during
steady-state hyperglycemia using plasma insulin and C-peptide
concentrations and C-peptide kinetics in individual patients. (Printed
with permission from Buchanan TA: Pancreatic β-cell defects in
gestational diabetes: Implications for the pathogenesis and prevention
of type 2 diabetes. J Clin Endocrinol Metab 86:989-993, 2001.)
958 CHAPTER 46 Diabetes in Pregnancy
type 1 diabetes have similar alterations in insulin sensitivity compared
with women with normal glucose tolerance.
Mechanism of Insulin Resistance
The mechanisms related to the changes in insulin resistance during
pregnancy are better characterized because of research in the past
decade. The insulin resistance of pregnancy is almost completely
reversed shortly after delivery,38
consistent with the clinically marked
decrease in insulin requirements. The placenta has long been suspected
of producing hormonal factors related to these alterations in metabo-
lism. The placental mediators of insulin resistance in late pregnancy
have been ascribed to alterations in maternal cortisol concentrations
and placenta-derived hormones such as human placental lactogen
(HPL), progesterone, and estrogen.39-41
Kirwan and associates42
ported that circulating tumor necrosis factor-α (TNF-α) concentra-
tions had an inverse correlation with insulin sensitivity as estimated
from clamp studies. Among leptin, HPL, cortisol, human chorionic
gonadotropin, estradiol, progesterone, and prolactin, TNF-α was the
only signiﬁcant predictor of the changes in insulin sensitivity from the
pregravid period through late gestation. TNF-α and other cytokines
are produced by the placenta, and 95% of these molecules are trans-
ported to maternal rather than fetal circulations.42
Other factors, such
as circulating free fatty acids, may contribute to the insulin resistance
Studies in human skeletal muscle and adipose tissue have demon-
strated defects in the post-receptor insulin-signaling cascade during
pregnancy. Friedman and colleagues showed that women in late
pregnancy have reduced insulin receptor substrate-1 (IRS-1) concen-
trations compared with those of matched nonpregnant women.44
Downregulation of the IRS-1 protein closely parallels insulin’s
decreased ability to induce additional steps in the insulin signaling
cascade that result in the transporter (GLUT-4) arriving at the cell
surface to allow glucose to enter the cell. Downregulation of IRS-1
closely parallels the decreased ability of insulin to stimulate 2-
deoxyglucose uptake in vitro in pregnant skeletal muscle. During late
pregnancy in women with GDM, in addition to decreased IRS-1 con-
centrations, the insulin receptor-β (i.e., component of the insulin
receptor within the cell rather than on the cell surface) has a decreased
ability to undergo tyrosine phosphorylation.44
This is an important
step in the action of insulin after it has bound to the insulin receptor
on the cell surface. This additional defect in the insulin-signaling
cascade is not found in pregnant or nonpregnant women with
normal glucose tolerance and results in a 25% lower glucose transport
activity. TNF-α also acts by means of a serine/threonine kinase,
thereby inhibiting IRS-1 and tyrosine phosphorylation of the insulin
These post-receptor defects may contribute in part to the
pathogenesis of GDM and an increased risk for type 2 diabetes in later
Complications of Diabetes
Women with pregestational diabetes are at risk for a number of obstet-
ric and medical complications. The relative risk of these problems is
proportional to the duration and severity of disease. Evers and cowork-
ers reported the maternal morbidity of a cohort of 323 type 1 diabetic
pregnancies followed prospectively in the Netherlands.46
control was excellent (Hb A1c ≤7.0% in 75%), but the rates of pre-
eclampsia (12.7%), preterm delivery (32%), cesarean section (44%),
and maternal mortality (60 deaths per 100,000 pregnancies) were con-
siderably higher than in the nondiabetic population.
Diabetic retinopathy is the leading cause of blindness between the ages
of 24 and 64 years.47
Some form of retinopathy is present in virtually
100% of women who have had type 1 diabetes for 25 years or more;
approximately 20% of these women are legally blind. The topic of
diabetic retinopathy has been reviewed elsewhere.48
The pattern of progression of diabetic retinopathy is predictable,
proceeding from mild nonproliferative abnormalities, which are asso-
ciated with increased vascular permeability, to moderate and severe
nonproliferative diabetic retinopathy, which is characterized by vascu-
lar closure, to proliferative diabetic retinopathy, which is characterized
by the growth of new blood vessels on the retina and posterior surface
of the vitreous. It has been proposed that pregnancy accelerates
these changes, although the mechanism is controversial.49
not shown any acceleration in microvascular complications when
pregnant and nonpregnant diabetic subjects were closely followed and
Vision loss resulting from diabetic retinopathy results from several
mechanisms. First, central vision may be impaired by macular edema
or capillary nonperfusion. Second, the new blood vessels of prolifera-
tive diabetic retinopathy and contraction of the accompanying ﬁbrous
tissue can distort the retina and lead to tractional retinal detachment,
producing severe and often irreversible vision loss. Third, the new
blood vessels may bleed, adding the further complication of preretinal
or vitreous hemorrhage.
FACTORS AFFECTING PROGRESSION OF
RETINOPATHY DURING PREGNANCY
Although past studies suggested that rapid induction of glycemic
control in early pregnancy stimulated retinal vascular proliferation,51
later investigations indicate that the severity and duration of diabetes
before pregnancy have a greater effect. Temple and colleagues52
179 women with pregestational type 1 diabetes, performing dilated
fundal examination at the ﬁrst prenatal visit, 24 weeks, and 34 weeks.
Progression to proliferative diabetic retinopathy occurred in only
2.2%, and moderate progression occurred in 2.8%. However, progres-
sion was signiﬁcantly greater in women who had had diabetes for more
than 10 years (10% versus 0%; P = .007) and in women with moderate
to severe background retinopathy before pregnancy (30% versus 3.7%;
P = .01). In the European Diabetes (EURODIAB) Prospective Compli-
cations Study, 793 potentially childbearing women at baseline com-
pleted the follow-up, and 21% gave birth. Duration of diabetes and
high HbA1c levels at recruitment were signiﬁcant risk factors for reti-
nopathy progression, whereas giving birth was not.50
Screening for retinopathy by a qualiﬁed ophthalmologist is recom-
mended before pregnancy and again during the ﬁrst trimester for
patients with pregestational diabetes because of the demonstrated
effectiveness of laser photocoagulation therapy in arresting progres-
sion. Patients with minimal disease should be re-examined once
or twice during the pregnancy and at 3 and 6 months after delivery.
Those with signiﬁcant retinal pathology may require monthly
959CHAPTER 46 Diabetes in Pregnancy
Diabetes is the most common cause of end-stage renal disease in the
United States and Europe. In the United States, diabetic nephropathy
accounts for about 45% of new cases of this condition. In 2003, the
cost for treatment of diabetic patients with end-stage renal disease was
in excess of $55,000 annually per person and more than $5 billion in
About 20% to 40% of patients with type 1 or type 2 dia-
betes develop evidence of nephropathy over time, but the rate and
extent of progression are highly individual.53
The pathophysiology of diabetic renal disease is incompletely
understood, but several factors play a role, including genetic suscepti-
bility, control of hyperglycemia, and the duration and severity of coex-
isting hypertension. Additional insults, such as repeated urinary tract
infections, excessive glycogen deposition, and papillary necrosis, all
hasten deterioration of renal function. The kidney is normal at the
onset of diabetes, but within a few years, glomerular basement mem-
brane thickening can be identiﬁed. By 5 years, there is expansion of the
glomerular mesangium, resulting in diffuse diabetic glomerulosclero-
sis. All patients with marked mesangial expansion exhibit proteinuria
exceeding 400 mg in 24 hours. The peak incidence of nephropathy
occurs after about 16 years of diabetes.
CATEGORIES OF DIABETIC NEPHROPATHY
Categories of diabetic nephropathy are distinguished by the level
of urinary protein excretion. Table 46-3 shows normal values and
the current clinical criteria for microalbuminuria and nephropathy.
Screening for microalbuminuria can be performed by three methods:
measurement of the albumin-to-creatinine ratio in a random spot
collection; 24-hour collection with creatinine, allowing the simultane-
ous measurement of creatinine clearance; and timed (e.g., 4-hour or
overnight) collection. The ﬁrst method is preferred because it is the
easiest to carry out in an ambulatory setting, and it provides adequately
accurate information. The other methods are rarely used.55
EFFECT OF PREGNANCY ON PROGRESSION
Although some clinicians discourage pregnancy in women with
diabetic renal disease because of concerns of permanent renal deterio-
ration as a result of the pregnancy, recent data consistently indicate
that pregnancy does not measurably alter the time course of diabetic
Progression of diabetic nephropathy is closely related to the degree
of glycemic control. To the extent that most women have better glyce-
mic control during pregnancy, delay or slowing of renal function dete-
rioration can be expected. A study of renal function for 4 years before
and 4 years after pregnancy in 11 patients with diabetic nephropathy56
showed that the gradual rise in serum creatinine over that period
was unaffected by the intervening pregnancy. Imbasciati and co-
performed a longitudinal study of 58 women with chronic
renal disease, following each through pregnancy. The mean serum
creatinine level was 6 mg/dL at the start of the study and 6 mg/dL after
delivery. Although they found that women with glomerular ﬁltration
rates less than 40 mL/min and with proteinuria greater than 1 g/day
had increased risk of delivering a child with a birth weight less than
2500 g (odds ratio [OR] = 5.1; 95% conﬁdence interval [CI], 1.03 to
25.6), the association was not related to renal disease, hypertension,
and maternal age. When the cohort was taken as a whole, even those
with lower glomerular ﬁltration rates and higher levels of proteinuria
had similarly modest changes in renal function when after- and before-
pregnancy indices were compared.57
Rossing and colleagues58
evaluated the effect of pregnancy on dete-
rioration of renal function in 93 women older than 20 years. They
compared groups of never-pregnant and ever-pregnant women who
received similar medical therapy and who had similar degrees of renal
function at the start of the study. The results are shown in Figure 46-7.
Based on this excellent prospective study, it is evident that pregnancy
neither alters the time course of renal disease nor increases the likeli-
hood of transition to end-stage renal disease.
COURSE OF DIABETIC NEPHROPATHY
In general, patients with underlying renal disease before pregnancy
can be expected to experience various degrees of deterioration during
pregnancy. The physiologic changes associated with normal pregnancy
increase renal blood ﬂow and glomerular ﬁltration by 30% to 50%.
Most women with preexisting diabetic nephropathy experience this
improvement in renal function, especially during the second trimes-
During the third trimester, however, when mean arterial pressure
and peripheral vascular resistance typically increase, women with
diabetic microvascular disease may experience marked diminution of
renal function, an exacerbation in hypertension, and in many cases,
preeclampsia. The third-trimester increase in maternal blood pressure
and serum creatinine concentration are among the most common
FIGURE 46-7 End-stage renal disease. Cumulative incidence of
end-stage renal disease (ESRD) in ever-pregnant (triangles) and never-
pregnant (circles) groups. (From Rossing K, Jacobsen P, Hommel E,
et al: Pregnancy and progression of diabetic nephropathy.
Diabetologia 45:36, 2002.)
TABLE 46-3 CATEGORIES OF DIABETIC
Category* Albumin-to-Creatinine Ratio (mg/mg)†
*Categories of diabetic nephropathy are distinguished by the level of
urinary protein excretion. Two of three collections in a 3- to 6-month
period should be abnormal for a diagnosis of microalbuminuria or
The ratio of albumin to creatinine was determined by random spot
Adapted from American Diabetes Association. Standards of medical
care in diabetes. Diabetes Care 28(Suppl 1):S4-S36, 2005.
961CHAPTER 46 Diabetes in Pregnancy
transplantation than in those with end-stage renal disease who are on
Cardiovascular complications experienced by pregnant women with
diabetes include chronic hypertension, pregnancy-induced hyperten-
sion, and rarely, atherosclerotic heart disease. In composite studies
of all types of diabetic pregnancies, the incidence of hypertensive
disorders during pregnancy varies from 15% to 30%,70,71
with the rate
of hypertension increased fourfold over that for the nondiabetic
Chronic hypertension (i.e., blood pressure at or above 140/90
mm Hg before 20 weeks’ gestation)73
complicates 10% to 20% of preg-
nancies in diabetic women and up to 40% of those in diabetic women
with preexisting renal or retinal vascular disease.74
The perinatal prob-
lems encountered with chronic hypertension include IUGR, maternal
stroke, preeclampsia, and abruptio placentae. In pregestational diabe-
tes, the prevalence of chronic hypertension increases with duration of
diabetes and is closely associated with nephropathy.72,75
The Diabetes in Early Pregnancy (DIEP) study reported that women
with type 1 diabetes have higher mean blood pressures throughout
pregnancy than do normal controls.76
In a signiﬁcant proportion
of patients, this difference is probably evidence of underlying renal
compromise. Preexisting chronic hypertension should be suspected
when the diabetic patient’s systolic blood pressure exceeds
130/80 mm Hg before the third trimester. The diagnosis is strength-
ened by ﬁnding a failure of mean blood pressure to decline normally
in the late second trimester, elevation in the blood urea nitrogen level
above 10 mg/dL, serum creatinine concentration above 1 mg/dL, cre-
atinine clearance less than 100 mL/min, or a combination of these
Preeclampsia is more common among women with diabetes, occur-
ring four times as frequently in women with pregestational diabetes as
in those without diabetes.72
The risk of developing preeclampsia is
proportional to the duration of diabetes before pregnancy and the
existence of nephropathy and hypertension; more than one third of
pregnant women who have had diabetes for more than 20 years develop
this condition. As is shown in Figure 46-9, patients with White class B
diabetes have a risk proﬁle similar to that of nondiabetic patients, but
women with evidence of renal or retinal vasculopathy (classes D, F, or
R) have a 50% excess risk of hypertensive complications over the rate
observed for those with no hypertension. Women with diabetic
nephropathy have similar rates of preeclampsia.
Renal function assessments should be performed in each trimester
in women with overt diabetic vascular disease and in those who have
had diabetes for more than 10 years. Signiﬁcant proteinuria, plasma
uric acid levels above 6 mg/dL, or evidence of HELLP syndrome
(hemolysis, elevated liver enzymes, and low platelets) should prompt a
workup for preeclampsia.
Although coronary heart disease is rarely encountered in preg-
nant women with diabetes, a study by Airaksinen and colleagues77
suggests that such women may have preclinical cardiomyopathy and
autonomic neuropathy. The diabetic women studied had less than the
expected increase in left ventricular size and stroke volume in preg-
nancy, lower heart rate increases, and smaller increments in cardiac
Although uncommon, atherosclerotic heart disease (White class H)
may afﬂict diabetic patients in the later reproductive years. Patients
with this complication have a mean age of 34 years and exhibit other
evidence of diabetic vascular involvement (White class D or R).78
diabetic women with cardiac involvement, pregnancy outcome is
Class B Class C Class D Class F/R
FIGURE 46-9 Likelihood of preeclampsia in diabetic pregnancy by White’s class and preexisting
hypertension. The risk of developing preeclampsia is proportional to the duration of diabetes before pregnancy
and the existence of nephropathy and hypertension. (From Sibai BM, Caritis S, Hauth J, et al: Risks of
preeclampsia and adverse neonatal outcomes among women with pregestational diabetes mellitus. National
Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am J Obstet
Gynecol 182:364, 2000.)
962 CHAPTER 46 Diabetes in Pregnancy
dismal, with a maternal mortality rate of 50% or higher and perinatal
loss rates approaching 30%.79
Recognition of cardiac compromise in
pregnant women with diabetes may be difﬁcult because of the decrease
in exercise tolerance that occurs during normal pregnancy. Compro-
mised cardiac function may also be difﬁcult to detect in patients
restricted to bed rest for hypertension or poor fetal growth. It is
prudent to obtain a detailed cardiovascular history in all diabetic
patients and to consider electrocardiography and maternal echocar-
diography in patients who have type 1 diabetes and are older than 30
years or in patients who have had diabetes for 10 years or more. With
intensive monitoring, successful pregnancy is possible, albeit hazard-
ous for women with signiﬁcant cardiac disease.80
Diabetic ketoacidosis (DKA) during pregnancy is a medical emergency
for the mother and fetus. Pregnant women with type 1 diabetes are at
increased risk for DKA, although the incidence and morbidity of this
complication have decreased from 20% or more in the older literature
to approximately 2% in later reports.81
The rate of intrauterine fetal
death, formerly as high as 35% with DKA during pregnancy, has
dropped to 10% or less.
Precipitating factors for ketoacidosis include pulmonary, urinary,
or soft tissue infections; poor compliance; and unrecognized new onset
of diabetes. Because severe DKA threatens the life of the mother and
fetus, prompt treatment is essential. Fetal well-being in particular is in
jeopardy until maternal metabolic homeostasis is reestablished. High
levels of plasma glucose and ketones are readily transported to the
fetus, which may be unable to secrete sufﬁcient quantities of insulin to
prevent DKA in utero.
DKA evolves from inadequate insulin action and functional hypo-
glycemia at the target tissue level. This leads to increased hepatic
glucose release but decreased or absent tissue disposal of glucose.
Glucose-lacking tissues release ketone bodies, and vascular hypergly-
cemia promotes osmotic diuresis. Over time, the diuresis causes pro-
found vascular volume depletion and loss of electrolytes. The release
of stress hormones (i.e., catecholamines, glucagon, growth hormone,
and cortisol) further impairs insulin action and contributes to insulin
resistance. Left unchecked, this cycle of dehydration, tissue hypoglyce-
mia, and electrolyte depletion can lead to multisystem collapse, coma,
Early in the illness, hyperglycemia and ketosis are moderate. If
hyperglycemia is not corrected, diuresis, dehydration, and hyperosmo-
lality follow. Pregnant women in the early stages of ketoacidosis
respond quickly to appropriate treatment of the initiating cause (e.g.,
broad-spectrum antibiotics), additional doses of regular insulin, and
Patients with advanced DKA usually present with typical ﬁndings,
including hyperventilation, normal or obtunded mental state (depend-
ing on severity of the acidosis), dehydration, hypotension, and a fruity
odor to the breath. Abdominal pain and vomiting may be prominent
symptoms. The diagnosis of DKA is conﬁrmed by the presence of
hyperglycemia (glucose >200 mg/100 mL) with positive test results for
serum ketones at a level of 1:4 or greater.
As many as one third of patients in the early or very late stages of
DKA may have initial blood glucose levels less than 200 mg/dL.82
pregnant diabetic patient with a history of poor food intake or vomit-
ing for more than 12 to 16 hours should have a thorough workup for
DKA, including a complete blood cell count and electrolyte determina-
tions. A serum bicarbonate level below 18 mg/dL should prompt per-
formance of an arterial blood gas analysis. In all cases of DKA, the
diagnosis is conﬁrmed by arterial blood gases demonstrating a meta-
bolic acidemia (i.e., base excess of −4 or lower).83
Table 46-4 contains a protocol for treatment of DKA. The impor-
tant steps in management should include the following:
Search for and treat the precipitating cause. Typical initiators
include pyelonephritis and pulmonary or gastrointestinal viral
Perform vigorous and sustained volume resuscitation. The
patient will continue to generate vascular volume deﬁcits
TABLE 46-4 TREATMENT PROTOCOL FOR DIABETIC KETOACIDOSIS*
Measures Initial Phase (6-24 hr) Recovery Phase
General Search for initiating cause of ketoacidosis.
Insert bladder catheter.
If patient is unconscious, establish nasogastric tube.
Continue treatment of initiating cause.
Remove bladder catheter when vascular volume is replaced.
Fluids Administer 0.9% NaCl at 1000 mL/hr × 2 hr and then
500 mL/hr until 5-8 L infused.
Continue 0.9% NaCl at 100 mL/hr for at least 48 hours to avoid
return of ketoacidosis.
Insulin Administer 20 U of insulin by IV bolus and then 5-10 U/hr
by IV infusion.
When acidosis is resolved and plasma glucose <160 mg/dL,
reduce insulin infusion to 0.7-2.0 U/hr.
Return to patient’s prior SC insulin dosing after plasma glucose
is stable for at least 12 hr.
Glucose When plasma glucose is <250 mg/dL, add 5% dextrose to
Potassium If serum K+
level is normal or low, infuse KCl at 20 mEq/hr.
If serum K+
level is high, wait until K+
is normal, then KCl
at 20 mEq/hr.
Measure serum K+
level every 2-4 hr.
Use oral potassium supplementation for 1 week.
Bicarbonate If pH is <7.1, add one ampule of bicarbonate (50 mEq) to
IV; repeat until pH >7.1.
*These are general guidelines. Because there may be wide variation in individual patient needs, there is no substitute for careful monitoring of each
patient, particularly in the initial phase of therapy.
IM, intramuscular; IV, intravenous; KCl, potassium chloride; NaCl, sodium chloride; SC, subcutaneous.
Adapted from American College of Obstetricians and Gynecologists (ACOG): Clinical management guidelines for obstetrician-gynecologists. ACOG
practice bulletin no. 60, March 2005. Pregestational diabetes mellitus. Obstet Gynecol 105:675-685, 2005.
963CHAPTER 46 Diabetes in Pregnancy
until her glucose levels and acidosis are largely resolved. A
physiologic ﬂuid such as 0.9% NaCl with 20 mEq/L of
potassium should be used and continued until the acidosis is
substantially corrected (base excess of −2 or less). This usually
requires an infusion at 1 to 2 L/hr for the ﬁrst 1 to 2 hours,
followed by reduced rates (150 to 200 mL/hr) until the base
deﬁcit approaches a normal level.
Place a bladder catheter to monitor urine output.
Use insulin to correct hyperglycemia. Although intermittent
injections can be used, a continuous infusion of regular or
short-acting insulin (i.e., lispro or aspart) allows frequent
adjustments. When giving insulin as a continuous infusion,
1 to 2 units/hr gradually corrects the patient’s glucose
abnormality over 4 to 8 hours. Attempts to normalize plasma
glucose levels rapidly (i.e., in less than 2 to 3 hours) may result
in hypoglycemia and further physiologic counterregulatory
Monitor serum bicarbonate levels and arterial blood gas base
deﬁcits every 1 to 3 hours to guide management. Even when
the plasma glucose level is normalized, acidemia may persist,
as evidenced by continuing abnormalities in the patient’s
electrolyte concentrations. Unless volume therapy is
continued until the patient’s electrolyte stores and plasma
concentrations have substantially returned to normal, DKA
may reappear, and the cycle of metabolic derangement will
When DKA occurs after 24 weeks’ gestation, fetal status should be
continuously monitored by fetal heart rate monitoring or a biophysical
proﬁle, or both. However, even when fetal status is questionable during
the phase of therapeutic volume and plasma glucose correction, emer-
gency cesarean section should be avoided. Usually, correction of the
maternal metabolic disorder is effective in normalizing fetal status.
Nevertheless, if a reasonable effort has been expended in correcting the
maternal metabolic disorder and the fetal status remains a concern,
delivery should not be delayed.
Fetal Morbidity and Mortality
Perinatal mortality in diabetic pregnancy has decreased 30-fold since
the discovery of insulin in 1922 and the institution of intensive
obstetric and infant care in the 1970s. Improved techniques of main-
taining maternal euglycemia have led to later timing of delivery and
reduced iatrogenic respiratory distress syndrome. Nevertheless, the
perinatal mortality rates reported for diabetic women remain appro-
ximately twice those observed in the nondiabetic population (Table
46-5). Congenital malformations, respiratory distress syndrome, and
extreme prematurity account for most perinatal deaths in diabetic
Studies of miscarriage rates from a decade ago indicated an increased
incidence of spontaneous abortion among women with pregestational
diabetes, especially those with poor glucose control during the peri-
conceptional period. Given the well-documented association between
congenital anomalies and hyperglycemia, such a ﬁnding is not surpris-
ing. Sutherland and Pritchard84
reported the outcomes of 164 diabetic
pregnancies managed with relaxed glycemic control and found a spon-
taneous abortion rate of almost double the expected rate. Miodovnik
studied spontaneous abortion in diabetic pregnancy
prospectively and found an increasing rate among patients with more
advanced classes of diabetes (rates for classes C, D, and F were 25%,
44%, and 22%, respectively). Later studies of populations with better
glycemic control report miscarriage rates similar to those in the non-
indicating that diabetic women with excellent
glycemic control have a risk of miscarriage equivalent to those without
These studies can be used to encourage patients who have not yet
conceived to achieve excellent glycemic control. Patients presenting in
early pregnancy with normal glycohemoglobin values can be reassured
that the overall elevation in risk of miscarriage is modest. However, for
patients with glycohemoglobin values 2 to 3 standard deviations above
the norm, intense early pregnancy surveillance is indicated.
Among women with overt diabetes before conception, the risk of a
structural anomaly in the fetus is increased fourfold to eightfold,88
compared with the 1% to 2% risk for the general population. In a
cohort study of 2359 pregnancies in women with pregestational dia-
betes, the major congenital anomaly rate was 4.6% overall, with 4.8%
for type 1 diabetes and 4.3% for type 2 diabetes, more than double the
expected rate. Neural tube defects were increased 4.2-fold and congeni-
tal heart disease by 3.4-fold. Of all anomalies conﬁrmed in the neonate,
only 65% were diagnosed antenatally.9
The typical congenital anoma-
lies observed in diabetic pregnancies and their frequency of occurrence
are listed in Table 46-6.
There is no increase in birth defects among offspring of diabetic
fathers and nondiabetic women and women who develop gestational
diabetes after the ﬁrst trimester, indicating that glycemic control during
embryogenesis is the main factor in the genesis of diabetes-associated
birth defects. A classic report by Miller and coauthors89
frequency of congenital anomalies in patients with normal or high
ﬁrst-trimester maternal glycohemoglobin levels and found only a 3.4%
rate of anomalies with an Hb A1c value less than 8.5%, whereas the rate
TABLE 46-5 PERINATAL MORTALITY RATES IN
Group Gestational Overt Normal†
Fetal mortality rate (%)* 4.7 10.4 5.7
Neonatal mortality rate (%)* 3.3 12.2 4.7
Perinatal mortality rate (%)* 8.0 22.6 10.4
*Mortality rates = deaths per 1000 live births.
Normal was determined from California data from 1986; ﬁgures were
corrected for birth weight, sex, and race.
TABLE 46-6 CONGENITAL MALFORMATIONS
IN INFANTS OF INSULIN-
DEPENDENT DIABETIC MOTHERS
All cardiac defects 18 8.5
All central nervous system anomalies 16 5.3
Spina biﬁda 20
All congenital anomalies 8 18.4
Adapted from Becerra JE, Khoury MJ, Cordero JF, et al: Diabetes
mellitus during pregnancy and the risks for speciﬁc birth defects:
A population based case-control study. Pediatrics 85:1, 1990.
964 CHAPTER 46 Diabetes in Pregnancy
of malformations in patients with poorer glycemic control in the peri-
conceptional period (Hb A1c above 8.5) was 22.4%. Lucas and cowork-
reported an overall malformation rate of 13.3% in 105 diabetic
patients. However, the risk of delivering a malformed infant was zero
with an Hb A1 value less than 7%, 14% with Hb A1 between 7.2% and
9.1%, 23% with Hb A1 between 9.2% and 11.1%, and 25% with Hb A1
greater than 11.2%.
The mechanism by which hyperglycemia disturbs embryonic devel-
opment is multifactorial. The potential teratologic role of disturbances
in the metabolism of inositol, prostaglandins, and reactive oxygen
species has been established.91
Embryonic hyperglycemia may promote
excessive formation of oxygen radicals in susceptible fetal tissues,
which are inhibitors of prostacyclin.92
The resulting overabundance of
thromboxanes and other prostaglandins may then disrupt the vascu-
larization of developing tissues. In support of this theory, addition of
prostaglandin inhibitors to mouse embryos in culture medium pre-
vented glucose-induced embryopathy.93
The pathogenic role of free
radical species in teratogenesis with diabetes has been underscored by
demonstrating the effect of dietary antioxidants experimentally. High
doses of vitamins C and E decreased fetal dysmorphogenesis to non-
diabetic levels in rat pregnancy and rat embryo culture.94,95
Because the critical time for teratogenesis is during the period 3 to
6 weeks after conception, nutritional and metabolic intervention must
be instituted preconceptionally to be effective. Several clinical trials of
preconceptional metabolic care have demonstrated that malformation
rates equivalent to those in the general population can be achieved
with meticulous glycemic control.96
Although studies of dietary folate
and vitamin C supplementation have demonstrated success in reduc-
ing the incidence of congenital anomalies in experimental diabetes in
the efﬁcacy of a high-antioxidant diet in preventing diabetes-
induced structural anomalies in humans has not been adequately
explored. Preconceptional management of pregestational diabetics is
discussed in the following sections.
Intrauterine Growth Restriction
Although the weights of infants of diabetic mothers (IDMs) usually
are skewed into the upper range, IUGR occurs with signiﬁcant fre-
quency in diabetic pregnancies, especially in women with underlying
vascular disease. Additional factors that increase the risk for IUGR in
a diabetic pregnancy include the higher incidence of structural anoma-
lies and maternal hypertension.
Asymmetrical IUGR is encountered most frequently in diabetic
patients with vasculopathy (i.e., retinal, renal, or chronic hyperten-
This association suggests that uteroplacental vasculopathy may
promote restricted fetal growth in these patients.98
Patients with poor
glycemic control and frequent episodes of ketosis and hypoglycemia
are also prone to preeclampsia and poor fetal growth. Whether fetal
growth restriction results from poor maternal-placental blood ﬂow or
intrinsically poor placental function is unresolved.99
Macrosomia has been deﬁned using various criteria, which include
birth weight greater than the 90th percentile, birth weight greater than
4000 g, and estimates of neonatal adiposity based on body composi-
tion measures. As early as 1923, research by Moulton100
ability in weight among various mammalian species that was attributed
to the amount of adipose tissue or fat mass rather than lean body mass.
Using autopsy data and chemical analysis of 169 stillbirths, Sparks101
described a relatively comparable rate of accretion of lean body mass
in fetuses that were small for gestational age (SGA), average for gesta-
tional age (AGA), and large for gestational age (LGA), but he found
considerable variation in the accretion of fetal fat in utero. The human
fetus at term has the greatest percent of body fat (approximately 10%
to 12%) compared with other mammals.102
The increased growth of the mother is composed primarily of total
body water and adipose tissue in early gestation.26
Relative to the feto-
placental unit, the human placenta attains most of its growth by the
middle of the second trimester. In contrast, approximately 70% of fetal
growth occurs over the last third of gestation (1000 g at 28 weeks to
3500 g at term). Yang and associates6
reported that IDMs with diabetes
still have an increased relative risk (RR) of being LGA (RR = 3.59;
95% conﬁdence interval [CI], 1.55 to 5.84) compared with the infants
of women with normal glucose tolerance.100
Ogata and colleagues,103
using serial ultrasound measures of the fetus of women with diabetes,
described an increase in the rate of abdominal circumference growth
after 24 weeks’ gestation. The increase in growth appears to affect pri-
marily insulin-sensitive tissues such as the subcutaneous fat included
in measures of abdominal circumference.104
Ninety-ﬁve percent of the
variance in fetal abdominal circumference can be accounted for by
subcutaneous fat rather than intra-abdominal measures such as liver
size. This is consistent with the inability of the fetal liver to store much
glycogen in early third trimester. Reece and coworkers105
fetuses of diabetic mothers have normal growth of lean body mass such
as head and skeletal growth, even when there is marked hyperglycemia.
In longitudinal ultrasound studies, Bernstein and associates106
that fetal fat and lean body mass demonstrate unique growth proﬁles.
These unique ultrasound proﬁles potentially provide a more sensitive
marker of abnormal fetal growth, particularly in infants of women
with diabetes based on the increased fat mass rather than lean mass of
At delivery, body composition studies by Catalano
have shown that birth weight alone, even when AGA,
may not be a sensitive enough measure of fetal growth in the infant of
the diabetic mother. They reported that although there were no sig-
niﬁcant differences in birth weight or lean body mass, the infants of
women with GDM had increased fat mass and percent body fat com-
pared with a normoglycemic control group (Table 46-7).
PATHOPHYSIOLOGY OF FETAL OVERGROWTH
Maternal Glucose Concentrations. Because glucose is the most
easily measured nutrient and marker of diabetes, most studies evaluat-
ing the effect of diabetes on fetal growth have used measures of glucose
as a reference. Findings from the DIEP indicate that birth weight cor-
related best with second- and third-trimester postprandial glucose
measures. When 2-hour postmeal glucose measures averaged 120 mg/
dL or less, approximately 20% of infants were macrosomic. In contrast,
when 2-hour postprandial glucose measures averaged up to 160 mg/
dL, the rate of macrosomia reached 35%.108
Similarly, Combs and
reported that macrosomia was signiﬁcantly associated
with postprandial glucose levels between 29 and 32 weeks’ gestation.109
In contrast, Persson and associates110
showed that fasting glucose
concentrations account for 12% of the variance in birth weight and
correlated best with estimates of neonatal fat. Uvena and colleagues111
found the strongest correlation was between fasting glucose and neo-
natal adiposity, rather than postprandial measures.
Fetal Insulin Concentrations. Based on the early work of Ped-
fetal insulin has long been considered a principal driving
965CHAPTER 46 Diabetes in Pregnancy
factor of in utero fetal growth. Experimental data gathered from non-
human primates by Susa and coworkers113
showed that in the rhesus
monkey when implanted with an Alzet pump, which delivered con-
tinuous, increasing insulin concentrations to the fetus independent of
the mother’s metabolic condition, there was evidence of fetal over-
In contrast, when genetic mutations such as glucokinase
deﬁciencies existed only in the fetus, the inability of the beta cell to
respond to increasing glucose concentrations results in fetal growth
Many studies have conﬁrmed the correspondence of
increased cord insulin concentrations with fetal macrosomia. Schwartz
found that umbilical cord insulin concentrations at
delivery correlated with the degree of macrosomia. Cordocentesis
studies in late third trimester showed that the ratio of fetal plasma
insulin to glucose and the degree of macrosomia were strongly corre-
Krew and colleagues116
reported that amniotic ﬂuid C-peptide
measures at term had a strong correlation with fetal adiposity but not
lean body mass.
The relationship between elevated insulin concentrations and fetal
macrosomia exists in late pregnancy, and there is evidence of altered
metabolic function in early gestation. Carpenter and colleagues117
reported that elevated amniotic ﬂuid insulin concentrations obtained
from normoglycemic patients at 14 to 20 weeks’ gestation and adjusted
for maternal age and weight correlated with the likelihood of subse-
quently diagnosed GDM (OR = 1.9; CI, 1.3 to 2.4). Each increase in
amniotic ﬂuid insulin multiple of the median (MOM) was associated
with a threefold increase in fetal macrosomia.117
These data support
the concept that the underlying pathophysiology of GDM and fetal
macrosomia may exist earlier in gestation than is routinely screened
for and that it is consistent with subclinical pregravid maternal meta-
Growth Factors. There has been considerable interest in the role
of insulin-like growth factors (IGFs) and fetal growth. Members of the
IGF family have been implicated in abnormalities of increased and
decreased fetal growth in humans. IGF-1 and the ratio of IGF-2 to
the IGF-2 soluble receptor have been positively correlated with the
However, there is also direct evidence using rodent
knockout models. Baker and coworkers119
reported that null mutations
for the IGF1 or IGF2 gene decreases neonatal weight by 40% in mice.
The effect of both genes is additive.119
Liu and associates120
reported that IGF-1, IGF-2, and IGF-binding protein-3 (IGFBP-3)
were signiﬁcantly elevated in women with type 1 and 2 diabetes com-
pared with a control group. These data are consistent with the ﬁndings
of other investigators, including data for women with type 1 and 2
Roth and colleagues123
reported that cord levels of IGF-1
were signiﬁcantly greater in macrosomic IDMs than in nonmacroso-
mic infants of glucose-tolerant or diabetic mothers. Radaelli and
showed that there was a strong negative correlation
between maternal circulating IGFBP-1 and lean body mass in the
infants. The study authors speculated that IGFBP-1 might inﬂuence
fetal growth by affecting IGF mediated placental nutrient transport,
particularly of glucose or amino acids rather than lipids. Decreased
IGFBP-1 levels are in keeping with a potential negative transcriptional
regulation of the IGFBP1 gene by insulin.124
Maternal Obesity. Obesity is an epidemic in developed countries
and the developing world.125
In the United States, the prevalence of
obesity, deﬁned as a body mass index (BMI = weight/height2
than 30 rose to 30.5% in 2000, compared with 22.9% from 1994
through 1998. The proportion of the population meeting the deﬁni-
tion of overweight (BMI > 25) increased from 55.9% to 64.5% during
the same period.18
The risk of obesity is disproportionate among the
races, increasing most among African Americans and Hispanics, the
same populations at risk for type 2 diabetes. Several studies suggest
that maternal obesity before conception has an independent effect on
fetal macrosomia. Vohr and associates126
analyzed various risk factors
for neonatal macrosomia in women with overt and GDM compared
with obese and normal weight controls.126
Multiple regression analyses
revealed the pre-pregnancy weight and weight gain were signiﬁcant
predictors for infants of GDM and control mothers. In an effort to
better understand the potential independent effect of maternal obesity
on growth of infants of GDM and normoglycemic women, Catalano
performed a stepwise logistic regression analysis on
data for 220 infants of mothers with normal glucose tolerance and 195
infants of GDM (Table 46-8). Gestational age at term had the strongest
correlation with birth weight and lean body mass. In contrast, maternal
pregravid BMI had the strongest correlation (approximately 7%) with
fat mass and percent body fat. Although almost 50% of the subjects
had GDM, only 2% fraction of the variance was correlated to fat
These data support an independent effect of maternal pre-
gravid obesity on fetal growth, particularly fat mass, independent of
Other Fuels. Many factors are related to fetal overgrowth of the
infant of a woman with diabetes. The signiﬁcant decreases in insulin
sensitivity in late gestation affect glucose and lipid and amino acid
metabolism. Although we clinically concentrate on glucose, other
nutrients most probably contribute to fetal overgrowth. This concept
is consistent with the hypothesis of fuel-mediated teratogenesis ﬁrst
proposed by Freinkel in 1980.128
Circulating amino acid concentrations
reﬂect the balance between protein breakdown and synthesis. Dug-
gleby and Jackson129
estimated that there is a 15% increase in protein
synthesis during the second trimester and a further 25% increase in
the third trimester compared with levels in nonpregnant women.
These differences appear to have a strong relationship to fetal growth,
particularly lean body mass. Butte and coworkers130
and Metzger and
independently reported higher amino acid concentrations
in women with GDM compared with a normoglycemic control group.
Zimmer and colleagues132
reported no signiﬁcant difference in amino
acid turnover in women with GDM and a control group. However, the
TABLE 46-7 NEONATAL ANTHROPOMETRICS
OF NEWBORNS OF WOMEN WITH
MELLITUS AND NORMAL
(n = 195)
(n = 220) P Value
Weight (g) 3398 ± 550 3337 ± 549 .26
Fat free mass (g) 2962 ± 405 2975 ± 408 .74
Fat mass (g) 436 ± 206 362 ± 198 .0002
Body fat (%) 2.4 ± 4.6 10.4 ± 4.6 .0001
Triceps 4.7 ± 1.1 4.2 ± 1.0 .0001
Subscapular 5.4 ± 1.4 4.6 ± 1.2 .0001
Flank 4.2 ± 1.2 3.8 ± 1.0 .0001
Thigh 6.0 ± 1.4 5.4 ± 1.5 .0001
Abdominal wall 3.5 ± 0.9 3.0 ± 0.8 .0001
*Data are presented as the mean ± SD.
GDM, gestational diabetes mellitus; NGT, normal glucose tolerance.
Adapted from Catalano PM, Thomas A, Huston-Presley L, Amini SB:
Increased fetal adiposity: A very sensitive marker of abnormal in utero
development. Am J Obstet Gynecol 189:1698-1704, 2003.
966 CHAPTER 46 Diabetes in Pregnancy
investigators found that hyperinsulinemia was required to maintain
normal amino acid turnover in the GDM women.132
reported that leucine turnover and oxidation were greater
in the obese woman with GDM compared with less obese control
subjects. The increased insulin concentrations required to maintain
appropriate amino acid levels in the woman with diabetes may be
another manifestation of the increased insulin resistance in pregnant
women with GDM.
Knopp and associates134
found that there is a twofold to fourfold
increase in triglyceride concentrations and a 25% to 50% increase in
cholesterol during gestation. This group also reported a further increase
in triglyceride and high-density lipoprotein cholesterol concentrations
in type 2 and GDM patients.135
Similarly, Xiang and colleagues43
described increased basal free fatty acid concentrations in Hispanic
women with GDM in the third trimester compared with a matched
Knopp and coworkers137
also reported that mid-tri-
mester triglyceride concentrations were a better predictor of macroso-
mia than glucose values during the glucose tolerance test. Similarly,
Kitajima and colleagues138
examined lipid proﬁles in women with an
abnormal glucose challenge test in pregnancy and reported that the
triglycerides had a signiﬁcant correlation with birth weight, even after
adjusting for signiﬁcant covariables. Although lipid transport from the
mother to fetus is not well understood, maternal lipid metabolism may
play a signiﬁcant role in fetal growth, particularly in accrual of adipose
Birth injury is more common among the offspring of diabetic mothers,
and macrosomic fetuses are at the highest risk.139
The most common
birth injuries associated with diabetes are brachial plexus palsy, facial
nerve injury, humerus or clavicle fracture, and cephalhematoma. Athu-
korala and associates140
studied women with gestational diabetes and
found a positive relationship between the severity of maternal fasting
hyperglycemia and the incidence of shoulder dystocia, with a doubling
of risk with each 1-mmol increase in the fasting plasma glucose value
on the OGTT. Shoulder dystocia occurred more often in diabetic deliv-
eries requiring operative vaginal assistance (RR = 9.58; CI, 3.70 to
24.81: P < .001) and in fetuses above the 90th percentile of birth weight
for age (RR = 4.57; CI, 1.74 to 12.01; P < .005) (Fig. 46-10).
Most of the birth injuries occurring in infants of diabetic pregnancy
are associated with difﬁcult vaginal delivery and shoulder dystocia.
Although shoulder dystocia occurs in 0.3% to 0.5% of vaginal deliver-
ies among normal pregnant women, the incidence is twofold to four-
fold higher for women with diabetes because the excessive fetal fat
deposition associated with hyperglycemia in poorly controlled diabetic
pregnancy causes the fetal shoulder and abdominal widths to become
Although one half of shoulder dystocias occur in infants of
normal birth weight (2500 to 4000 g), the incidence of shoulder dys-
TABLE 46-8 STEPWISE REGRESSION
ANALYSIS OF FACTORS RELATING
TO FETAL GROWTH AND BODY
COMPOSITION IN INFANTS OF
WOMEN WITH GESTATIONAL
DIABETES MELLITUS (n = 195)
AND NORMAL GLUCOSE
TOLERANCE (n = 220)
Factor r 2
Estimated gestational age 0.114 —
Pregravid weight 0.162 0.048
Weight gain 0.210 0.048
Smoking (−) 0.227 0.017
Parity 0.239 0.012 .0001
Lean Body Mass
Estimated gestational age 0.122 —
Smoking (−) 0.153 0.031
Pregravid weight 0.179 0.026
Weight gain 0.212 0.033
Parity 0.225 0.013
Maternal height 0.241 0.016
Paternal weight 0.250 0.009 .0001
Pregravid BMI 0.066 —
Estimated gestational age 0.136 0.070
Weight gain 0.171 0.035
Group (GDM) 0.187 0.016 .0001
Percent Body Fat*
Pregravid BMI 0.072 —
Estimated gestational age 0.116 0.044
Weight gain 0.147 0.031
Group (GDM) 0.166 0.019 .0001
*Pregravid maternal obesity has the strongest correlation with
neonatal measures of fat mass/% body fat in contrast to lean body
BMI, body mass index; GDM, gestational diabetes mellitus.
Adapted from Catalano PM, Ehrenberg HM: The short and long term
implications of maternal obesity on the mother and her offspring.
BJOG 113:1126-1133, 2006.
Assisted, no DM
Unassisted, no DM
Birth weight (grams)
FIGURE 46-10 Risk of shoulder dystocia by diabetes status and
instrumental delivery. Shoulder dystocia occurred more often in
diabetic deliveries requiring operative vaginal assistance and in
fetuses above the 90th percentile of birth weight for age. DM,
diabetes mellitus. (From Nesbitt TS, Gilbert WM, Herrchen B:
Shoulder dystocia and associated risk factors with macrosomic
infants born in California. Am J Obstet Gynecol 179:476, 1998.)
967CHAPTER 46 Diabetes in Pregnancy
tocia rises 10-fold to 5% to 7% among infants weighing 4000 g or
more. However, if maternal diabetes is present, the risk at each birth-
weight class is increased ﬁvefold.141
These risks are further magniﬁed
if a forceps or vacuum delivery is performed.142
The level of glycemic control is strongly correlated with the risk of
shoulder dystocia and birth injury, presumably because increasing
levels of hyperglycemia are associated with greater fetal fat deposition.
Athukorola and colleagues140
reported a positive correlation between
the severity of maternal fasting hyperglycemia and the risk of shoulder
dystocia, with each 1-mmol increase in the fasting value in the OGTT
associated with an increasing relative risk of 2.09 (CI, 1.03 to 4.25).
Although it would be desirable to predict shoulder dystocia on
the basis of warning signs during labor such as labor protraction, a
suspected macrosomic infant, or the need for midpelvic forceps
delivery, less than 30% of these events can be predicted from clinical
Neonatal Morbidity and Mortality
Polycythemia and Hyperviscosity
Polycythemia (i.e., central venous hemoglobin concentration >20 g/dL
or hematocrit >65%) occurs in 5% to 10% of IDMs and is apparently
related to glycemic control. Hyperglycemia is a powerful stimulus for
fetal erythropoietin production, which is probably mediated by
decreased fetal oxygen tension.144
Untreated, neonatal polycythemia
may promote vascular sludging, ischemia, and infarction of vital
tissues, including the kidneys and central nervous system.
Approximately 15% to 25% of neonates delivered from women with
diabetes during gestation develop hypoglycemia during the immediate
Neonatal hypoglycemia is less common when tight
glycemic control is maintained during pregnancy146
and in labor.
A detailed study by Taylor and associates147
found no correlation
between the likelihood of neonatal hypoglycemia and Hb A1c, whereas
mean maternal glucose levels during labor were strongly predictive.
Because unrecognized postnatal hypoglycemia may lead to neonatal
seizures, coma, and brain damage, it is imperative that the neonatal
team caring for the neonate follow a protocol of frequent postnatal
glucose monitoring until metabolic stability is ensured.
Neonatal Hypocalcemia and Hyperbilirubinemia
Low levels of serum calcium (<7 mg/100 mL) have been reported in
up to 50% of IDMs during the ﬁrst 3 days of life, although later series
record an incidence of 5% or less with better-managed pregnancies.148
Neonatal hyperbilirubinemia occurs in approximately 25% of IDMs,
a rate approximately double that for normal infants, with prematurity
and polycythemia being the primary contributing factors. Close moni-
toring of the newborn of diabetic pregnancy is necessary to avoid the
further morbidity of kernicterus, seizures, and neurologic damage.
Hypertrophic and Congestive Cardiomyopathy
In some macrosomic, plethoric infants of mothers with poorly con-
trolled diabetes, a thickened myocardium and signiﬁcant asymmetrical
septal hypertrophy has been described.149
The prevalence of clinical
and subclinical asymmetrical septal hypertrophy in IDMs has been
estimated to be as high as 30% at birth, with resolution by 1 year of
Kjos and colleagues151
found that cardiac dysfunction associated
with this entity often leads to respiratory distress, which may be mis-
taken for hyaline membrane disease.
IDMs who manifest cardiac dysfunction in the neonatal period
may have congestive or hypertrophic cardiomyopathy. This condition
is often asymptomatic and unrecognized. Echocardiograms show a
hypercontractile, thickened myocardium, often with septal hypertro-
phy disproportionate to the ventricular free walls.152
chambers are often smaller than normal, and there may be anterior
systolic motion of the mitral valve, producing left ventricular outﬂow
Neonatal septal hypertrophy may be a response to chronic hyper-
glycemia. The maternal level of IGF-1, which is elevated in subopti-
with asymmetrical septal hypertrophy. Because IGF-1 does not cross
the placenta, it may exert its action through binding to the IGF-1
receptor on the placenta.153
Halse and coworkers154
found that the level
of B-type natriuretic protein (BNP), a marker for congestive cardiac
failure, is elevated in neonates whose mothers had poor glycemic
control during the third trimester.
Septal hypertrophy can be identiﬁed with sonography in the pre-
natal period. Cooper and coworkers155
performed serial fetal echocar-
diography on 61 pregnant, diabetic women, demonstrating excessive
ventricular septal thickness in the fetuses that were diagnosed postna-
tally with asymmetrical septal hypertrophy. When the newborns with
asymmetrical septal hypertrophy were compared with normal infants,
birth weights (4009 versus 3457 g; P < .01) and maternal glycosylated
hemoglobin levels (6.7% versus 5.7%) were higher in infants with
Respiratory Distress Syndrome
Until recently, respiratory distress syndrome was the most common
and most serious disease in IDMs. In the 1970s, improved prenatal
maternal management for diabetes and new techniques in obstetrics
for timing and mode of delivery resulted in a dramatic decline in its
incidence, from 31% to 3%.156
However, even when matched by gesta-
tional week of pregnancy, IDMs are more than 20 times as likely as
infants from normal pregnancies to develop respiratory distress
The increased susceptibility to respiratory distress may result from
altered production of alveolar surfactant or abnormal pulmonary
function. Kulovich and Gluck158
reported delayed timing of phospho-
lipid production in diabetic pregnancy, as indicated by a delay in the
appearance of phosphatidylglycerol in the amniotic ﬂuid. In their
study, maturational delay occurred only in gestational diabetes (White
class A patients); fetuses of women with other forms of diabetes showed
normal or accelerated maturation of pulmonary phospholipid proﬁles.
Although some investigators have failed to demonstrate a delay in
lung maturation in diabetic pregnancy,159,160
most reports in the litera-
ture indicate a signiﬁcant biochemical and physiologic delay in IDMs.
Tyden and colleagues161
and Landon and coworkers162
fetal lung maturity occurred later in pregnancies with poor glycemic
control (mean plasma glucose level >110 mg/dL), regardless of class of
diabetes, when the infants were stratiﬁed by maternal plasma glucose
levels. These ﬁndings were conﬁrmed by Moore,163
no differences in the rate of rise of the amniotic ﬂuid lecithin-to-
sphingomyelin ratio among types of diabetes or degree of glucose
control but found that amniotic ﬂuid phosphatidylglycerol was delayed
approximately 1.5 weeks in women with pregestational or GDM dia-
betes compared with controls (Fig. 46-11). The delay in phosphatidyl-
glycerol was associated with an earlier and higher peak in the level of
phosphatidyl inositol, suggesting that elevated maternal plasma levels
of myoinositol in diabetic women may inhibit or delay the production
of phosphatidylglycerol in the fetus.
968 CHAPTER 46 Diabetes in Pregnancy
It is possible that poor neonatal respiratory performance in the
IDM may have a histologic basis in addition to a biochemical
cause. Kjos and coauthors151
identiﬁed respiratory distress in 3.4% of
infants delivered of diabetic women, but surfactant-deﬁcient airway
disease accounted for less than one third of cases, with transient tachy-
pnea, hypertrophic cardiomyopathy, and pneumonia responsible for
The near-term infant of a mother with poorly controlled diabetes
is more likely to have neonatal respiratory dysfunction than is the
infant of a nondiabetic mother. The observations of Moore163
that the average nondiabetic fetus achieves pulmonary maturity at 34
to 35 weeks’ gestation, with more than 99% of normal newborns
having a mature phospholipid proﬁle by 37 weeks. In diabetic preg-
nancy, however, it cannot be assumed that lung maturity exists until
approximately 10 days after the nondiabetic time (38.5 gestational
weeks). Any delivery contemplated before 38.5 weeks’ gestation for
other than the most urgent fetal and maternal indications should be
preceded by documentation of pulmonary maturity by amniocentesis.
The neonatal complications of the offspring of diabetic pregnancy is
discussed further in Chapter 58.
Long-Term Risks for the Fetus of the
Although much has been written about the increased risk of the meta-
bolic syndrome (i.e., obesity, hypertension, insulin resistance, and dys-
lipidemia) in infants born SGA, evidence points toward an increase in
adolescent and adult obesity in infants born LGA or macrosomic.
There has been abundant evidence linking higher birth weights to
increased obesity of adolescents and adults for at least 25 years.164
cohort studies such as the Nurses Health Study165
and the Health Pro-
fessional Follow-up Study166
report a J-shaped curve (i.e., a slightly
greater BMI among subjects born small but a much greater prevalence
of overweight and obesity in those born large).167
The increased preva-
lence of adolescent obesity is related to an increased risk of the meta-
bolic syndrome. The increased incidence of obesity accounts for much
of the 33% increase in type 2 diabetes, particularly among the young.
Between 50% and 90% of adolescents with type 2 diabetes have a BMI
greater than 27,168
and 25% of obese children between 4 and 10 years
old have impaired glucose tolerance.169
The epidemic of obesity and
subsequent risk for diabetes and components of the metabolic syn-
drome may begin in utero with fetal overgrowth and adiposity, rather
A retrospective cohort study by Whitaker170
enrolling more than
8400 children in the United States in the early 1990s reported that
children who were born to obese mothers (based on BMI in the ﬁrst
trimester) were twice as likely to be obese when they were 2 years old.
If a woman had a BMI of 30 or more in the ﬁrst trimester, the preva-
lences of childhood obesity (BMI > 95th percentile based on criteria
of the Centers for Disease Control and Prevention [CDC]) at ages 2,
3, and 4 years were 15.1%, 20.6%, and 24.1%, respectively. This was
between 2.4 and 2.7 times the prevalence of obesity observed in
children of mothers whose BMI values were in the normal range (18.5
to 24.9). This effect was only slightly modiﬁed by birth weight.
There is an independent effect of maternal pregravid weight and
diabetes on birth weight and on the adolescent risk of obesity. Langer
reported that in obese women with GDM whose
glucose was well controlled on diet alone, the odds of fetal macrosomia
(birth weight >4000 g) were signiﬁcantly increased (OR = 2.12) com-
pared with women with well-controlled (diet only) GDM and normal
BMIs. Similar results were reported for women with GDM who were
poorly controlled with diet or with insulin. In well-controlled, insulin-
requiring women with GDM, there was no signiﬁcant increased risk
of macrosomia with increasing pregravid BMI. Dabelea and associ-
reported that the mean adolescent BMI was 2.6 kg/m2
sibling offspring of diabetic pregnancies compared with the index
siblings born when the mothers previously had normal glucose toler-
ance. Both maternal pregravid obesity and the presence of maternal
diabetes may independently affect the risk of adolescent obesity in the
This risk of developing the metabolic syndrome in adolescents was
addressed by Boney and colleagues173
in longitudinal cohort study of
AGA and LGA infants of women with normal glucose tolerance and
GDM. The metabolic syndrome was deﬁned as the presence of two or
more of the following components: obesity, hypertension, glucose
intolerance, and dyslipidemia. Maternal obesity was deﬁned as a pre-
gravid BMI higher than 27.3. Children who were LGA at birth had an
increased hazard ratio (HR) for metabolic syndrome (HR = 2.19; CI,
1.25 to 3.82; P = .01) by age 11 years, as did children of obese women
(HR = 1.81; CI, 1.03 to 3.19; P = .04). The presence of maternal GDM
was not independently signiﬁcant, but the risk for developing meta-
bolic syndrome was signiﬁcantly different between LGA and AGA off-
spring of GDM by age 11 years (RR = 3.6).
Childhood Neurologic Abnormalities
Several reports have suggested childhood neurodevelopmental abnor-
malities in offspring of diabetic mothers. Rizzo and colleagues174
pared the offspring of 201 mothers with diabetes with 83 children of
normal mothers and correlated subsequent childhood obesity in the
offspring of diabetic mothers with internalizing behavior problems,
31 33 35
Gestational week at amniocentesis
37 39 41 43
FIGURE 46-11 Delay in fetal pulmonary phosphatidyl
glycerol. The delay in fetal pulmonary phosphatidyl glycerol was
associated with a sustained peak in phosphatidyl inositol in diabetic
pregnancy, suggesting that elevated maternal plasma levels of
myoinositol in a diabetic woman may inhibit or delay the production
of phosphatidyl glycerol in the fetus. DM, diabetes mellitus; GDM,
gestational diabetes mellitus; PG, phosphatidyl glycerol. (From Moore
TR: A comparison of amniotic ﬂuid fetal pulmonary phospholipids in
normal and diabetic pregnancy. Am J Obstet Gynecol 186:641, 2002.)
969CHAPTER 46 Diabetes in Pregnancy
somatic complaints, anxiety or depression, and social problems. Ornoy
assessed IQ scores on the Wechsler Intelligence Scale
for Children–Revised (WISC-R) and Bender tests of the children born
to diabetic mothers. No differences were found between the study
groups in various sensorimotor functions compared with controls, but
the children of diabetic mothers performed less well than controls in
ﬁne and gross motor functions, and they scored lower on the Pollack
taper test, which is designed to detect inattention and hyperactivity.
These investigators also found a negative correlation between the
severity of maternal hyperglycemia, as assessed by glycosylated hemo-
globin levels in the third trimester, and performance on neurodevel-
opmental and behavioral tests.
Management of Women with
Although widely underused,176
preconceptional care programs have
consistently been associated with decreased morbidity and mortality.177
Patients enrolled in preconceptional diabetes-management programs
obtain earlier prenatal care and have lower Hb A1c values in the ﬁrst
A comparison of outcomes among women participating
in a intensive preconceptional program with outcomes among women
receiving standard care demonstrated lower perinatal mortality (0%
versus 7%) and reduced congenital anomalies (2% versus 14%). When
the preconceptional program was discontinued because of a lack of
funds, the congenital anomaly rate increased by more than 50%.7
Several factors should be considered in preconceptional diabetes risk
assessment (Table 46-9):
Glycemic control should be assessed directly from glucose logs
and by glycosylated hemoglobin levels.
For patients who have had diabetes for 10 years or longer, an
electrocardiogram, an echocardiogram, and microalbuminuria
and serum creatinine studies should be performed.
Because retinopathy can progress during pregnancy, the patient
should establish a relationship with a qualiﬁed ophthalmologic
provider. A baseline retinal evaluation should be completed
within the year before conception, with laser photocoagulation
performed if needed. Previous laser treatment is not a
contraindication to pregnancy and may avoid signiﬁcant
hemorrhage during pregnancy.
Thyroid function (i.e., thyroid-stimulating hormone and free
thyroxine) should be evaluated and corrected as necessary in
all patients with pregestational diabetes because of the frequent
coincidence of autoimmune thyroid disease and diabetes.
A daily prenatal vitamin that provides 1 mg of folic acid should
be prescribed for a minimum of 3 months before conception,
because folate supplementation signiﬁcantly reduces the risk of
congenital neural tube defects.
The patient’s occupational, ﬁnancial, and personal situation
should be reviewed, because job and family pressures can
become barriers to achieving and maintaining excellent
glycemic control. In patients with pre-pregnancy hypertension
or proteinuria, particular emphasis should be given to deﬁning
support systems that permit extended bed rest in the third
trimester, if it becomes necessary.
The patient’s preconception medications should be reviewed
and altered to avoid teratogenicity and potential embryonic
toxicity. Statins are pregnancy category X drugs and should
be discontinued before conception. Angiotensin-converting
enzyme (ACE) inhibitors and angiotensin receptor blockers
(ARBs) should be discontinued before conception because of
ﬁrst trimester teratogenicity and fetal renal toxicity in the
second half of pregnancy. Among oral antidiabetic agents used
by reproductive-aged women, metformin and acarbose are
classiﬁed as pregnancy category B drugs, although systematic
data on safety are lacking. All other agents are category C
drugs, and unless the potential risks and beneﬁts of oral
antidiabetic agents in the preconception period have been
TABLE 46-9 PRECONCEPTIONAL EVALUATION OF THE DIABETIC PATIENT
Procedure Tests Recommendations
Medical history, family history, review of
Selected patients: fasting and postprandial
C-peptide determinations to clarify type
Avoid pregnancy until Hb A1c value is in the
normal, nonpregnant range
Physical examination ﬁndings
Hypertension ECG, cardiac, renal evaluation Antihypertensive medications
Retinopathy Retinal evaluation Ophthalmology consultation
Goiter T4, thyroid-stimulating hormones, antibodies
Neuropathy Vascular, podiatric evaluations
Obesity Exercise, weight loss
Proteinuria 24-hr urine for protein, creatinine Nephrology consultation if renal function
Diabetes assessment Hb A1c
Glycemic control Home glucose monitoring
Stable glycemic proﬁle
Nutrition Dietitian consultation
Occupational and family life assessment Help prepare patient for lifestyle commitments
necessary for tight glycemic control
ECG, electrocardiogram; Hb, hemoglobin; T4, thyroxine.
970 CHAPTER 46 Diabetes in Pregnancy
carefully weighed, they usually should be discontinued in
The goal of preconceptional metabolic management is to achieve an
Hb A1c level within the normal range before conception using a safe
and reliable medication regimen that permits a smooth transition
through the ﬁrst trimester. The patient should be skilled in managing
her glucose levels in a narrow range well before pregnancy begins, so
that the inevitable insulin adjustments necessitated by the appetite,
metabolic, and activity changes of early pregnancy can be accom-
A regimen of regular monitoring of preprandial and postprandial
capillary glucose levels should be instituted. Although there are no data
indicating that postprandial glucose monitoring is required before
pregnancy to achieve adequate control, monitoring these levels
increases the preconceptional woman’s awareness of the interaction of
dietary content and quality with postprandial glycemic excursions.179
The insulin regimen should result in a smooth glucose proﬁle through-
out the day, with no hypoglycemic reactions between meals or at
Oral Hypoglycemic Agents
A longitudinal trial in the United Kingdom of intensiﬁed metabolic
therapy in nonpregnant women with type 2 diabetes180
that oral agents were more effective than insulin in lowering Hb A1c
levels. This effect was attributed to improved compliance and fewer
hypoglycemic reactions. For this and other reasons, most women with
type 2 diabetes use one or more oral agents for glycemic control—typi-
cally metformin and a sulfonylurea or thiazolidinediones. Details of
the mechanism of action and pharmacology of these oral hypoglyce-
mic agents are discussed later. Despite the absence of evidence of tera-
togenicity for most of these compounds, none is recommended for use
in pregnancy. Standard practice is to transition these patients to insulin
A possible exception is the use of metformin in infertile patients
with polycystic ovary syndrome who are otherwise oligo-ovulatory.
These patients have higher conception and lower miscarriage rates
with metformin treatment.181
Although two small series documenting
the apparent safety of continuing metformin during pregnancy have
discontinuing metformin after pregnancy is
established is recommended.
Metformin readily crosses the placenta, exposing the fetus to con-
of such exposure (i.e., effects on neonatal obesity and insulin resis-
tance) remain unknown. A study of perfused human placental lobules
from gestational diabetic and normoglycemic women demonstrated
that metformin was readily transferred from the maternal to the fetal
A more direct assessment of maternal and fetal pharmacodynamics
was performed by Charles and coworkers185
by obtaining maternal
blood in the third trimester from metformin takers with gestational
or type 2 diabetes. Cord blood also was obtained. Mean metformin
concentrations in cord and maternal plasma were 0.81 and 1.2 mg/L,
respectively. The maternal plasma half-life is 5.1 hours. Because these
pharmacokinetics are similar to those in nonpregnant patients, no
dosage adjustment is warranted.185
With regard to teratogenicity associated with metformin use in
pregnancy, Gilbert and associates performed a meta-analysis of eight
available studies. The malformation rate in the disease-matched control
group was approximately 7.2%, statistically signiﬁcantly higher than
the rate found in the metformin group (1.7%). After adjustment for
confounders, ﬁrst-trimester metformin treatment was associated with
a statistically signiﬁcant 57% reduction in birth defects.186
In a study of women with type 2 diabetes mellitus, 93 of whom
took metformin (61 in the ﬁrst trimester and 32 throughout the
pregnancy) and 121 of whom did not take metformin, there was no
difference between the metformin and control groups in the rate of
preeclampsia (13% versus 14%; P = .84), perinatal loss (3% versus 2%;
P = .65), or neonatal morbidity, including rate of prematurity (23%
versus 22%; P = .7), admission to the neonatal unit (40% versus 48%;
P = .27), respiratory distress (9% versus 18%; P = .07), and neonatal
hypoglycemia (20% versus 31%; P = .08).187
The concentrations of metformin in breast milk are generally low,
and the mean infant exposure to metformin has been reported in the
range of 0.28% to 1.08% of the weight-normalized maternal dose. No
adverse effects on blood glucose of nursing infants have been
Hypertension is a common comorbidity of diabetes and is found in
20% to 30% of women who have had diabetes for longer than 10 years.
Although treatment of modest degrees of hypertension (<160 mm Hg
systolic) during pregnancy has not been shown to be beneﬁcial in
improving perinatal outcome,74
treatment in nonpregnant diabetic
women is recommended when blood pressure is consistently higher
than 130/80 mm Hg.19
The U.K. Prospective Diabetes Study and the
Hypertension Optimal Treatment trial demonstrated improved out-
comes, especially in preventing stroke, in patients assigned to lower
blood pressure targets. Patients frequently enter the preconceptional
period taking one or more antihypertensive medications.189
ceptional and pregnant patients with diabetes and chronic hyperten-
sion, blood pressure target goals of 110/65 to 129/79 mm Hg are
recommended in the interest of long-term maternal health and mini-
mizing impaired fetal growth.19
None of the commonly used antihypertensive medications (e.g.,
calcium channel blockers, β-blockers, methyldopa) is teratogenic. ACE
inhibitors deserve special mention because in nonpregnant subjects
with diabetic nephropathy, they have been shown to ameliorate pro-
teinuria and delay progression to end-stage renal disease. These medi-
cations are therefore considered ﬁrst-line agents for diabetic women
with signiﬁcant proteinuria.180
Many women with type 1 diabetes
present for consultation preconceptionally or even in early pregnancy
while taking these medications. It is not clear whether these medica-
tions have teratogenic effects when used in the ﬁrst trimester, but use
in the second trimester and beyond can cause a marked reduction in
fetal renal blood ﬂow, resulting in oligohydramnios and even frank
fetal renal failure.190
These medications should not be used during
pregnancy, especially after the ﬁrst trimester. Similar concerns exist for
other agents in this family (i.e., ARBs and angiotensin receptor
Patients with type 1 diabetes are typically diagnosed during an episode
of hyperglycemia, ketosis, and dehydration. Type 1 diabetes is rarely
971CHAPTER 46 Diabetes in Pregnancy
diagnosed during pregnancy. The diagnosis of type 2 diabetes cannot
be accomplished during pregnancy because of the overlap with early-
onset gestational diabetes. Although the ﬁnding of an elevated Hb A1c
level in early pregnancy may be suggestive, deﬁnitive diagnosis of type
2 diabetes must be made after pregnancy. The diagnostic criteria rec-
ommended by the ADA for diabetes are listed in Table 46-2.
Hyperglycemia not sufﬁcient to meet the diagnostic criteria for
diabetes is categorized as IFG or IGT, depending on whether it is
identiﬁed through a fasting plasma glucose level or a 75-g, 2-hour
IFG: fasting plasma glucose level of 100 to 125 mg/dL (5.5 to
IGT: 2-hour plasma glucose level of 140 to 199 mg/dL (7.8 to
Patients with IFG or IGT before pregnancy should be considered
at extremely high risk for developing GDM. GDM patients whose
postpartum testing results in the diagnosis of IFG or IGT are at sig-
niﬁcant risk for the disease evolving into frank diabetes within 5 to 10
Patients with IFG or IGT should be counseled regarding weight loss
and provided instruction for increasing physical activity. Monitoring
for the development of diabetes in those with prediabetes should be
performed every 1 to 2 years. Screening for and appropriate treatment
for other cardiovascular risk factors (e.g., tobacco use, hypertension,
dyslipidemia) is important. There is insufﬁcient evidence to support
the use of drug therapy in women with IFG or IGT.
Risk Factor Screening
Risk factor assessment for GDM should be performed at the ﬁrst pre-
natal visit. High-risk clinical characteristics include the following:
Age older than 35 to 40 years
Obesity (BMI > 30)
History of GDM
Delivery of a previous LGA infant
Polycystic ovary syndrome
A strong family history of diabetes
Patients with these risk factors should receive plasma glucose
screening without delay. High-risk women not found to have GDM at
the initial screening should be tested again between 24 and 28 weeks’
Previously, screening of all pregnant women for GDM was recom-
mended, but the ADA192
modiﬁed this recommendation such that
screening can be omitted for low-risk women meeting all of the criteria
listed in Table 46-10. This policy is based on the ﬁndings of Naylor and
who reported that women with one or no risk factors had
a 0.9% risk of GDM, whereas 4% to 7% of those with two to ﬁve risk
factors were diagnosed with GDM, resulting in a sensitivity of approxi-
mately 80% with a false-positive rate of 13%.
One- or Two-Step Screening
The diagnosis of GDM is based on a positive OGTT result. Guidelines
issued by the Fourth International Workshop-Conference on Gesta-
tional Diabetes Mellitus194
and reafﬁrmed by the Fifth International
and the American College of Obstetricians and Gyne-
recommend the use of the Carpenter and Coustan
diagnostic criteria for the 3-hour, 100-g glucose OGTT (Table 46-11).
However, these expert bodies also acknowledge the alternative use of
a single-step, 2-hour, 75-g glucose OGTT.
The one-step, 75-g glucose, 2-hour OGTT, which is commonly used
outside the United States, is no longer recommended because of its
inferior detection rate of GDM. Mello and colleagues197
diagnostic efﬁciency of the 75-g, 2-hour OGTT with the 3-hour, 100 g-
OGTT and found that the 2-hour test was less than one half as sensitive
in diagnosing GDM (5% versus 12%).
The current one-step option involves direct administration of the
3-hour, 100-g glucose OGTT. Two or more values must be met or
exceeded for the diagnosis of GDM. The critical cutoff values for the
3-hour OGTT are listed in Table 46-11. Direct, one-step administra-
tion of the 3-hour, 100-g OGTT test should be considered in women
with prior GDM, especially those with additional risk factors such as
In the two-step approach, a screening glucose challenge test (GCT)
is administered using 50 g of glucose in the fasting or nonfasting state.
TABLE 46-10 LOW-RISK CRITERIA FOR
American Diabetes Association: Gestational diabetes mellitus: A
position statement. Diabetes Care 27(Suppl 1):S88, 2004.
TABLE 46-11 THREE-HOUR 100-GRAM ORAL
GLUCOSE TOLERANCE TEST FOR
1-hr, 50-g glucose challenge result ≥135 mg/dL
Overnight fast of 8-14 hr
Carbohydrate loading for 3 days, including ≥150 g of carbohydrate
Seated, not smoking during the test
Two or more values must be met or exceeded for a diagnosis of
Assessment for Gestational
Plasma Glucose Level after a
100-g Glucose Load mg/dL
Fasting 95 (5.3)
1 hr 180 (10.0)
2 hr 155 (8.6)
3 hr 140 (7.8)
972 CHAPTER 46 Diabetes in Pregnancy
For those whose plasma glucose value obtained after 1 hour exceeds a
critical threshold value, a 100-g, 3-hour OGTT is administered, using
the diagnostic criteria listed in Table 46-11.
THRESHOLD VALUE FOR THE GLUCOSE
The sensitivity of the GDM testing regimen depends on the thresh-
old value used for the 50-g GCT. Recommendations from the ADA19
explain that using a threshold value of 140 mg/dL results
in approximately 80% detection of GDM, whereas using a threshold
of 130 mg/dL results in 90% detection. A potential disadvantage of
using the lower value of 130 mg/dL is an approximate doubling in the
number of OGTTs performed. The Canadian study,193
receiver-operator curve analysis, calculated that diagnostic efﬁciency
was optimized when a GCT threshold of 130 mg/dL was used for
intermediate-risk women (i.e., two to four risk factors) and 128 mg/dL
for higher-risk women. These issues are summarized in Table 46-12.
A threshold plasma glucose value of 130 mg/dL is recommended
for use in practices with a signiﬁcant proportion of higher-risk gravi-
das (e.g., multiracial, obese). This approach provides excellent test
sensitivity for GDM (>90%) with acceptable cost. Deﬁnitive random-
ized trials regarding cost-effectiveness with respect to perinatal out-
comes and neonatal costs have not yet been performed.198
MAXIMUM VALUE FOR THE GLUCOSE
The risk of GDM is approximately proportional to the result of the
1-hour GCT. Dooley and coworkers199
found that among nonwhite
women, the risk of GDM with a 1-hour glucose value of 200 mg/dL or
more is greater than 90%. Bobrowski and colleagues200
all patients with a screening result above 216 mg/dL had a positive 3-
hour OGTT result. Most experts omit the 3-hour OGTT for patients
with GCT results of 200 mg/dL or greater and manage the patient as
a gestational diabetic.
SINGLE ABNORMAL VALUE ON THE 3-HOUR
ORAL GLUCOSE TOLERANCE TEST
A fasting plasma glucose level exceeding 126 mg/dL should be con-
sidered highly suspicious for diabetes in pregnant and nonpregnant
patients. Individuals with fasting plasma glucose levels above 126 mg/
dL should have another fasting test; if the result of the second test is
high, GDM is conﬁrmed.
Patients with a single abnormal OGTT value are at increased risk
for infants with macrosomia and neonatal morbidity. Berkus and col-
followed 764 patients with GDM, stratiﬁed by the number
of abnormal values on their OGTTs. Patients with one or more
abnormal OGTT values had double the incidence of macrosomic
infants (23% to 27% versus 13%; P < .01). When Langer and cowork-
compared perinatal outcomes in patients with a single abnormal
OGTT value with normal women and with aggressively managed
GDM patients, they found the incidence of macrosomia to be more
than threefold higher in the single abnormal value group than in the
normal (34% versus 9%) and GDM (34% versus 12%) groups. Neo-
natal morbidity was ﬁvefold higher in the single abnormal OGTT value
group (15%) compared with the control and GDM groups (3%).
McLaughlin and colleagues203
reviewed the perinatal outcomes of
14,036 women who had normal 1-hour or 3-hour glucose levels using
standard criteria (i.e., 1-hour GCT cutoff of 140 mg/dL and 3-hour
OGTT [see Table 46-11]). Of these, 3% had a single elevated value on
the 3-hour test. Comparing the single elevated value group to those
with all normal values, higher rates of cesarean delivery, preeclampsia,
chorioamnionitis, birth weights higher than 4000 g and 4500 g, and
neonatal intensive care unit admission were recorded (adjusted
OR = 1.6, 1.5, 1.5, 1.7, 2.2, and 1.5, respectively; P < .03).203
These results underscore the problems associated with the methods
used to identify patients with GDM. The relationships among carbo-
hydrate metabolism, macrosomia, and neonatal morbidity create a
continuum that deﬁes a single, clear-cut criterion for diagnosis in all
populations. The recommended schemes identify at most 90% of preg-
nancies susceptible to hyperglycemia and fetal macrosomia. The astute
clinician should approach women with several GDM risk factors and
a single abnormal OGTT value with caution. When in doubt, a trial of
capillary glucose testing may help to clarify the patient’s metabolic
Other Tests for Gestational Diabetes
Several investigators have searched for a single, nonglucose blood test
that can accurately predict the results of the OGTT. Because of the
proportional relationship of glycated proteins and long-term plasma
glucose concentrations, fructosamine and Hb A1c screening have been
evaluated. Roberts and colleagues204
suggested that fructosamine
screening for GDM could produce a sensitivity of 85% with a speciﬁc-
ity of 95%. A positive relationship between fructosamine levels and
macrosomia was demonstrated.205,206
However, subsequent studies
have reported signiﬁcantly lower sensitivities.207,208
Inferior sensitivity and predictive values have been reported for
glycohemoglobin measurements (i.e., Hb A1 and Hb A1c) by Shah and
Baxi and associates,210
and Artal and coworkers211
63%, and 74%, respectively). A study by Agarwal and associates212
assessed the use of lower cutoffs for fructosamine and Hb A1c to exclude
subjects from further GDM screening and higher cutoffs for one-step
diagnosis. The lower cutoffs achieved sensitivities of 90% and negative
predictive values of more than 85%. However, the upper cutoff values
did not achieve acceptable positive predictive values to be useful for
diagnosing GDM. Thus the role of these tests would be to identify
patients rather than to screen for GDM, but using them would impose
TABLE 46-12 SENSITIVITY AND COST
ASSOCIATED WITH UNIVERSAL
AND SELECTIVE SCREENING
WITH VARIOUS GLUCOSE
Threshold Value for 1-hr, 50-g
130 mg/dL 140 mg/dL
Sensitivity (%) 100 79
Percent of population (%)
Value (mg/dL) Sensitivity (%)
Universal 140 90
Risk factors + age ≥25 yr 140 85
OGTT, oral glucose tolerance test.
Adapted from Coustan DR, Nelson C, Carpenter MW, et al: Maternal
age and screening for gestational diabetes: A population based study.
Obstet Gynecol 73:557, 1989.
973CHAPTER 46 Diabetes in Pregnancy
an additional step and cost on the diagnostic regimen. Although
screening with glycosylated proteins could theoretically reduce the
number of two-step diagnostic procedures, their lack of sensitivity in
diagnosis and the additional time and cost have left these studies of
limited use in screening for GDM.
Timing of Gestational Diabetes Screening
The timing of glucose tolerance testing during pregnancy is critical,
because delayed diagnosis increases the duration of deranged maternal
metabolism and accelerated fetal growth. However, because the preva-
lence of GDM increases with advancing gestation due to rising insulin
resistance mediated by placental hormones, testing too early can over-
look some patients who will develop disease later.
A surprising percentage of patients (6% to 20%) with GDM can be
diagnosed in the ﬁrst trimester. Most have signiﬁcant risk factors for
glucose intolerance. Moses and associates213
assessed the prevalence of
GDM in patients with various risk factors. GDM was identiﬁed in 6.7%
overall, in 8.5% of women 30 years old or older, in 12.3% of women
with a BMI of 30 or more, and in 11.6% of women with a family
history of diabetes. A combination of risk factors predicted GDM in
61% of cases compared with 4.8% of those without risk factors. The
additional effect of ethnicity on the prevalence of GDM is summarized
in Table 46-13.
Risk factor assessment for GDM (i.e., maternal age, ethnicity,
obstetric and family history, body habitus, prior GDM, prior IGT, prior
macrosomic infant, or unexplained stillbirth) should be performed at
the ﬁrst prenatal visit of all pregnant women. Patients with any of these
risk factors (Table 46-14) should undergo screening as soon as feasible,
and if results are negative, tests should be repeated at 24 to 28 weeks’
Because the insulin resistance that causes hyperglycemia increases
as the third trimester progresses, early testing may miss some patients
who later become glucose-intolerant. Performing the test too late in
the third trimester limits the time in which metabolic intervention can
take place. For this reason, it is recommended that glucose tolerance
testing be performed in all patients at 24 to 28 weeks’ gestation.214
Whether administered at 12 or 26 weeks, the GCT can be per-
formed without regard to recent food intake (i.e., nonfasting state).
Coustan and coworkers215
have shown that tests performed in fasting
subjects are more likely to yield falsely elevated results than are tests
conducted between meals. This ﬁnding was conﬁrmed by Sermer and
of Women with
The primary goals of metabolic management (i.e., glycemic monitor-
ing, dietary regulation, and insulin therapy) in diabetic pregnancy are
to prevent or minimize the postnatal sequelae of diabetes—macroso-
mia, shoulder dystocia, birth injury, and postnatal metabolic instabil-
ity—in the newborn. A secondary goal is to reduce the risk of pediatric
and adult metabolic syndrome in the offspring. If this goal is to be
achieved, glycemic control must be instituted early and aggressively.
Principles of Medical
There is a surprising lack of well-controlled research on the optimal
diet for lean or obese women with diabetes. Most recommendations
regarding dietary therapy are based on common sense and experience.
Because women with all types of diabetes experience inadequate
insulin action after feeding, the goal of medical nutritional therapy is
to avoid single, large meals containing foods with a high percentage of
simple carbohydrates that release glucose rapidly from the maternal
gut. Three major meals and three snacks are preferred, because this
multiple-feeding regimen limits the amount of calories presented to
the bloodstream during any given interval. The use of nonglycemic
foods that release calories from the gut slowly also improves metabolic
control. Examples include foods with complex carbohydrates and ﬁber,
such as whole-grain breads and legumes. Carbohydrates should
account for no more than 50% of the diet, with protein and fats equally
accounting for the remainder.19
Medical nutritional therapy should be supervised by a trained
professional—ideally, a registered dietitian. In many programs, die-
TABLE 46-14 RISK FACTORS FOR
Patients with any of these factors should be screened for GDM at
the ﬁrst prenatal visit:
Maternal age >25 yr
Previous macrosomic infant
Previous unexplained fetal demise
Previous pregnancy with GDM
Strong immediate family history of NIDDM or GDM
Obesity (>90 kg)
Fasting glucose >140 mg/dL (7.8 mM) or random glucose
>200 mg/dL (11.1 mM)
GDM, gestational diabetes mellitus; NIDDM, non–insulin-dependent
TABLE 46-13 PREVALENCE OF GESTATIONAL
DIABETES IN VARIOUS NATIONAL
AND ETHNIC GROUPS
Study Population Prevalence (%)
Harris et al, 1997 Native American (Cree) 8.3
Henry et al, 1993 Australian 7.8
Nahum et al, 1993 African American 7.5
Lopez-de la Pena et al,
Yalcin et al, 1996 Turkish 6.6
Rith-Najarian et al, 1996 Native American
Fraser et al, 1994 Israeli 5.7
Rizvi et al, 1992 Pakistani 3.5
Miselli et al, 1994 Italian 2.3
Serirat et al, 1992 Thai 2.2
Jang et al, 1995 Korean 2.2
Mazze et al, 1992 White, Minnesota 1.5
974 CHAPTER 46 Diabetes in Pregnancy
tary counseling is capably provided by a certiﬁed diabetes educator.
In any case, formal dietary assessment and counseling should be
provided at several points during the pregnancy to design a dietary
prescription that can provide adequate quantity and distribution of
calories and nutrients to meet the needs of the pregnancy and support
achieving the plasma glucose targets that have been established. For
obese women (BMI > 30 kg/m2
), a 30% to 33% calorie restriction
(to 25 kcal/kg of actual weight per day or less) has been shown to
reduce hyperglycemia and plasma triglycerides with no increase in
Moderate restriction of dietary carbohydrates to 35% to 40% of
calories has been shown to decrease maternal glucose levels and
improve maternal and fetal outcomes.217
In a nonrandomized study,
subjects with low-carbohydrate intake (<42%) frequently required the
addition of insulin for glucose control (RR = 0.14; P < .05), had a sig-
niﬁcantly lower rate of macrosomia (RR = 0.22; P < .04), and had a
lower rate of cesarean deliveries for cephalopelvic disproportion and
macrosomia (RR = 0.15; P < .04).
Manipulation of the type of carbohydrate in the diet can provide
additional beneﬁts in glycemic control. Crapo and coauthors218
pared the blood glucose excursions induced by the ingestion of 50 g of
carbohydrate from dextrose, rice, potatoes, corn, and bread. They
observed that the highest glucose response occurred with dextrose and
potatoes, with much lower peaks occurring after intake of corn and
rice. This led to the concept of classifying foods by their glycemic index
related to their tendency to induce hyperglycemia. In general, low-
glycemic foods, such as complex (rather than simple) carbohydrates
and those with higher soluble ﬁber content, are associated with a more
gradual release of glucose into the bloodstream.
Formal dietary consultation at periodic intervals during the preg-
nancy improves metabolic control. Timing and content of meals
should be reviewed at each visit together with the patient’s individual
food preferences. In all pregnant women, the continuing fetal con-
sumption of glucose from the maternal bloodstream results in a steady
downward drift in maternal glucose levels unless feeding occurs. In
patients taking insulin or oral hypoglycemics, prolonged periods (>4
hours) without food intake increase the risk of hypoglycemic episodes.
In these patients, a rather rigid schedule of three meals plus snacks
at mid-morning, mid-afternoon, and bedtime is often necessary to
achieve smooth control. Because insulin resistance changes dynami-
cally during pregnancy, the dietary prescription must be continually
adjusted according to the patient’s weight gain, insulin requirement,
and pattern of exercise.
Avoiding Nocturnal Hypoglycemia
Unopposed intermediate-acting insulin action during the hours of
sleep frequently results in severe nocturnal hypoglycemia at 3 to 4 AM
in individuals with type 1 diabetes. Reducing the insulin dose to avoid
this complication typically leads to unacceptably high glucose levels on
rising at 6 to 7 AM, whereas adding a bedtime snack helps to moderate
the effect of bedtime insulin and to sustain glucose levels during the
night. The snack should contain a minimum of 25 g of complex car-
bohydrate and enough protein or fat to help prolong release from the
gut during the hours of sleep.
The issue of maternal ketosis and its potential effect on childhood
mental performance is a source of continuing controversy. Churchill
reported that ketonuria during pregnancy is associ-
ated with impairment of neuropsychological development of offspring.
This report has resulted in admonitions to avoid caloric reduction in
any pregnant woman. The methodology in Churchill and associates’
study has been criticized, however, because the ketonuria data were
obtained from many different hospitals by having a nurse obtain a
single urine sample for ketone testing on the day of delivery.
Coetzee and colleagues220
found morning ketonuria in 19% of
women with insulin-independent diabetes on a 1000-calorie diet, 14%
of those on a 1400- to 1800-calorie diet, and 7% of normal pregnant
women on a free diet. There were no untoward neonatal events in
infants of any of the ketonuric mothers. Rizzo and coworkers174
223 pregnant women with diabetes and their offspring and 35 with
normal glucose tolerance and found no relationship between maternal
hypoglycemia and intellectual function of the offspring.
There may be a difference between starvation ketosis and the ketosis
that develops with poorly controlled diabetes. Ketonuria develops in
10% to 20% of normal pregnancies after an overnight fast and may
protect the fetus from starvation in the nondiabetic mother. In the ﬁnal
analysis, signiﬁcant maternal ketonemia resulting in maternal acid-
emia is probably unfavorable for the mother and fetus. The small
degrees of ketosis occurring in many pregnant women, including
those with diabetes, are unlikely to lead to measurable deﬁcits in the
Principles of Glucose Monitoring
Measurements of glycosylated hemoglobin have proved to be a useful
index of glycemic control over the long term (4 to 6 weeks), providing
a numeric index of the patient’s overall compliance.221
ing Hb A1c levels every 4 to 6 weeks during pregnancy rarely alters
management signiﬁcantly, it can provide the patient with a score by
which she can rate the success of her hourly efforts to keep her blood
glucose levels within a narrow range. Glycohemoglobin levels are too
crude to guide the adjustments to insulin.
Self-Monitoring of Blood Glucose
The availability of capillary glucose chemical test strips has revolution-
ized the management of diabetes, and they should be considered the
standard of care for pregnancy monitoring. The discipline of measur-
ing and recording blood glucose levels before and after meals has a
positive effect on improving glycemic control.222
TIMING OF CAPILLARY GLUCOSE MONITORING
The frequency and timing of self-monitoring of blood glucose
should be individualized (Table 46-15). However, because postprandial
values have the strongest correlation with fetal growth, checking after
meals is essential. The DIEP study reported that when postprandial
glucose values averaged 120 mg/dL, approximately 20% of infants were
macrosomic, whereas a modest 30% rise in postprandial glucose levels
to a mean level of 160 mg/dL resulted in a 35% rate of macrosomia.223
Similar results emphasizing postprandial blood glucose monitoring
were reported by de Veciana and associates,224
who randomized dia-
betic women to use of preprandial or postprandial blood glucose levels
for dietary and insulin management. The women managed using post-
prandial levels had markedly better results than did those managed
using preprandial levels. In the postprandial group, with the mean
(± standard deviation) change in the glycosylated hemoglobin value
greater (−3 ± 2.2% versus 0.6 ± 1.6%; P < .001), the birth weights were
lower (3469 ± 668 g versus 3848 ± 434 g; P = .01), and the rates of
975CHAPTER 46 Diabetes in Pregnancy
neonatal hypoglycemia (3% versus 21%; P = .05) and macrosomia
(12% versus 42%; P = .01) were lower.
With these facts in mind, a typical glucose monitoring schedule
involves capillary glucose checks on rising in the morning, 1 or 2 hours
after breakfast, before and after lunch, before dinner, and at bedtime.
For patients taking intermediate- or long-acting medication at bedtime,
a capillary glucose level between 3 and 4 AM (the lowest glucose level
of the day) two to three times per week is helpful in interpreting the
glucose values in the morning.
The clinician should be aware of the speciﬁc type of capillary
glucose reﬂectance meter being used by the patient, because plasma
glucose values are 10% to 15% less than those measured in whole
blood from the same sample. Most of the newer reﬂectance meters are
calibrated for plasma glucose readings. The target glucose values used
in management depend on the type of meter used.
TARGET CAPILLARY GLUCOSE LEVELS
Controversy exists about whether the target glucose levels to be
maintained during diabetic pregnancy should be designed to limit
macrosomia or to closely mimic nondiabetic pregnancy proﬁles. The
Fifth International Workshop-Conference on Gestational Diabetes195
recommends the following:
Fasting plasma glucose level of 90 to 99 mg/dL (5.0 to
1-hour postprandial plasma glucose level less than 140 mg/dL
2-hour postprandial plasma glucose level less than 120 to 127 mg/
dL (<6.7 to 7.1 mmol/L)
Only recently have data been reported that describe normal glucose
variations during pregnancy in nondiabetic gravidas. The proﬁles
described by Cousins and colleagues225
(Fig. 46-12) are derived from
highly controlled studies in which volunteer subjects were fed test
meals with speciﬁc caloric content on a rigid schedule. Parretti and
proﬁled normal pregnant women twice monthly prepran-
dially and postprandially during the third trimester. Testing was done
with capillary glucose meters, and the women followed an ad libitum
diet. The results of the 95th percentile of the plasma glucose excursions
are shown in Figure 46-13. Fasting and premeal plasma glucose levels
are usually below 80 mg/dL and often below 70 mg/dL. Peak postpran-
dial plasma glucose values rarely exceed 110 mg/dL.
Yogev and colleagues227
obtained continuous glucose information
from nondiabetic pregnant women using a sensor that monitored
TABLE 46-15 TIMING OF HOME CAPILLARY GLUCOSE MONITORING
Capillary Glucose Assessment Advantage Disadvantage
Preprandial Permits prospective adjustment of food intake,
supplementation of preprandial insulin
Preprandial or fasting glucose levels correlate
poorly with fetal morbidity. Signiﬁcant
postprandial hyperglycemia may go
Postprandial Permits supplementation of insulin to reduce postprandial
glucose overshoots; improved postprandial control
correlates with improved fetal or neonatal outcome
Results are obtained after food intake.
Bedtime Permits adjustment of calories at bedtime snack,
adjustment of bedtime insulin
3-4 AM Enables detection of nocturnal hypoglycemia Interrupts sleep, may increase stress
Fasting ϭ 85.2 Ϯ 3.8
24 hr mean ϭ 93.4 Ϯ 1.9
Fasting ϭ 77.7 Ϯ 2.3
24 hr mean ϭ 85.6 Ϯ 2.9
2000 2400 0400 0800
Fasting ϭ 74 Ϯ 2.7
24 hr mean ϭ 87.3 Ϯ 1.7
FIGURE 46-12 Glucose variations during pregnancy. Proﬁle of
blood glucose over 24 hours in the second and third trimesters of
pregnancy, with postpartum observations used as a control. Error
bars represent standard error. Arrows indicate time of test meal
administration. (From Cousins L, Rigg L, Hollingsworth D, et al: The
24-hour excursion and diurnal rhythm of glucose, insulin and C
peptide in normal pregnancy. Am J Obstet Gynecol 136:483, 1980.)
978 CHAPTER 46 Diabetes in Pregnancy
3. The kinetics of NPH insulin are such that care must be taken to
time peak action at 5 to 7 AM and avoid peaking at 4 AM, when
maternal glucose levels are lowest. For many women, whose bedtime
may be at 8 or 9 PM, NPH peaks early and exposes the mother and
fetus to nocturnal hypoglycemia. It is often better to administer
NPH at a set time between 10 and 11 PM, not the less accurate
timing of “bedtime,” to optimize needed insulin action during the
hours of 5 to 7 AM.
4. A combination of short- and intermediate-acting insulins is
employed to maintain glucose levels in an acceptable range. A
typical regimen involves intermediate-acting insulin (NPH) before
breakfast and at bedtime, with injections of regular or short-acting
insulin before breakfast and before dinner. Two thirds of insulin is
given in the morning and one third in the afternoon and at bedtime.
For example, the regimen may be 20 units of NPH and 10 units of
regular insulin in the morning, 8 units of regular insulin with
dinner, and 8 units of NPH at 10 PM. The AM dose of NPH covers
the periods before and after lunch. Avoid NPH injections at din-
nertime because the peak occurs at 2 to 3 AM, creating symptomatic
5. Preprandial doses of regular insulin sufﬁcient to keep 1-hour post-
prandial plasma glucose levels below 130 mg/dL may result in hypo-
glycemia 2 to 4 hours later (e.g., regular insulin before breakfast
often causes hypoglycemia at 10 AM). When regular insulin is used
to cover the major meals, snacks are essential in the late morning,
the late afternoon, and before bedtime to avoid interprandial hypo-
glycemia. This interprandial hypoglycemia effect is intensiﬁed if the
regular insulin injection is not given at least 20 to 30 minutes before
the meal. This precaution is particularly relevant for hospitalized
patients (because meals do not always arrive on schedule) and when
taking meals in restaurants.
6. The short-acting insulins lispro or aspart are preferred during dia-
betic pregnancy. Lispro is manufactured by inverting a short amino
acid sequence within the insulin molecule, resulting in a signiﬁ-
cantly faster onset of action. Lispro injections immediately before
meals reduce the risk of hangover hypoglycemia because of
the short duration of action. Using an in vitro perfusion model,
Holcberg and colleagues230
reported that lispro does not cross the
human placenta. Compared with regular human insulin, the peak
serum lispro concentration is three times higher, time to peak is 4.2
times faster, the absorption rate constant is double, and the dura-
tion of action is one half as long.228
These kinetics allow the patient
to inject insulin just before eating, rather than having to delay 20
to 30 minutes to allow regular insulin to begin its effect. Compared
with regular insulin, lispro reduced postprandial hyperglycemia and
decreased the rate of mild hypoglycemic episodes; it was also associ-
ated with lower predelivery Hb A1c values and received higher
patient satisfaction scores.231
Similar ﬁndings have been reported
when insulin aspart was compared with regular insulin.232
summary, lispro or aspart can be substituted 1:1 for regular insulin,
and each is highly effective when given before meals in reducing
postprandial glycemia while avoiding insulin hangover, which
increases patient compliance. Short-acting insulins are effective
when used in the insulin pump (discussed later).233
With regard to
safety and effectiveness, small studies have indicated equivalent
Mathieson and coworkers236
similar perinatal outcomes but improved maternal glycemic control
in pregnant women randomized to aspart or regular insulin, dem-
onstrating signiﬁcantly lower mean postprandial plasma glucose
levels with aspart (P = .003). A more detailed study of glucose
dynamics after administration of aspart or regular insulin to women
with gestational diabetes by Pettitt and associates237
glucose areas under the curve were signiﬁcantly lower with insulin
aspart (180-min area, 7.1 mg·h·dL−1
; P = .018) but not with regular
insulin (30.2 mg·h·dL−1
; P = .997) or with no insulin (29.4 mg·h·dL−
), indicating the potential for improved glycemic control with
short-acting insulins compared with regular insulin.
7. The use of insulin glargine during pregnancy is problematic because
of its 20- to 26-hour duration. In three large comparative trials of
nonpregnant subjects, glargine decreased glycosylated hemoglobin
or fasting blood glucose levels, or both, to an extent similar to that
seen with NPH insulin. A lower incidence of hypoglycemia, espe-
cially at night, was reported in most trials with insulin glargine
compared with NPH insulin.238
Experience is limited in pregnancy,
but the few studies existing demonstrate satisfactory results.239,240
Although the relatively ﬂat activity proﬁle of glargine is attractive,
the dose must be regulated to keep basal insulin action during the
night from causing hypoglycemia. During the day, when insulin
resistance and insulin requirements are higher, the nocturnal basal
rate is usually inadequate, and NPH must be added. As shown in
Figure 46-14, the nocturnal low glucose level (typically at 4 AM)
decreases as the third trimester progresses. Great care must be exer-
cised in using glargine to avoid severe nocturnal hypoglycemia.
Glargine appears to be safe for use during embryogenesis if glucose
control is adequate.241
Adjusting Insulin Dosage Using Carbohydrate
Counting, Preprandial Glucose Levels, and
Intermediate- and long-acting insulins should be adjusted no more
frequently than weekly or biweekly to maintain preprandial plasma
glucose levels in the target range (70 to 105 mg/dL). However, with
short-acting insulins, glycemic control is better when the patient is able
to vary, within a reasonable range, the insulin dose she uses to cover a
meal, depending on its calorie content (or grams of carbohydrate) and
the plasma glucose level existing at the time she begins eating. This
often means varying short-acting insulin dosage with every injection.
Patients with pregestational diabetes are usually taught to count the
grams of carbohydrate in their meals and adjust the short-acting
insulin dosage accordingly. A typical meal containing 60 grams of
carbohydrate may require 4 to 6 units of lispro (ratio of 1 unit of
insulin to grams of carbohydrate of 1:15) in the nonpregnant indi-
vidual. In the ﬁrst trimester, a typical ratio is approximately 1:12.
However, by the second trimester, more insulin is required (1:10 to
1:6), and in the third trimester, especially in patients with some degree
of insulin resistance, ratios fall to 1:6 or even 1:2. The clinician should
anticipate these increases in insulin as pregnancy progresses, because
the patient often interprets these changes as errors or failure.
Carbohydrate counting has limits in accuracy (e.g., miscalculation
of carbohydrate content, individual differences in glucose uptake
dynamics), which may result in erratic control. During pregnancy,
women who relatively strictly regiment their food quantity, content,
and timing, so that carbohydrate calculations are within a reasonably
narrow range, have better control.
PREPRANDIAL GLUCOSE LEVELS
Given the same calorie content of a meal, achieving target post-
prandial plasma glucose levels requires more insulin if the preprandial
glucose level is higher. Allowing patients to add 2 units of lispro when
979CHAPTER 46 Diabetes in Pregnancy
the preprandial glucose level exceeds 120 mg/dL and to reduce lispro
dosage by 2 units when the preprandial glucose level is below 80 mg/dL
provides smoother control and avoids undesired postprandial glyce-
mic excursions when the preprandial glucose is outside the target
Women with pregestational diabetes are frequently taught how to
perform preprandial and postprandial insulin corrections. A typical
regimen is to add 1 to 2 units of lispro for every 50 mg/dL that the
glucose level is out of target range. A preprandial glucose level of
130 mg/dL would require 1 unit of lispro over the prescribed dose for
that meal. As pregnancy progresses, corrections increase from 1 per
50 mg/dL to 1 per 20 mg/dL. However, the patient must be instructed
not to take more than 4 to 6 correction units in a single bolus during
pregnancy and instead retest glucose in 1 to 2 hours and apply an
additional correction at that time.
Use of the Insulin Pump
Most of the principles described to enhance and smooth glycemic
control by manipulating timing, quantity, and type of insulin can be
used with greater facility with continuous, subcutaneous insulin infu-
sion delivered by a programmable pump. These devices, which infuse
insulin by means of a convenient catheter placed into the subcutaneous
tissue near the abdomen, can be programmed to provide varying basal
and bolus levels of insulin, which change smoothly even while the
patient sleeps or exercises.
The effectiveness of continuous, subcutaneous insulin infusion in
pregnancy is well established.242-244
Hieronimus and colleagues245
pared outcomes of 33 pregnant women managed with insulin pumps
with 23 receiving multiple injections and reported similar Hb A1c levels
and rates of macrosomia and cesarean deliveries. Lapolla and cowork-
reported a small cohort of 25 women treated with insulin pumps
in pregnancy compared with conventional insulin treatment (n = 68)
and found no differences in glycemic control or perinatal outcome.
Use of continuous, subcutaneous, programmable insulin infusion
has several advantages over conventional intermittent insulin admin-
istration, including the convenience of changing basal rates automati-
cally when the patient is asleep or otherwise occupied and providing
adjustable boluses discreetly from a pump worn under the clothing
without the need for needles, syringes, and medication vials. Because
pump malfunctions, precipitation of insulin inside the pump mecha-
nism, abscess formation, and poor uptake from the infusion site can
occur unexpectedly, successful insulin pump use requires a meticulous
patient, a knowledgeable diabetologist or perinatologist, and prompt
availability of emergency counseling and assistance on a 24-hour
A properly designed insulin pump infusion scheme allows conve-
nient tailoring of the insulin administration proﬁle to the patient’s
individual metabolic and lifestyle rhythms. A sample regimen is shown
in Table 46-18. The lowest infusion rate of the day is between 11 PM
and 4 AM, when it is set at about 70% of the mean rate needed during
the day. The basal rate must be increased to 1.3 to 1.5 times the mean
daily rate between 5 AM and 10 AM to provide extra insulin coverage
for the high insulin-resistance period as the day begins (i.e., dawn
effect). For the remainder of the day (10 AM to 11 PM), a steady mean
infusion rate is usually sufﬁcient. Insulin boluses, programmed to limit
the postprandial excursion to 130 mg/dL or less at 1 hour, are given as
often as needed. The enhanced ability for the patient to administer
extra insulin doses without syringes and insulin vials is of great value
in improving the smoothness of glycemic control.
Starting Insulin with Gestational Diabetes
Clinicians and patients are reluctant to start insulin in patients with
gestational diabetes, but this intervention may be essential if macroso-
mia is to be reduced or avoided. Because the period of maximum fetal
growth velocity (200 g/wk) and fat accretion occurs at approximately
to correct a suboptimal glucose proﬁle with dietary adjustments may,
by 33 to 34 weeks, have missed the time when glycemic intervention
is most effective in modulating fetal growth. It is reasonable to allow
a 1- to 2-week trial of dietary management before resorting to other
measures, but waiting longer does not signiﬁcantly increase the likeli-
hood of good control. McFarland and colleagues248
have shown that
approximately 50% of patients achieve good glycemic control during
the ﬁrst 2 weeks of dietary therapy, but by the 4th week, only an addi-
tional 10% attain acceptable blood glucose levels.
The value of insulin administration in gestational diabetes was
assessed by Crowther and associates,249
who randomized 1000 women
with gestational diabetes to insulin treatment or no medical therapy
in the Australian Carbohydrate Intolerance Study in Pregnant Women
(ACHOIS trial). Controls with normal OGTT results were included
in the trial. In the insulin group, glucose levels were maintained at
less than 99 mg/dL before meals and less than 126 mg/dL 2 hours
postprandially. The rate of serious perinatal complications was signiﬁ-
cantly lower among the infants of 490 women in the intervention
group than among the infants of 510 women in the routine-care group
(1% versus 4%; RR adjusted for maternal age, race or ethnic group,
and parity = 0.33; CI, 0.14 to 0.75; P = .01). The intervention group
had a signiﬁcantly higher rate of labor induction than the routine-care
group (39% versus 29%), but the rates of cesarean delivery were
similar. Cord plasma glucose levels were higher in women receiving
routine care compared with controls, but it was normalized by
treatment for mild GDM (P = .01). At 3 months after delivery, the
TABLE 46-18 TYPICAL SECOND-TRIMESTER CONTINUOUS ADMINISTRATION PROFILE USING A
SUBCUTANEOUS INSULIN INFUSION PUMP
Time Basal Rate Bolus (U) Comment
12 midnight 0.6 U/hr Lower basal rate for sleep
5 AM 1.5 U/hr Higher basal rate opposes the “dawn effect” of rising serum glucose from 4 to 6 AM
7 AM 8 Prebreakfast bolus
9 AM 1.0 U/hr Lower basal rate to match increased physical activity, decreased insulin needs
12 noon 4 Prelunch bolus
6 PM 4 Predinner bolus
10 PM 0.6 U/hr Lower basal rate for sleep
980 CHAPTER 46 Diabetes in Pregnancy
intervention group had lower rates of depression and higher quality-
With regard to newborn outcomes in the ACHOIS trial, umbilical
cord serum insulin and insulin to glucose ratio were similar between
the three groups, but leptin concentration, an indicator of fat mass,
was lower in treated women with GDM compared with routine care
(P = .02), suggesting that treatment of GDM using diet, blood glucose
monitoring, and insulin, if necessary, inﬂuences the fetal adipoinsular
axis, which may reduce the risk of childhood and adult obesity late in
Jovanovic-Peterson and colleagues251
reported a protocol in which
GDM patients were treated with insulin if any fasting glucose level
exceeded 90 mg/dL or postprandial glucose level exceeded 120 mg/dL.
Over a period of 6 years, this protocol resulted in a decrease in the rate
of macrosomic infants from 18% to 7% and a drop in the cesarean rate
from 30% to 20%. Buchanan and associates252
used ultrasound screen-
ing of fetal abdominal circumference in 303 diet-controlled GDM
patients at 28 weeks to identify early macrosomia that might beneﬁt
from insulin treatment. When pregnancies with a fetal abdominal cir-
cumference above the 75th percentile were randomized to continued
diet or twice-daily insulin therapy, birth weights and percentage of
macrosomic infants were reduced in the insulin group (3647 ± 67 g
versus 3878 ± 84 g; P < .02 and 13% versus 45%; P < .02). Neonatal
obesity, as reﬂected by skinfold measurements at three sites (P < .005),
also was lower.
The insulin regimen used in managing women with gestational
diabetes should be designed to address the patient’s individual glucose
proﬁle, because some women require insulin to prevent only fasting
AM hyperglycemia and others only for postprandial excursions. Typi-
cally, one to several postprandial glucose levels become consistently
above target as the patient’s ability to compensate for rising insulin
resistance becomes inadequate with diet alone. In such cases, giving
short-acting insulin such as lispro or aspart (4 to 8 units to start) before
meals is helpful. If more than 10 units of short-acting insulin is needed
before the noon meal, adding a 6- to 8-unit dose of NPH before break-
fast helps to achieve smoother control. If the fasting glucose levels rise
above 90 to 95 mg/dL, 4 to 6 units of NPH insulin should be admin-
istered between 10 to 11 PM. The doses are scaled up as necessary, twice
weekly or more often, to keep glucose levels within the target range.
Use of Oral Hypoglycemic Agents
Maintaining glucose levels within the target range requires meticulous
attention to diet and physical activity. For many patients, injecting
insulin frequently is impossible, and there are many initiatives to
augment glucose control with oral agents, particularly in patients with
insulin-resistant type 2 diabetes. An ideal treatment would reduce
insulin resistance, improve insulin secretion or action, and delay the
uptake of glucose from the gut. Current strategies are aimed at aug-
mentation of insulin supply (i.e., sulfonylurea and insulin therapy),
amelioration of insulin resistance (i.e., exercise, weight loss, and met-
formin and troglitazone therapy), and limitation of postprandial
hyperglycemia (i.e., acarbose therapy).
Pharmacology and Safety
Sulfonylurea compounds, commonly prescribed in the past for patients
with type 2 diabetes, have been considered contraindicated during
pregnancy because of the high degree of transplacental penetration of
most of these agents and the clinical reports of drug concentrations in
the neonate higher than maternal levels associated with prolonged and
severe neonatal hypoglycemia.253
However, rigorously designed trials
have not been performed to assess these agents during pregnancy.
Reports of fetal anomalies have been largely anecdotal. An increased
rate of congenital malformations, particularly ear anomalies, has been
evaluated the frequency of birth defects in fetuses of patients who
took oral hypoglycemics during the periconceptional period, they
found that the ﬁrst-trimester glycohemoglobin level and duration of
diabetes were strongly associated with fetal congenital anomalies but
that use of oral hypoglycemic medications was not.
Interest in glyburide, a second-generation oral sulfonylurea avail-
able in the United States since 1984, has recently been rekindled. When
glyburide was compared with ﬁrst-generation sulfonylureas, it was
equally effective, had a lower incidence of side effects, and reduced
fasting blood glucose and glycohemoglobin levels, without the incon-
venience of the additional training required to administer insulin.
Because of its ability to enhance target tissue insulin sensitivity, glybu-
ride has been shown to improve glycemic control in many type 2 dia-
glyburide can reduce the daily dosage for those who require large
amounts of insulin.256
A unique characteristic of glyburide that allows its use in pregnancy is
its minimal transport across the human placenta.257
A study by Elliott
evaluated glyburide transport in 10 term human
placentas with the single-cotyledon placental model and found virtu-
ally no transfer of glyburide even at concentrations 100 times the
typical therapeutic levels. This surprisingly low placental transfer may
result from the very high plasma-protein binding of glyburide coupled
with a short elimination half-life of 4 to 8 hours.257,259
Based on ﬁndings consistently showing minimal transfer of glybu-
ride across the placenta, Langer and colleagues260
designed a random-
ized trial to compare this oral agent with insulin in patients with
gestational diabetes. They randomized 404 women with second- and
third-trimester singleton pregnancies who had gestational diabetes
requiring treatment to receive glyburide or insulin in an intensiﬁed
treatment protocol. At the conclusion of the trial, there was no differ-
ence between the groups in mean maternal blood glucose, percentage
of infants who were LGA (12% and 13%, respectively), birth weight at
or above 4000 g (7% and 4%), or neonatal complications (pulmonary,
8% and 6%; hypoglycemia, 9% and 6%; admission to neonatal inten-
sive care unit, 6% and 7%; fetal anomalies, 2% and 2%). Only 4% of
the glyburide group required insulin therapy. Glyburide was not
detected in the cord serum of any infant in the glyburide group.
However, only 82% of the glyburide and 88% of the insulin-treated
patients achieved the target level of glycemic control, representing a
glyburide “failure rate” of 18%. With regard to glyburide dosing during
the trial, 31% of patients were treated with 2.5 mg, 21% with 5 mg,
19% with 10 mg, 9% with 15 mg, and 20% with 20 mg. The mean
glyburide dose was 9.2 mg. Of the maternal outcome variables assessed,
none was signiﬁcantly different between groups except the dramatic
(P = .03) reduction in maternal hypoglycemic episodes in the glybu-
ride-treated group (2%) compared with the 20% rate for insulin.
Beyond this single encouraging study, further nonrandomized
experience with glyburide during pregnancy is accumulating.261,262
Chmait and coworkers,263
describing their experience with 69 patients
with gestational diabetes managed on glyburide, reported that 19% of
patients required adjunctive insulin therapy to keep glucose values in
the target range. The adjunctive insulin rate was higher for women
diagnosed earlier in pregnancy (20 versus 27 weeks; P < .003) and those
whose average fasting glucose in the week before starting glyburide was
981CHAPTER 46 Diabetes in Pregnancy
higher (126 versus 101 mg/dL). No cases of neonatal hypoglycemia
occurred in the glyburide group.
Langer and colleagues264
reanalyzed the previously cited random-
ized, controlled trial, addressing the issues of glyburide dose, GDM
severity, and pregnancy outcome and grouping trial participants into
low (≤10 mg) and high (>10 mg) daily glyburide dose groups and low
(≤95 mg/dL) or high (>95 mg/dL) GDM severity groups based on
fasting OGTT values. The rates of macrosomia were 16% versus 5%,
and the rates of infants who were LGA were 22% versus 8%, (P = .01),
respectively, in the high-dose and low-dose glyburide groups. Stratiﬁ-
cation by disease severity (using the level of fasting glucose on glucose
tolerance testing) revealed equally lower rates of LGA for the glybu-
ride- and insulin-treated subjects in the low-severity group. In the
higher-severity group, the rates of macrosomia and LGA were similar
in the glyburide and insulin arms. The study authors suggested that
achieving an excellent level of glycemic control, rather than the mode
of pharmacologic therapy, is the key to improving outcomes in cases
There is a growing acceptance of glyburide use as a primary therapy
Although no new randomized trials have been completed,
several retrospective series have been published comprising 504
glyburide-treated patients, and these studies have been summarized by
Jacobson and coworkers267
performed a retrospective cohort com-
parison of glyburide and insulin treatment of gestational diabetes.
Patients with fasting plasma glucose levels greater than 140 mg/dL on
glucose tolerance testing were excluded. The insulin group (n = 268)
consisted of those diagnosed in 1999 through 2000, and the glyburide
group (n = 236) was diagnosed in 2001 through 2002. Glyburide
dosing was begun with 2.5 mg in the morning and increased by 2.5 to
5.0 mg weekly. If the dose exceeded 10 mg daily, twice-daily dosing was
considered. If glycemic goals were not met on a maximum daily dose
of 20 mg, patients were changed to insulin. The study size was insufﬁ-
cient to detect less than a doubling of the rate of macrosomia or LGA
and a 44% increase in neonatal hypoglycemia, but there were no sta-
tistically signiﬁcant differences in gestational age at delivery, mode of
delivery, birth weight, LGA, or percent of macrosomic infants. The rate
of preeclampsia doubled in the glyburide group (12% versus 6%; P <
.02). Women in the glyburide group also had signiﬁcantly lower post-
treatment fasting and postprandial blood glucose levels. The glyburide
group was superior in achieving target glycemic levels (86% versus
63%; P < .001). The failure rate (i.e., transfer to insulin) was 12%.
Conway and associates268
reported a retrospective cohort of 75
glyburide-treated GDM patients. Good glycemic control was achieved
by 84% of the subjects with glyburide, and 16% were switched to
insulin. The rate of fetal macrosomia was similar between women suc-
cessfully treated with glyburide and those who converted to insulin
(11.1% versus 8.3%; P = 1.0), and the mean birth weight was also
similar. A not signiﬁcantly higher proportion of infants in the gly-
buride group required intravenous glucose infusions because of
hypoglycemia (25.0% versus 12.7%; P = .37).
Small cohorts reported by Kremer and colleagues269
demonstrated glyburide failure requiring adjunctive
or substitutive insulin rates in the range of 15% to 20%. In these
studies, higher GCT results (>160 to 200 mg/dL) were predictive of an
approximate 50% failure rate.271
The recommended glyburide dosing regimen, based largely on
animal studies and a few human studies of nonpregnant subjects, is to
administer the agent once daily, with twice-daily doses reserved for
refractory cases. Later studies of glyburide pharmacodynamics suggest
that the previously recommended dosing protocols may not be optimal
in pregnancy. During development of the drug in the late 1960s, single-
dose studies in nondiabetic subjects demonstrated glyburide absorp-
tion within 1 hour, peak levels at about 4 hours, and low but detectable
levels at 24 hours. The decrease of glyburide in the serum yielded a
terminal half-life of about 10 hours, and the glucose-lowering effect
could be expected to persist for 24 hours after a single morning dose.
Later data have shown that glyburide peaks earlier in the serum and
has a signiﬁcantly shorter half-life than previously believed. These
effects reﬂect the fact that glyburide has two major hydroxyl metabo-
lites, both of which are biologically active and excreted equally in the
bile and urine. Although advice in the Physician’s Desk Reference indi-
cates that the glyburide metabolites provide no signiﬁcant contribu-
tion to glyburide’s hypoglycemic action (1
/400 and 1
/40, respectively, of
glyburide’s potency), these data were obtained in rabbits.
Yin and associates272
studied the glucose and insulin responses to
glyburide in a group of nonpregnant, nondiabetic subjects. After a 5-
mg oral dose, serum glyburide levels peaked at 2.75 hours and had
sustained levels with a half-life ranging from 2 to 4 hours, considerably
shorter than the quoted half-life of 10 hours.
To clarify the potential difference in drug action when given as a
single dose or chronically over weeks, Jaber and colleagues273
glyburide pharmacodynamics during multiple-dose administration. A
signiﬁcant prolongation in the half-life (week 0 = 4.0 ± 1.9 hr; week 6
= 13.7 ± 10.5 hr; and week 12 = 12.1 ± 8.2 hr) was observed during
chronic dosing. These results suggest possible drug accumulation or
tissue sensitization by glyburide.
Yogev and coworkers274
examined the prevalence of undiagnosed,
asymptomatic hypoglycemic events in diabetic patients using a con-
tinuous glucose monitoring system for 72 consecutive hours. Hypo-
glycemia was deﬁned as more than 30 consecutive minutes of a glucose
value below 50 mg/dL. Asymptomatic hypoglycemic events were
recorded in 63% of insulin-treated patients but in only 28% of glybu-
ride-treated patients. The mean number of hypoglycemic episodes per
day was signiﬁcantly higher in insulin-treated patients (4.2 ± 2.1) than
in glyburide-treated patients (2.1 ± 1.1; P = .03). In insulin-treated
patients, most hypoglycemic events were nocturnal (84%), whereas in
glyburide-treated patients, episodes occurred equally during the day
and night, suggesting a potential beneﬁt of glyburide over insulin
therapy in clinical use.
Based on these data, glyburide should be taken at least 30 minutes—
and preferably 60 minutes—before meals so that the peak action (2.5
hours after dosing) covers the postprandial glucose surge. Because of
its extended duration of action, glyburide taken at 10 to 11 PM is effec-
tive in lowering fasting plasma glucose levels in the morning. Signiﬁ-
cant interprandial hypoglycemia can occur with glyburide, and patients
should carry glucose tablets with them at all times as a precaution. The
maximum dose is 20 mg per day, and no more than 7.5 mg should be
taken at a single time.
Metformin is frequently employed in patients with polycystic ovary
syndrome and type 2 diabetes to improve insulin resistance and
Although it has been documented that metformin
therapy improves the success of ovulation induction276
reduces ﬁrst-trimester pregnancy loss in women with polycystic
the effects of continuing metformin during
pregnancy are not clear. Coetzee and Jackson277
and gestational diabetics with metformin, but the treatment failed
in 54% and 29%, respectively. The perinatal mortality rate among
the metformin patients was 61 per 1000, and the rate of neonatal
jaundice was increased. Hellmuth and colleagues278
reported a series of
982 CHAPTER 46 Diabetes in Pregnancy
women with gestational diabetes treated with metformin or tolbuta-
mide before 1984. Women treated with metformin had a fourfold
increase in preeclampsia and a higher perinatal mortality rate
compared with those who were receiving tolbutamide. However,
metformin-treated women were older, more obese, and treated later in
A cohort study of metformin in pregnancy reported by Hughes and
in 2006 included 93 women with metformin treatment
(only 32 continued until delivery) and 121 controls. There was no dif-
ference in perinatal outcomes between the groups. Glueck and cowork-
compared nondiabetic women with polycystic ovary syndrome
(n = 28) who conceived while taking metformin and continued the
agent through delivery with matched women without metformin
therapy (n = 39). Gestational diabetes developed in 31% of women
who did not take metformin and in 3% of those who did (OR = 0.115;
CI, 0.014 to 0.938).
Because of the beneﬁcial effect of metformin on ﬁrst-trimester
miscarriage, many patients with polycystic ovary syndrome enter pre-
natal care taking this medication. Because metformin readily crosses
greater experience with this agent is necessary before
it can be recommended for use throughout pregnancy.279
properly powered, randomized, controlled trial is in progress to explore
The α-glucosidase inhibitors, another class of oral agents, reversibly
inhibit pancreatic amylase and α-glucosidase enzymes in the small
intestine, delaying cleavage of complex sugars to monosaccharides and
reducing the increase of blood glucose levels after a meal. Although
these agents offer particular promise in pregnant women because of
limited uptake from the gut, only a few studies of the drugs in preg-
nancy are available. Bertini and colleagues281
compared insulin treat-
ment (n = 27), glyburide (n = 24), and acarbose (n = 19) in gestational
diabetes. No difference was observed in maternal glucose levels or in
mean birth weight, although the rates of LGA fetuses were 3.7%, 25%,
and 10.5% for the groups, respectively. Neonatal hypoglycemia was
observed in eight newborns, six of whom were from the glyburide
group. Glucose control was not achieved in ﬁve (20.8%) of the patients
using glyburide and in eight (42.1%) of the patients using acarbose.
Acarbose is given before meals, initially in a dose of 25 mg taken orally
three times daily up to a maximum of 100 mg taken orally three times
of the Diabetic Patient
The goals of third-trimester management of diabetic pregnancy are to
prevent stillbirth and asphyxia while optimizing the opportunity for a
safe vaginal delivery. This involves monitoring fetal growth to deter-
mine the proper timing and route of delivery and testing for fetal
well-being at frequent intervals.
A regimen for fetal surveillance throughout pregnancy is provided
in Table 46-19. The goals are to
Verify fetal viability in the ﬁrst trimester
Validate fetal structural integrity in the second trimester
Monitor fetal growth during most of the third trimester
Ensure fetal well-being in the late third trimester
A variety of fetal biophysical tests are available, including fetal heart
rate testing, fetal movement counting, ultrasound biophysical scoring,
and fetal Doppler studies. These tests, which are described in Chapter
21, are summarized in Table 46-20.
Testing should be initiated early enough to avoid the risk of still-
birth but not so early that a high rate of false-positive results is encoun-
tered. Because the risk of fetal death is roughly proportional to the
degree of hyperglycemia, testing should begin as early as 28 weeks’
gestation in patients with poor glycemic control or signiﬁcant hyper-
tension. In lower-risk patients, testing should begin at 34 to 36 weeks.
Fetal movement counting should be performed in all pregnancies from
28 weeks onward. A fetal movement card for monitoring fetal move-
ment is shown in Figure 46-16.
Timing and Route of Delivery
Assessing Fetal Size
Monitoring fetal growth and predicting birth weight continue to be
challenging and highly inexact processes. The purpose of such moni-
toring is to identify the obese fetus and, if possible, avoid birth injury.
Newborns weighing more than 4000 g are responsible for 42% to 74%
of shoulder dystocias and 56% to 76% of all brachial plexus injuries,
even though they account for only 6% of births.282
To identify the
highest-risk fetuses, use of third-trimester ultrasound has been pro-
posed, including serial plotting of biometric parameters, using a cutoff
value for estimated fetal weight and applying a cutoff to a speciﬁc
parameter (e.g., abdominal circumference).283
Because the risk of birth injury is proportional to birth weight,142
much effort has been focused on sonographic estimation of fetal
weight (EFW). Several polynomial formulas using combinations of
head, abdomen, and limb measurements have been developed.284,285
Unfortunately, even small errors in measurements of the head,
abdomen, and femur are multiplied together in such formulas, result-
ing in accuracies of no better than ± 15%. In the obese fetus, the inac-
TABLE 46-19 FETAL SURVEILLANCE IN TYPES I
AND II DIABETIC PREGNANCIES
Preconception Maternal glycemic control
8-10 wk Sonographic crown-rump measurement
16 wk Maternal serum α-fetoprotein level
20-22 wk High-resolution sonography, fetal cardiac
echography in women in suboptimal diabetic
control (abnormal Hb A1c value) at ﬁrst prenatal
24 wk Baseline sonographic growth assessment of the
28 wk Daily fetal movement counting by the mother
32 wk Repeat sonography for fetal growth
34 wk Biophysical testing:
Two times weekly nonstress test or
Weekly contraction stress test or
Weekly biophysical proﬁle
36 wk Estimation of fetal weight by sonography
37-38.5 wk Amniocentesis and delivery for patients in poor
control (persistent daily hyperglycemia)
38.5-40 wk Delivery without amniocentesis for patients in
good control who have excellent dating criteria
983CHAPTER 46 Diabetes in Pregnancy
curacies are further magniﬁed. Perhaps this is why no single formula
has proved adequate for identifying the macrosomic fetus.286
study by Combs and colleagues,287
an EFW of 4000 g had a sensitivity
of 45% and a positive predictive value of 81%. To achieve 90% sensitiv-
ity would have required using an EFW cutoff of 3535 g, which would
have included 46% of the population and produced a 42% false-posi-
In an attempt to improve detection of macrosomia, Hackmon and
performed a retrospective comparison of sonographic
imaging results (i.e., EFW and amniotic ﬂuid index [AFI]) for 50
newborns with severe macrosomia (birth weight ≥ 97th percentile) and
100 infants of normal weight. The mean middle-third-trimester AFI
percentile and EFW percentiles for severe macrosomic infants were
signiﬁcantly higher than for controls (P < .0001). Signiﬁcant correla-
TABLE 46-20 TESTS OF FETAL WELL-BEING
Test Frequency Reassuring Result Comment
Fetal movement counting Every night from 28 wk 10 movements in <60 min Performed in all patients
Nonstress test Twice weekly 2 heart-rate accelerations in 20 min Begin at 28-34 wk with insulin-
dependent diabetes; start at 36 wk
in diet-controlled gestational diabetes
Contraction stress test Weekly No heart-rate decelerations in response
to ≥3 contractions in 10 min
Same as for nonstress test
Ultrasound biophysical proﬁle Weekly Score of 8 in 30 min 3 movements = 2
1 ﬂexion = 2
30-sec breathing = 2
2-cm amniotic ﬂuid = 2
FETAL MOVEMENT RECORD
Number of weeks
11/4/91 6:50 p.m. 7:28 p.m. 38 minutes
Movement Felt Total Time
Count the baby’s movements EVERY NIGHT.
A movement may be a kick, swish or roll. Do not count
hiccups or small flutters.
You can start counting any time in the evening when the
baby is active. BUT: COUNT EVERY NIGHT.
Count baby’s movement while lying down, preferably on
your left side.
Mark down the time you feel the baby move for the first
Mark down the time you feel the 10th fetal movement.
You should feel at least 10 fetal movements within one
hour. Call Labor and Delivery immediately if
you do not feel 10 movements with 1 hour;
it takes longer and longer for your baby to move
you have not felt the baby move all day
DO NOT WAIT UNTIL TOMORROW.
FIGURE 46-16 Fetal movement card. The patient is instructed to note the time at which she begins monitoring fetal movements and
then note the time at which the 10th movement is felt. If she has not recorded 10 movements in 1 hour, she is to call her physician.
984 CHAPTER 46 Diabetes in Pregnancy
tions were detected for birth weight and the AFI and EFW percentiles
(r = 0.44 and r = 0.72, respectively; P < .0001). The best predictors of
macrosomia were an AFI equal to the 60th percentile or higher and an
EFW equal to the 71st percentile or higher, with a positive predictive
value of 85%. However, even this enhanced protocol had a high-false
Considering the inaccuracy of weight prediction from a single set
of sonographic measurements, serial analysis of parameters every 1.5
to 3 weeks is commonly used. However, trended serial EFW calcula-
tions compared with a single measurement appear to be no better
than a single estimate performed near term. Predictions based on the
average of serial EFWs, linear extrapolation from two estimates,
or extrapolation by second-order equations ﬁtted to four estimates
were no better than the prediction from the last estimate before
In view of the inadequate methods used to diagnose macrosomia
antenatally, the widespread practice of estimating fetal weight using
ultrasound near term in diabetic pregnancy must be questioned. Parry
compared the cesarean rate for neonates falsely diag-
nosed on ultrasound as macrosomic (i.e., false positives) with the rate
for those correctly diagnosed as nonmacrosomic (i.e., true negatives).
They found that the cesarean rate was signiﬁcantly higher among
the false-positive macrosomics than among the true negatives (42.3%
versus 24.3%; RR = 1.74; P < .05). Even with nonmacrosomic fetuses,
the availability to the clinician of a sonographic estimate of fetal weight
signiﬁcantly increases the risk of cesarean delivery.
Predicting Shoulder Dystocia
Because of the asymmetrical adipose deposition around the fetal chest
and trunk, deliveries of macrosomic infants from women with diabetes
are at high risk for shoulder dystocia and injury. However, prediction
of this risk is not possible with adequate precision to avoid excessive
In a subanalysis of the ACHOIS trial, Athukorala and associates138
identiﬁed a linear increase in the risk of shoulder dystocia and the
fasting glucose level on the glucose tolerance test, with an 18-mg/dL
(1-mmol) increase in the fasting oral glucose tolerance test result
leading to a relative risk of 2.09 (CI, 1.03 to 4.25). As reported by
others, shoulder dystocia was 10-fold more common with operative
vaginal delivery of GDM infants. However, there was no clear cutoff
for the glucose tolerance test fasting value that was adequately predic-
tive of shoulder dystocia.
In an effort to minimize the incidence of shoulder dystocia and
associated birth injury associated with suspected macrosomia, a
number of management schemes have been proposed. Weeks and col-
assessed the management of 500 pregnancies with suspected
macrosomia and found a high bias toward cesarean section and failed
induction. Patients with a sonographic EFW greater than 4200 g
underwent induction more often (42.5% versus 26.6%), failed to
achieve active labor more frequently (49% versus 16.5%), and under-
went cesarean section more frequently (52% versus 30%), regardless
of actual birth weight. Despite these changes in labor management, the
incidence of shoulder dystocia in the predicted and nonpredicted
groups was the same (11.8% and 11.7%, respectively).
There is no clinical method of reliably identifying the fetus likely
to experience shoulder dystocia and injury during birth without an
unacceptably high false-positive rate. Because 8% to 20% of fetuses
from diabetic pregnancy weighing 4500 g or more will have shoulder
dystocia, 15% to 30% of these will have recognizable brachial plexus
injury, and 5% to 15% of these injuries will result in permanent deﬁcit,
approximately 443 to 489 cesarean sections would have to be per-
formed for suspected macrosomia to prevent one case of permanent
injury from shoulder dystocia.293
Timing of delivery should minimize neonatal morbidity and mortality
while maximizing the likelihood of vaginal delivery. Delaying delivery
to as near the estimated due date as possible increases cervical ripeness
and improves the chances of vaginal birth. However, the risks of fetal
macrosomia, birth injury, and fetal death increase as the due date
approaches. Earlier delivery may reduce the risk of shoulder dystocia,
but the increase in failed labor inductions and neonatal respiratory
distress is appreciable.
Rayburn and colleagues294
reported a case-control study of out-
comes of women with GDM requiring insulin who delivered at 38
weeks compared with normoglycemic controls. The study group was
more likely to have an unfavorable cervix, but cesarean rates were not
different between the study and control groups (12.7% versus 11.7%;
P < .8). Mean birth weights and the frequency of birth weights greater
than 4000 g were not different between the groups, suggesting that
delivery at 38 to 39 weeks does not compromise maternal and infant
When all these factors are considered, the optimal time for delivery
of most diabetic pregnancies is between 38.5 and 40 weeks. Indications
for delivery of the diabetic pregnancy are summarized in Table 46-21.
Because of the apparent delay in fetal lung maturity in diabetic preg-
nancies, delivery before 38.5 weeks’ gestation should be performed
only for compelling maternal or fetal reasons.
It may be tempting to consider early delivery in a diabetic preg-
nancy with evolving macrosomia identiﬁed on ultrasonography.
Because fetal growth between 37 and 40 weeks’ gestation in a 90th-
percentile fetus is approximately 100 to 150 g per week, inducing labor
2 weeks early may reduce the risk of shoulder dystocia in some cases.
Kjos and coauthors295
compared the outcomes associated with labor
induction at 38 weeks with expectant management of women with
gestational diabetes. They found that expectant management increased
the gestational age at delivery by 1 week, but the cesarean delivery rate
was not signiﬁcantly different. Macrosomia was present in 23% of
the expectantly managed group versus 10% in those induced at 38
Fetal lung maturity should be veriﬁed in all patients delivered
before 38.5 weeks by the presence of greater than 3% phosphatidyl-
glycerol or the equivalent on an amniocentesis specimen (Table 46-22).
If obstetric dating is suboptimal, amniocentesis should be performed.
TABLE 46-21 INDICATIONS FOR DELIVERY IN
Type Indications for Delivery
Fetal Nonreactive, positive contraction stress test
Reactive positive contraction stress test, mature fetus
Sonographic evidence of fetal growth arrest
Decline in fetal growth rate with decreased amniotic
40-41 weeks’ gestation
Maternal Severe preeclampsia
Mild preeclampsia, mature fetus
Markedly falling renal function (creatinine clearance
Obstetric Preterm labor with failure of tocolysis
Mature fetus, inducible cervix
985CHAPTER 46 Diabetes in Pregnancy
After more than 40 weeks, the beneﬁts of continued conservative man-
agement are less than the danger of fetal compromise. Induction of
labor before 42 weeks in diabetic pregnancy—regardless of the readi-
ness of the cervix—is prudent.
Labor or Cesarean
has recommended that primary cesarean delivery be
discussed with diabetic gravidas with an EFW greater than 4500 g. This
may reduce the risk of shoulder dystocia to some degree for an indi-
vidual patient, but the effect on the larger obstetric population is less
Gonen and associates297
retrospectively assessed the impact of a
policy of elective cesarean in cases with an EFW above 4500 g. During
the 4 years of the study with more than 16,000 deliveries, macrosomia
was correctly predicted in only 18% of cases. Of the 115 undiagnosed
macrosomic cases, 13 infants were delivered by emergency cesarean,
and 99 were delivered vaginally. Three infants (3%) with macrosomia
and 14 infants (0.1%) without macrosomia sustained brachial plexus
injury. The policy of preemptive cesarean for an EFW greater than
4500 g prevented at most a single case of brachial palsy.
Conway and Langer298
performed a prospective trial enrolling dia-
betic women among whom those with an EFW of 4250 g or more
underwent elective cesarean section. Ultrasonography correctly identi-
ﬁed the presence or absence of macrosomia in 87% of patients. The
cesarean section rate increased slightly after the protocol was initiated
(22% versus 25%), but overall, shoulder dystocia was less common
(2.4% versus 1.1%).
conducted a cost-effectiveness analysis of “prophylactic”
delivery (i.e., induction or cesarean) of the fetus with an EFW greater
than 4500 g using risk and beneﬁt rates estimated from the existing
For an infant of a normoglycemic pregnancy
weighing 4500 g or more, routine obstetric management was the least
expensive ($4014 per injury-free child) compared with elective cesar-
ean cost of $5212 and induction cost of $5165. However, a sensitivity
analysis suggested that with a shoulder dystocia risk higher than 10%
(as is the case with a fetus weighing more than 4500 g in a diabetic
pregnancy), primary cesarean or early induction is somewhat more
ﬁnancially advantageous. The current recommendation that cesarean
section be considered when fetal weight is suspected to exceed 4500 g
appears to confer a modest improvement in neonatal outcome.
The decision to attempt vaginal delivery or perform a cesarean
delivery is inevitably based on limited data. The patient’s obstetric
history, the best EFW, a fetal adipose proﬁle (i.e., abdomen larger than
head), and clinical pelvimetry should all be considered. Midpelvic
operative deliveries should be avoided when macrosomia is suspected,
and low pelvic or even outlet operative deliveries must be approached
with extreme caution if labor is protracted. With an EFW greater than
4500 g, a prolonged second stage of labor or arrest of descent in the
second stage is an indication for cesarean delivery.296
Most large series
of diabetic pregnancies report a cesarean section rate of 30% to 50%.
The best means by which this rate can be lowered is by early and strict
glycemic control in pregnancy. Conducting long labor inductions in
patients with a large fetus and a marginal pelvis may increase, rather
than lower, morbidity and costs.
Intrapartum Glycemic Management
Perinatal asphyxia and neonatal hypoglycemia correlate with maternal
hyperglycemia during labor.300
Unfortunately, strict maternal euglyce-
mia during labor does not guarantee newborn metabolic stability in
infants with macrosomia and islet cell hypertrophy. The use of a
combined insulin and glucose infusion during labor maintains the
maternal plasma glucose level in a narrow range (80 to 110 mg/dL)
and reduces the incidence of neonatal hypoglycemia.301
A protocol for
administration of a continuous insulin infusion in labor is outlined in
Table 46-23. Typical infusion rates are 5% dextrose in Ringer’s lactate
at 100 mL per hour and lispro or aspart insulin at 0.5 to 1 units per
hour. Capillary blood glucose is monitored hourly in these patients.
For patients with diet-controlled GDM or mild type 2 diabetes, avoid-
ing dextrose in all intravenous ﬂuids during labor usually maintains
excellent glucose control.
When cesarean section is planned in a woman with diabetes, the
procedure should be performed early in the day to avoid prolonged
TABLE 46-22 CONFIRMATION OF FETAL
MATURITY BEFORE INDUCTION
OF LABOR OR PLANNED
CESAREAN DELIVERY IN
Phosphatidylglycerol >3% in amniotic ﬂuid collected from vaginal
pool or by amniocentesis
Completion of 38.5 weeks’ gestation
Normal last menstrual period
First pelvic examination before 12 wk conﬁrms dates
Sonogram before 24 wk conﬁrms dates
Documentation of more than 18 wk of unampliﬁed (fetoscope)
fetal heart tones
TABLE 46-23 INTRAPARTUM MATERNAL
Insulin Infusion Method
1. Withhold AM insulin injection.
2. Begin and continue glucose infusion (5% dextrose in water) at
100 mL/hr throughout labor.
3. Begin infusion of regular insulin at 0.5 U/hr.
4. Begin oxytocin as needed.
5. Monitor maternal glucose levels hourly using a capillary
reﬂectance meter at bedside or laboratory determinations,
6. Adjust insulin infusion.
Plasma/Capillary Glucose (mg/dL) Infusion Rate (U/hr)
<80 Insulin off
Intermittent Subcutaneous Injection Method
1. Give one half of the usual insulin dose in AM.
2. Begin and continue glucose infusion (5% dextrose in water) at
100 mL/hr throughout labor.
3. Begin oxytocin as needed.
4. Monitor maternal glucose levels hourly using a capillary
reﬂectance meter at bedside or laboratory determinations, or
5. Administer regular insulin in small doses (2 to 5 U) to maintain
glucose levels of 80 to 120 mg/dL.
*Intravenous bolus of 2 to 5 units when the rate increases.
986 CHAPTER 46 Diabetes in Pregnancy
periods of fasting. On the night before surgery, patients should be
instructed to take their full dose of NPH or glyburide. No morning
insulin or glyburide should be taken. A glucose-containing intravenous
line should be established promptly on arrival at the hospital, with
insulin given as intravenous boluses on a sliding scale as needed every
1 to 4 hours to maintain maternal plasma glucose in the range of 80
to 160 mg/dL.
Postpartum Metabolic Management
In the recovery room and after delivery, insulin can be given subcuta-
neously to women with type 2 diabetes using a sliding scale until a
regular diet is established. The insulin doses required after delivery are
typically 30% to 50% of the preprandial doses required during preg-
nancy just before delivery. Type 1 diabetes patients require more inten-
sive glucose monitoring after delivery, because many experience a
honeymoon phase, in which insulin requirements fall dramatically.
The glucose-insulin intravenous infusion should be continued in type
1 diabetes patients, especially those who have had a cesarean delivery,
until the diet has normalized.
Management of the Neonate
Neonatal Transitional Management
Unmonitored and uncorrected neonatal hypoglycemia can lead to
neonatal seizures, brain damage, and death. The degree of hypoglyce-
mia correlates roughly with the degree of maternal glycemic control
during the 6 weeks before birth. Pancreatic hypertrophy and chronic
fetal hyperinsulinemia—holdovers from the chronically glucose-rich
intrauterine environment—can lead to signiﬁcant hypoglycemia after
the umbilical supply of nutrients is interrupted by delivery. IDMs also
appear to have disorders of catecholamine and glucagon metabolism
and have diminished capability to mount normal compensatory
responses to hypoglycemia. The current recommendations specify fre-
quent blood glucose checks and early oral feeding when possible
(ideally from the breast), with infusion of intravenous glucose if oral
measures prove insufﬁcient.
Ordinarily, blood glucose levels can be controlled satisfactorily with
an infusion of 10% glucose. If greater amounts of glucose are required,
bolus administration of 5 mL/kg of 10% glucose is recommended, with
gradually increasing concentrations of glucose administered every 30
to 60 minutes, if necessary.
Considering the number of perinatal complications experienced by
many women with diabetes (e.g., preeclampsia, macrosomia-induced
cesarean section, neonatal hypoglycemia), achieving a high rate of
breastfeeding may seem to be a superﬂuous goal. However, mounting
evidence indicates that breastfed infants have a much lower risk of
developing diabetes than do those exposed to the proteins in cow’s
Pettitt and associates304
found that children who were exclu-
sively breastfed had signiﬁcantly lower rates of non–insulin-dependent
diabetes mellitus than did those who were exclusively bottle-fed in all
age groups. The odds ratio for non–insulin-dependent diabetes melli-
tus in exclusively breastfed persons, compared with exclusively bottle-
fed individuals, was 0.41 (CI, 0.18 to 0.93), adjusted for age, sex, birth
date, parental diabetes, and birth weight. A study by Gimeno and de
found that a shorter duration of exclusive breastfeeding was
a risk factor for childhood diabetes (OR = 2.13; CI, 1.8 to 3.55) and
that the introduction to cow’s milk products before age 8 days was an
important risk factor for the disease. Given the increased risk of dia-
betes in offspring of women with diabetes, these data underscore the
importance of encouraging breastfeeding in all postpartum women
Most neonatologists maintain strict monitoring of glucose levels in
newborn IDMs for at least 4 to 6 hours (frequently 24 hours), often
necessitating admission to a newborn special care unit. This early sepa-
ration of mother and neonate impedes breastfeeding and infant attach-
ment, and it may delay the onset of lactogenesis in the diabetic mother.
Neubauer and colleagues306
observed that milk of women with insulin-
dependent diabetes came in later than it did in controls and had sig-
niﬁcantly lower lactose and higher total nitrogen at 2 to 3 days after
delivery. The infants of these diabetic mothers had signiﬁcantly less
milk intake 7 to 14 days after delivery than did those of the control
women. Delayed lactogenesis in the women with insulin-dependent
diabetes most likely occurred in those with poor metabolic control. A
study by van Beusekom and coauthors307
analyzed concentrations of
micronutrients and macronutrients in milk and capillary blood and
found that tight glycemic control was associated with normal propor-
tions of milk nutrients, compared with the multitude of milk abnor-
malities seen with moderate and poor control.
Evidence indicates that with proper encouragement, sustained
breastfeeding is possible for a signiﬁcant proportion of patients with
overt diabetes. Webster and coworkers308
breastfeeding habits between women with diabetes and normal women.
At discharge, 63% of mothers with insulin-dependent diabetes and
78% of mothers without diabetes were breastfeeding. At 8 weeks, the
proportions of each were nearly identical (58% and 56%, respectively),
and when the infants were 3 months old, 47% of mothers with insulin-
dependent diabetes and 33% of women without diabetes continued to
breastfeed. The study showed that IDMs were delivered atraumatically,
and infants who are well oxygenated with mature lungs and who have
excellent antecedent glucose control can be kept with their mothers
under close glycemic monitoring for the ﬁrst 1 to 2 hours of life. This
permits early breastfeeding, which may reduce the need for intrave-
nous glucose therapy.
The actual techniques of infant nursing require some modiﬁcation
in women with overt diabetes, especially insulinopenic patients
with type 1 diabetes. Increased maternal calorie and ﬂuid intake
is necessary to maintain milk supply in all women. The calorie
expenditure during nursing and for the 30 to 45 minutes thereafter
(probably during post-nursing lactogenesis) may precipitate severe
hypoglycemia if compensatory calories are not ingested. This is espe-
cially common during nursing late at night. Breastfeeding women with
type 1 diabetes should be encouraged to take in ﬂuids and food (100
to 300 calories per feeding episode) while nursing to avoid reactive
Fortunately, studies of breastfeeding women with diabetes indicate
that lactation, even for a short duration, has a beneﬁcial effect on
overall maternal glucose and lipid metabolism. For postpartum women
who have GDM during their pregnancies, breastfeeding may offer a
practical, low-cost intervention that helps to reduce or delay the risk
of subsequent diabetes.
1. Wild S, Roglic G, Green A, et al: Global prevalence of diabetes. Estimates
for the year 2000 and projections for 2030. Diabetes Care 27:1047-1053,
987CHAPTER 46 Diabetes in Pregnancy
2. National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK): Prevalence of Diabetes by Race/Ethnicity Among People Aged
20 Years or Older, United States, 2005. Available at http://diabetes.niddk.
nih.gov/pubs/statistics/index.htm#age (accessed January 2008).
3. Ferrara A, Kahn HS, Quesenberry CP, et al: An Increase in the Incidence
of Gestational Diabetes Mellitus: Northern California, 1991-2000. Obstet
Gynecol 103:526-533, 2004.
4. Harris MI, Flegal KM, Cowie CC: Prevalence of diabetes, impaired fasting
glucose and impaired glucose tolerance in US adults. Diabetes Care 21:518,
5. American Diabetes Association: ADA consensus statement: Type 2 diabe-
tes in children and adolescents. Diabetes Care 12:381-389, 2000.
6. Yang JE, Cummings EA, O’Connell C, Jangaard K: Fetal and neonatal
outcomes of diabetic pregnancies. Obstet Gynecol 108(Pt 1):644-650,
7. McElvy SS, Miodovnik M, Rosenn B, et al: A focused preconceptional and
early pregnancy program in women with type 1 diabetes reduces perinatal
mortality and malformation rates to general population levels. J Matern
Fetal Med 9:14, 2000.
8. Wylie BR, Kong J, Kozak SE, et al: Normal perinatal mortality in type 1
diabetes mellitus in a series of 300 consecutive pregnancy outcomes. Am
J Perinatol 19:169, 2002.
9. Macintosh MC, Fleming KM, Bailey JA, et al: Perinatal mortality and
congenital anomalies in babies of women with type 1 or type 2 diabetes
in England, Wales, and Northern Ireland: Population based study. BMJ
10. Rudge MV, Calderon IM, Ramos MD, et al: Perinatal outcome of pregnan-
cies complicated by diabetes and by maternal daily hyperglycemia not
related to diabetes: A retrospective 10-year analysis. Gynecol Obstet Invest
11. Kjos SL, Schaefer-Graf U, Sardesi S, et al: A randomized controlled trial
using glycemic plus fetal ultrasound parameters versus glycemic para-
meters to determine insulin therapy in gestational diabetes with fasting
hyperglycemia. Diabetes Care 24:1904-1910, 2001.
12. Expert Committee on the Diagnosis and Classiﬁcation of Diabetes Melli-
tus: Report of the Expert Committee on the Diagnosis and Classiﬁcation
of Diabetes Mellitus. Diabetes Care 20:1183-1197, 1997.
13. Expert Committee on the Diagnosis and Classiﬁcation of Diabetes Melli-
tus: Follow up Report on the diagnosis of diabetes mellitus. Diabetes Care
14. Hare JW, White P: Gestational diabetes and the White classiﬁcation. Dia-
betes Care 3:394, 1980.
15. American Diabetes Association: Clinical practice recommendations—
2007: Diagnosis and classiﬁcation of diabetes. Diabetes Care 30(Suppl 1):
16. Bergman RN, Phillips LS, Cobelli C: Physiologic evaluation of factors
controlling glucose disposition in man. Measurement of insulin sensitivity
and B-cell sensitivity from the response to intravenous glucose. J Clin
Invest 68:1456-1467, 1981.
17. Bloomgarden ZT: Development of diabetes and insulin resistance. Diabe-
tes Care 29:161-167, 2006.
18. Flegal KM, Carroll MD, Ogden Cl, Johnson LL: Prevalence and trends
in obesity among U.S. Adults, 1999-2000. JAMA 288:1728-1732,
19. American Diabetes Association: Clinical practice recommendations 2007.
Standards of Medical Care—2007. Diabetes Care 30(Suppl 1):S4-S41,
20. Proceedings of the Fourth International Workshop Conference on Gesta-
tional Diabetes Mellitus. Diabetes Care 21:B161-B167, 1998.
21. Mauricio D, de Leiva A: Autoimmune gestational diabetes mellitus: A
distinct clinical entity. Diabetes Metab Res Rev 17:422-428, 2001.
22. Catalano PM, Tyzbir ED, Sims EAH: Incidence and signiﬁcance of islet
cell antibodies in women with previous gestational diabetes mellitus. Dia-
betes Care 13:478-482, 1990.
23. Saker PJ, Hattersley AT, Barrow B, et al: High prevalence of a missense
mutation of the glucokinase gene in gestational diabetes due to a founder-
effect in a local population. Diabetalogia 39:1125-1128, 1996.
24. Zaidi FK, Wareham NJ, McCarthy MI, et al: Homozygosity for a common
polymorphism in the islet speciﬁc promoter of the glucokinase gene is
associated with a reduced early insulin response to oral glucose in preg-
nant women. Diabet Med 14:228-234, 1997.
25. Hattersley AT, Beards F, Ballantyne E, et al: Mutations in the glucokinase
gene of the fetus result in reduced birth weight. Nat Genet 19:268-270,
26. Hytten FE: Weight gain in pregnancy. In Hytten F, Chamberlain G (eds):
Clinical Physiology in Obstetrics. Oxford, UK: Blackwell Scientiﬁc, 1991,
27. Catalano PM, Tyzbir ED, Wolfe RR, et al: Longitudinal changes in basal
hepatic glucose production and suppression during insulin infusion in
normal pregnant women. Am J Obstet Gynecol 167:913-919, 1992.
28. Catalano PM, Huston L, Amini SB, Kalhan SC: Longitudinal changes in
glucose metabolism during pregnancy in obese women with normal
glucose tolerance and gestational diabetes. Am J Obstet Gynecol 180:903-
29. Matthews DR, Hosker JP, Rudenski AS, et al: Homeostasis model assess-
ment: Insulin resistance and β-cell function from fasting plasma glucose
and insulin concentrations in man. Diabetes 28:412-419, 1985.
30. Matsuda M, DeFronzo R: Insulin sensitivity indices obtained from oral
glucose tolerance testing. Diabetes Care 22:1462-1470, 1999.
31. Pacini G, Bergman RN: MINMOD: A computer program to calculate
insulin sensitivity and pancreatic responsitivity from the frequently
sampled intravenous glucose tolerance test. Comput Methods Programs
Biomed 23:113-122, 1986.
32. DeFronzo RA, Tobin JD, Andres R: Glucose clamp technique: A method
for quantifying insulin secretion and resistance. Am J Physiol 237:E214-
33. Catalano PM, Tyzbir ED, Roman NM, et al: Longitudinal changes in
insulin release and insulin resistance in non-obese pregnant women. Am
J Obstet Gynecol 165:1667-1672, 1991.
34. Catalano PM, Tyzbir ED, Wolfe RR, et al: Carbohydrate metabolism
during pregnancy in control subjects and women with gestational diabe-
tes. Am J Physiol 264:E60-E67, 1993.
35. Catalano PM, Bernstein IM, Wolfe RR, et al: Subclinical abnormalities of
glucose metabolism in former gestational diabetics subjects. Am J Obstet
Gynecol 155:1255-1262, 1986.
36. Buchanan TA: Pancreatic β-cell defects in gestational diabetes: Implica-
tions for the pathogenesis and prevention of type 2 diabetes. J Clin Endo-
crinol Metab 86:989-993, 2001.
37. Schmitz O, Klebe J, Moller J, et al: In vivo insulin action in type 1 (insulin-
dependent) diabetic pregnant women as assessed by the insulin clamp
technique. J Clin Endocrinol Metab 61:877-81, 1985.
38. Ryan EA, O’Sullivan MJ, Skyler JS: Insulin action during pregnancy:
Studies with the euglycemic clamp technique. Diabetes 34:380-389,
39. Ryan EA, Enns L: Role of gestational hormones in the induction of insulin
resistance. J Clin Endocrinol Metab 67:341-347, 1988.
40. Kalkoff RK, Kissebah AH, Rim H-J: Carbohydrate and lipid metabolism
during normal pregnancy: Relationship to gestational hormone action. In
Merkatz IR, Adam PAJ (eds): The Diabetic Pregnancy: A Perinatal Per-
spective. New York, Grune & Stratton, 1979, pp 3-21.
41. Barbieri RL: Endocrine disorders in pregnancy. In Yan SSC, Jaffe RB,
Barbier RL (eds): Reproductive Endocrinology, 4th ed. Philadelphia, WB
42. Kirwan JP, Hauguel-de Mouzon S, Lepercq J, et al: TNFα is a predictor of
insulin resistance in human pregnancy. Diabetes 51:2207-2213, 2002.
43. Xiang AH, Peters RH, Trigo E, et al: Multiple metabolic defects during late
pregnancy in women at high risk for type 2 diabetes. Diabetes 48:848-854,
44. Friedman JE, Ishizuka T, Shao J, et al: Impaired glucose transport and
insulin receptor tyrosine phosphorylation in skeletal muscle from obese
women with gestational diabetes. Diabetes 49:1807-1814, 1999.
45. Aguirre V, Werner ED, Giraud J, et al: Phosphorylation of Ser307 in insulin
receptor substrate-1 blocks interactions with the insulin receptor and
inhibits insulin action. J Biol Chem 272:1531-1537, 2002.
988 CHAPTER 46 Diabetes in Pregnancy
46. Evers IM, de Valk HW, Visser GH: Risk of complications of pregnancy
in women with type 1 diabetes: Nationwide prospective study in the
Netherlands. BMJ 328:915, 2004.
47. Elman KD, Welch RA, Frank RN, et al: Diabetic retinopathy in pregnancy:
A review. Obstet Gynecol 75:119, 1990.
48. Bhavsar AR: Diabetic retinopathy: The latest in current management.
Retina 26:S71-S79, 2006.
49. Schocket LS, Grunwald JE, Tsang AF: The effect of pregnancy on retinal
hemodynamics in diabetic versus nondiabetic mothers. Am J Ophthalmol
50. Verier-Mine O, Chaturvedi N, Webb D, Fuller JH: Is pregnancy a risk
factor for microvascular complications? The EURODIAB Prospective
Complications Study. Diabet Med 22:1503-1509, 2005.
51. The Kroc Collaborative Study Group: Diabetic retinopathy after two years
of intensiﬁed insulin treatment. Follow-up of the Kroc Collaborative
Study. JAMA 260:37-41, 1988.
52. Temple RC, Aldridge VA, Sampson MJ, et al: Impact of pregnancy on the
progression of diabetic retinopathy in type 1 diabetes. Diabet Med 18:573-
53. American Diabetes Association. Standards of medical care in diabetes.
Diabetes Care 28(Suppl 1):S4-S36, 2005.
54. U.S. Renal Data System, USRDS 2006 Annual Data Report: Atlas of End-
Stage Renal Disease in the United States. Bethesda, MD, National Institutes
of Health, National Institute of Diabetes and Digestive and Kidney Dis-
55. Eknoyan G, Hostetter T, Bakris GL, et al: Proteinuria and other markers
of chronic kidney disease: A position statement of the National
Kidney Foundation (NKF) and the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK). Am J Kidney Dis 42:617-622,
56. Reece EA, Winn HN, Hayslett JP, et al: Does pregnancy alter the rate of
progression of diabetic nephropathy? Am J Perinatol 7:193, 1990.
57. Imbasciati E, Gregorini G, Cabiddu G, et al: Pregnancy in CKD stages 3
to 5: Fetal and maternal outcomes. Am J Kidney Dis 49:753-762, 2007.
58. Rossing K, Jacobsen P, Hommel E, et al: Pregnancy and progression of
diabetic nephropathy. Diabetologia 45:36, 2002.
59. Jovanovic R, Jovanovic L: Obstetric management when normoglycemia is
maintained in diabetic pregnant women with vascular compromise. Am
J Obstet Gynecol 149:617, 1984.
60. Reece EA, Leguizamon G, Homko C: Pregnancy performance and
outcomes associated with diabetic nephropathy. Am J Perinatol 15:413,
61. Purdy LP, Hantsch CE, Molitch ME, et al: Effect of pregnancy on renal
function in patients with moderate-to-severe diabetic renal insufﬁciency.
Diabetes Care 19:1067-1074, 1996.
62. Ekbom P, Damm P, Feldt-Rasmussen B, et al: Pregnancy outcome in type
1 diabetic women with microalbuminuria. Diabetes Care 24:1739, 2001.
63. Hou S: Historical perspective of pregnancy in chronic kidney disease. Adv
Chronic Kidney Dis 14:116-118, 2007.
64. Reddy SS, Holley JL: Management of the pregnant chronic dialysis patient.
Adv Chronic Kidney Dis 14:146-155, 2007.
65. Romao JE Jr, Luders C, Kahhale S, et al: Pregnancy in women on chronic
dialysis: A single-center experience with 17 cases. Nephron 78:416, 1998.
66. Gomez Vazquez JA, Martinez Calva IE, Mendiola Fernandez R, et al:
Pregnancy in end-stage renal disease patients and treatment with perito-
neal dialysis: Report of two cases. Perit Dial Int 27:353-358, 2007.
67. Davison JM: Renal transplantation in pregnancy. Am J Kidney Dis 9:374,
68. Yassaee F, Moshiri F: Pregnancy outcome in kidney transplant patients.
Urol J 4:14-17, 2007.
69. Kashanizadeh N, Nemati E, Shariﬁ-Bonab M, et al: Impact of pregnancy
on the outcome of kidney transplantation. Transplant Proc 39:1136-1138,
70. Gabbe SG, Mestman JH, Freeman RK, et al: Management and outcome of
diabetes mellitus. Am J Obstet Gynecol 127:465, 1977.
71. Gabbe SG, Mestman JH, Freeman RK, et al: Management and outcome of
diabetes mellitus, classes B to R: Am J Obstet Gynecol 129:723, 1977.
72. Feig DS, Razzaq A, Sykora K, et al: Trends in deliveries, prenatal care, and
obstetrical complications in women with pregestational diabetes: A popu-
lation-based study in Ontario, Canada, 1996-2001. Diabetes Care 29:232-
73. Chobanian AV, Bakris GL, Black HR, et al: The seventh report of the Joint
National Committee on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure: The JNC 7 report. JAMA 289:2560-2572, 2003.
74. Sibai BM: Risk factors, pregnancy complications, and prevention of
hypertensive disorders in women with pregravid diabetes mellitus.
J Matern Fetal Med 9:62, 2000.
75. Leguizamon G, Reece EA: Effect of medical therapy on progressive
nephropathy: Inﬂuence of pregnancy, diabetes and hypertension. J Matern
Fetal Med 9:70-78, 2000.
76. Peterson CM, Jovanovic-Peterson L, Mills JL, et al: Changes in cholesterol,
triglycerides, body weight, and blood pressure: The National Institute of
Child Health and Human Development—the Diabetes in Early Pregnancy
Study. Am J Obstet Gynecol 166:513, 1992.
77. Airaksinen KEJ, Ikaheimo MJ, Salmela PI, et al: Impaired cardiac adjust-
ment to pregnancy in type 1 diabetes. Diabetes Care 9:376, 1986.
78. Silfen SL, Wapner RL, Gabbe SG: Maternal outcome in class H diabetes
mellitus. Obstet Gynecol 56:749, 1980.
79. Gordon MC, Landon MB, Boyle J, et al: Coronary artery disease in insulin-
dependent diabetes mellitus of pregnancy (class H): A review of the litera-
ture. Obstet Gynecol Surv 51:437, 1996.
80. Reece EA, Egan JFX, Coustan DR, et al: Coronary artery disease in diabetic
pregnancies. Am J Obstet Gynecol 154:150, 1986.
81. Carroll MA, Yeomans ER: Diabetic ketoacidosis in pregnancy. Crit Care
Med 33:S347-S353, 2005.
82. Cullen MT, Reece EA, Homko CJ, et al: The changing presentations of
diabetic ketoacidosis during pregnancy. Am J Perinatol 13:449, 1996.
83. American College of Obstetricians and Gynecologists (ACOG): Clinical
management guidelines for obstetrician-gynecologists. ACOG practice
bulletin no. 60, March 2005. Pregestational diabetes mellitus. Obstet
Gynecol 105:675-685, 2005.
84. Sutherland HW, Pritchard CW: Increased incidence of spontaneous
abortion in pregnancies complicated by maternal diabetes mellitus. Am J
Obstet Gynecol 155:135, 1986.
85. Miodovnik M, Lavin JP, Knowles HC, et al: Spontaneous abortion among
insulin-dependent diabetic women. Am J Obstet Gynecol 150:372,
86. Jovanovic L, Knopp RH, Kim H, et al: Elevated pregnancy losses at high
and low extremes of maternal glucose in early normal and diabetic
pregnancy: Evidence for a protective adaptation in diabetes. Diabetes Care
87. Platt MJ, Stanisstreet M, Casson IF, et al: St Vincent’s declaration 10 years
on: Outcomes of diabetic pregnancies. Diabet Med 19:216, 2002.
88. Reece EA, Sivan E, Francis G, et al: Pregnancy outcomes among
women with and without diabetic microvascular disease (White’s
classes B to FR) versus non-diabetic controls. Am J Perinatol 15:549,
89. Miller E, Hare JW, Cloherty JP, et al: Elevated maternal hemoglobin A1c
in early pregnancy and major congenital anomalies in infants of diabetic
mothers. N Engl J Med 304:1331, 1981.
90. Lucas MJ, Leveno KJ, Williams ML, et al: Early pregnancy glycosylated
hemoglobin, severity of diabetes, and fetal malformations. Am J Obstet
Gynecol 161:426, 1989.
91. Eriksson UJ, Borg LA, Cederberg J, et al: Pathogenesis of diabetes-induced
congenital malformations. Ups J Med Sci 105:53, 2000.
92. Warso MA, Lands WEM: Lipid peroxidation in relation to prostacyclin
and thromboxane physiology and pathophysiology. Br Med Bull 39:277,
93. Pinter E, Reece EA, Leranth CZ, et al: Arachidonic acid prevents
hyperglycemia-associated yolk sac damage and embryopathy. Am J Obstet
Gynecol 155:691, 1986.
94. El-Bassiouni EA, Helmy MH, Abou Rawash N, et al: Embryopathy in
experimental diabetic gestation: Assessment of oxidative stress and anti-
oxidant defence. Br J Biomed Sci 62:71-76, 2005.
989CHAPTER 46 Diabetes in Pregnancy
95. Cederberg J, Eriksson UJ: Antioxidative treatment of pregnant diabetic
rats diminishes embryonic dysmorphogenesis. Birth Defects Res A Clin
Mol Teratol 73:498-505, 2005.
96. Fuhrmann K, Reiher H, Semmler K, et al: Prevention of congenital mal-
formations in infants of insulin-dependent diabetic mothers. Diabetes
Care 6:219, 1983.
97. Cederberg J, Siman CM, Eriksson UJ: Combined treatment with vitamin
E and vitamin C decreases oxidative stress and improves fetal outcome in
experimental diabetic pregnancy. Pediatr Res 49:755, 2001.
98. Van Assche FA, Holemans K, Aerts L: Long-term consequences
for offspring of diabetes during pregnancy. Br Med Bull 60:173,
99. Padmanabhan R, Shaﬁullah M: Intrauterine growth retardation in experi-
mental diabetes: Possible role of the placenta. Arch Physiol Biochem
100. Moulton CR: Age and chemical development in mammals. J Biol Chem
101. Sparks JW: Human intrauterine growth and nutrient accretion. Semin
Perinatol 8:74-93, 1984.
102. Girard J, Ferre P: Metabolic and hormonal changes around birth. In Jones
CT (ed): Biochemical Development of the Fetus and Neonate. New York,
Elsevier Biomedical Press, 1982, p 517.
103. Ogata ES, Sabbagha R, Metzger B, et al: Serial ultrasonography to assess
evolving fetal macrosomia. Studies in 23 pregnant diabetic women. JAMA
104. Kehl RJ, Krew MA, Thomas A, Catalano PM: Fetal growth and body
composition in infants of women with diabetes mellitus. J Matern Fetal
Med 5:273-280, 1996.
105. Reece EA, Winn HN, Smikle C, et al: Sonographic assessment of growth
of the fetal head in diabetic pregnancies compared with normal gestations.
Am J Perinatol 7:18-22, 1990.
106. Bernstein IM, Goran MI, Amini SB, Catalano PM: Differential growth of
fetal tissues during the second half of pregnancy. Am J Obstet Gynecol
107. Catalano PM, Thomas A, Huston-Presley L, Amini SB: Increased fetal
adiposity: A very sensitive marker of abnormal in utero development. Am
J Obstet Gynecol 189:1698-1704, 2003.
108. Jovanovic-Peterson L, Peterson CM, Reed GF, et al: Maternal postprandial
glucose levels and infant birth weight: The diabetes in early pregnancy
study. The National Institutes of Child Health and Human Develop-
ment—Diabetes in Early Pregnancy study. Am J Obstet Gynecol 164:103-
109. Combs CA, Gunderson E, Kitzmiller J, et al: Relationship of fetal macro-
somia to maternal postprandial glucose control during pregnancy. Diabe-
tes Care 15:1251-1257, 1992.
110. Persson B, Hason U: Fetal size at birth in relation to quality of blood
glucose control in pregnancies complicated by pregestational diabetes
mellitus. BJOG 103:427-433, 1996.
111. Uvena-Celebrezze J, Fung C, Thomas AJ, et al: Relationship of neonatal
body composition to maternal glucose control in women with gestational
diabetes mellitus. J Matern Fetal Neonatal Med 12:396-401, 2002.
112. Pedersen J: The pregnant diabetic and her newborn. In Problems
and Management, 2nd ed. Baltimore, MD, Williams & Wilkins,
113. Susa JB, Boylan JM, Sehgal P, Schwartz R: Impaired insulin secretion in
the neonatal monkey after chronic hyperinsulinemia in utero. Proc Soc
Exp Biol Med 194:209-215, 1990.
114. Schwartz R, Grupposo PA, Petzold K, et al: Hyperinsulinemia and macro-
somia in the fetus of the diabetic mother. Diabetes Care 17:640-648,
115. Salvesen DR, Brudenell JM, Proudler AJ, et al: Fetal pancreatic beta-cell
function in pregnancies complicated by maternal diabetes mellitus: Rela-
tionship to fetal academia and macrosomia. Am J Obstet Gynecol
116. Krew MA, Kehl RJ, Thomas A, Catalano PM: Relationship of amniotic
ﬂuid C-peptide levels to neonatal body composition. Obstet Gynecol
117. Carpenter MW, Canick JA, Hogan JW, et al: Amniotic ﬂuid insulin at 14-
20 weeks’ gestation: Association with maternal glucose intolerance and
birth macrosomia. Diabetes Care 24:1259-1263, 2001.
118. Ong K, Kratzsch J, Kiess W, et al: Size at birth and cord blood levels of
insulin, insulin-like growth factors I (IGF-I), IGF-II, IGF-binding protein-
1 (IGFBP-1), IGFBP-3 and the soluble IGF-II/mannose-6-phosphate
receptor in term human infants. The ALSPAC Study Team. Avon Longi-
tudinal Study of Pregnancy and Childhood. J Clin Endocrinol Metab
119. Baker J, Liu JP, Robertson EJ, Efstratiadis A: Role of insulin-like
growth factors in embryonic and postnatal growth. Cell 75:73-82,
120. Liu YJ, Tsushima T, Minei S, et al: Insulin-like growth factors (IGFs) and
IGF-binding proteins (IGFBP-1, -2 and -3) in diabetic pregnancy: Rela-
tionship to macrosomia. Endocr J 43:221-231, 1996.
121. Delmis J, Drazancic A, Ivanisevic M, Suchanek E: Glucose, insulin HGH
and IGF-I levels in maternal serum, amniotic ﬂuid and umbilical venous
serum: A comparison between late normal pregnancy and pregnancies
complicated with diabetes and fetal growth retardation. J Perinat Med
122. Lauszus FF, Klebe JG, Flyvbjerg A: Macrosomia associated with maternal
serum insulin-like growth factor-I and -II in diabetic pregnancy. Obstet
Gynecol 97:734-741, 2001.
123. Roth S, Abernathy MP, Lee WH, et al: Insulin-like growth factors I and II
peptide and messenger RNA levels in macrosomic infants of diabetic
pregnancies. J Soc Gynecol Invest 3:78-84, 1996.
124. Radaelli T, Uvena-Celebrezze J, Minium J, et al: Maternal interleukin-6:
Marker of fetal growth and adiposity. J Soc Gynecol Invest 13:53-57,
125. World Health Organization (WHO): Obesity: Preventing and Managing
a Global Epidemic. Technical support series no. 894. Geneva, World
Health Organization, 2000, pp 1-4.
126. Vohr BR, McGarvey ST, Coll CG: Effects of maternal gestational diabetes
and adiposity on neonatal adiposity and blood pressure. Diabetes Care
127. Catalano PM, Ehrenberg HM: The short and long term implications of
maternal obesity on the mother and her offspring. BJOG 113:1126-1133,
128. Freinkel N: The Banting Lecture, 1980: Of pregnancy and progeny. Dia-
betes 29:1023, 1980.
129. Duggleby SL, Jackson AA: Protein, amino acid and nitrogen metabolism
during pregnancy: How might the mother meet the needs of her fetus?
Curr Opin Clin Nutr Metab Care 5:503-509, 2002.
treated gestational diabetes. Diabetes Care 22:806-811, 1999.
131. Metzger BE, Phelps RL, Freinkel N, Navickas IA: Effects of gestational
diabetes on diurnal proﬁles of plasma glucose, lipids and individual amino
acids. Diabetes Care 3:402-409, 1980.
132. Zimmer DM, Golichowski AM, Karn CA, et al: Glucose and amino acid
turnover in untreated gestational diabetes. Diabetes Care 19:591-596,
133. Kalhan SC, Denne SC, Patel DM, et al: Leucine kinetics during a brief
fast in diabetes in pregnancy. Metab Clin Exp 43:378-384, 1994.
134. Knopp RH, Humphrey J, Irvin S: Biphasic metabolic control of hypertri-
glyceridemia in pregnancy. Clin Res 25:161A, 1977.
135. Knopp RH, Chapman M, Bergelin RO, et al: Relationship of lipoprotein
lipids to mild fasting hyperglycemia and diabetes in pregnancy. Diabetes
Care 3:416-420, 1980.
136. Xiang AH, Peters RK, Trigo E, et al: Multiple metabolic defects during late
pregnancy in women at high risk for type 2 diabetes. Diabetes 48:848-854,
137. Knopp RH, Magee MS, Walden CE, et al: Prediction of infant birth weight
by GDM screening test. Importance of plasma triglyceride. Diabetes Care
138. Kitajima M, Satoshi O, Yasuhi I, et al: Maternal serum triglyceride at 24-32
weeks’ gestation and newborn weight in nondiabetic women with positive
diabetic screens. Obstet Gynecol 97:776-789, 2001.
990 CHAPTER 46 Diabetes in Pregnancy
139. Gilbert WM, Nesbitt TS, Danielsen B: Associated factors in 1611 cases of
brachial plexus injury. Obstet Gynecol 93:536, 1999.
140. Athukorala C, Crowther CA, Willson K: Women with gestational diabetes
mellitus in the ACHOIS trial: Risk factors for shoulder dystocia. Aust N
Z J Obstet Gynaecol 47:37-41, 2007.
141. Langer O, Berkus MD, Huff RW, et al: Shoulder dystocia: Should the fetus
weighing greater than or equal to 4000 grams be delivered by cesarean
section? Am J Obstet Gynecol 165:831, 1991.
142. Nesbitt TS, Gilbert WM, Herrchen B: Shoulder dystocia and associated
risk factors with macrosomic infants born in California. Am J Obstet
Gynecol 179:476, 1998.
143. Sandmire HF, O’Halloin TJ: Shoulder dystocia: Its incidence and associ-
ated risk factors. Int J Gynaecol Obstet 26:65, 1988.
144. Widness JA, Teramo KA, Clemons GK, et al: Direct relationship
of antepartum glucose control and fetal erythropoietin in human
type 1 (insulin dependent) diabetic pregnancy. Diabetologia 33:378,
145. Alam M, Raza SJ, Sherali AR, Akhtar AS: Neonatal complications in
infants born to diabetic mothers. J Coll Physicians Surg Pak 16:212-215,
146. Banerjee S, Ghosh US, Banerjee D: Effect of tight glycaemic control on
fetal complications in diabetic pregnancies. J Assoc Physicians India
147. Taylor R, Lee C, Kyne-Grzebalski D, et al: Clinical outcomes of pregnancy
in women with type 1 diabetes (1). Obstet Gynecol 99:537, 2002.
148. Cordero L, Treuer SH, Landon MB, et al: Management of infants of dia-
betic mothers. Arch Pediatr Adolesc Med 152:249, 1998.
149. Halliday HL: Hypertrophic cardiomyopathy in infants of poorly-con-
trolled diabetic mothers. Arch Dis Child 56:258, 1981.
150. Mace S, Hirschfeld SS, Riggs T, et al: Echocardiographic abnormalities in
infants of diabetic mothers. J Pediatr 95:1013, 1979.
151. Kjos SL, Walther FJ, Montoro M, et al: Prevalence and etiology of respira-
tory distress in infants of diabetic mothers: Predictive value of fetal lung
maturation tests. Am J Obstet Gynecol 163:898, 1990.
152. Jaeggi ET, Fouron JC, Proulx F: Fetal cardiac performance in uncompli-
cated and well-controlled maternal type I diabetes. Ultrasound Obstet
Gynecol 17:311, 2001.
153. Hayati AR, Cheah FC, Tan AE, Tan GC: Insulin-like growth factor-1 recep-
tor expression in the placentae of diabetic and normal pregnancies. Early
Hum Dev 83:41-46, 2007.
154. Halse KG, Lindegaard ML, Goetze JP, et al: Increased plasma pro-B-type
natriuretic peptide in infants of women with type 1 diabetes. Clin Chem
155. Cooper MJ, Enderlein MA, Dyson DC, et al: Fetal echocardiography:
Retrospective review of clinical experience and an evaluation of indica-
tions. Obstet Gynecol 86:577, 1995.
156. Frantz ID, Epstein MF: Fetal lung development in pregnancies compli-
cated by diabetes. Semin Perinatol 2:347-352, 1978.
157. Robert MF, Neff RK, Hubbell JP, et al: Association between maternal
diabetes and the respiratory distress syndrome. N Engl J Med 12:357,
158. Kulovich MV, Gluck L: The lung proﬁle. II. Complicated pregnancy. Am
J Obstet Gynecol 135:64, 1979.
159. Tabsh KM, Brinkman CR III, Bashore RA: Lecithin:sphingomyelin ratio
in pregnancies complicated by insulin-dependent diabetes mellitus. Obstet
Gynecol 59:353, 1982.
160. Ojomo EO, Coustan DR: Absence of evidence of pulmonary maturity at
amniocentesis in term infants of diabetic mothers. Am J Obstet Gynecol
161. Tyden O, Berne C, Eriksson UJ, et al: Fetal maturation in strictly controlled
diabetic pregnancy. Diabetes Res 1:131, 1984.
162. Landon MB, Gabbe SG, Piana R, et al: Neonatal morbidity in pregnancy
complicated by diabetes mellitus: Predictive value of maternal glycemic
proﬁles. Am J Obstet Gynecol 156:1089, 1987.
163. Moore TR: A comparison of amniotic ﬂuid fetal pulmonary phospholip-
ids in normal and diabetic pregnancy. Am J Obstet Gynecol 186:641,
164. Garn SM, Clark DC: Trends in fatness and the origins of obesity. Pediatrics
165. Curhan GC, Cherton GM, Willet WC, et al: Birth weight and adult hyper-
tension and obesity in women. Circulation 94:1310-1315, 1996.
166. Curhan GC, Willett WC, Rimm EB, et al: Birth weight and adult hyperten-
sion, diabetes mellitus and obesity in U.S. men. Circulation 94:3246-3250,
167. Martorell R, Stein AD, Schroeder DG: Early nutrition and adiposity. J Nutr
168. Mokdad AH, Ford ES, Bowman BA, et al: Diabetes trends in the U.S.
1990-1998. Diabetes Care 23:1278-1283, 2000.
169. Sinha R, Fisch G, Teague B, et al: Prevalence of impaired glucose tolerance
among children and adolescents with marked obesity. N Engl J Med
170. Whitaker RC: Predicting preschooler obesity at birth: The role of maternal
obesity in early pregnancy. Pediatrics 114:29-36, 2004.
171. Langer O, Yogev Y, Xenakis EMJ, Brustman L: Overweight and obese in
gestational diabetes: The impact on pregnancy outcome. Am J Obstet
Gynecol 192:1368-1376, 2005.
172. Dabelea D, Hanson RL, Lindsay RS, et al: Intrauterine exposure to diabetes
conveys risks for type 2 diabetes and obesity: A study of discordant sib-
ships. Diabetes 49:2208-2211, 2000.
173. Boney CM, Verma A, Tucker R, Vohr BR: Metabolic syndrome in child-
hood: Association with birth weight, maternal obesity and gestational
diabetes mellitus. Pediatrics 115:290-296, 2005.
174. Rizzo TA, Metzger BE, Burns WJ, et al: Correlations between antepartum
maternal metabolism and intelligence of offspring. N Engl J Med 325:911,
175. Ornoy A, Ratzon N, Greenbaum C, et al: School-age children born to
diabetic mothers and to mothers with gestational diabetes exhibit a high
rate of inattention and ﬁne and gross motor impairment. J Pediatr Endo-
crinol Metab 14(Suppl 1):681, 2001.
176. Varughese GI, Chowdhury SR, Warner DP, Barton DM: Preconception
care of women attending adult general diabetes clinics—are we doing
enough? Diabetes Res Clin Pract 76:142-145, 2007.
177. Jovanovic L, Nakai Y: Successful pregnancy in women with type 1 diabetes:
From preconception through postpartum care. Endocrinol Metab Clin
North Am 35:79-97, vi, 2006.
178. Dunne FP, Brydon P, Smith T, et al: Pre-conception diabetes care in
insulin-dependent diabetes mellitus. QJM 92:175, 1999.
179. Rendell MS, Jovanovic L: Targeting postprandial hyperglycemia. Metabo-
lism 55:1263-1281, 2006.
180. UK Prospective Diabetes Study Group: Tight blood pressure control and
risk of macrovascular and microvascular complications in type 2 diabetes.
BMJ 317:703, 1998.
181. Jakubowicz DJ, Iuorno MJ, Jakubowicz S, et al: Effects of metformin on
early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol
Metab 87:524, 2002.
182. Glueck CJ, Phillips H, Cameron D, et al: Continuing metformin through-
out pregnancy in women with polycystic ovary syndrome appears to safely
reduce ﬁrst-trimester spontaneous abortion: A pilot study. Fertil Steril
183. Glueck CJ, Wang P, Kobayashi S, et al: Metformin therapy throughout
pregnancy reduces the development of gestational diabetes in women with
polycystic ovary syndrome. Fertil Steril 77:520, 2002.
184. Nanovskaya TN, Nekhayeva IA, Patrikeeva SL, et al: Transfer of metformin
across the dually perfused human placental lobule. Am J Obstet Gynecol
185. Charles B, Norris R, Xiao X, Hague W: Population pharmacokinetics of
metformin in late pregnancy. Ther Drug Monit 28:67-72, 2006.
186. Gilbert C, Valois M, Koren G: Pregnancy outcome after ﬁrst-trimester
exposure to metformin: A meta-analysis. Fertil Steril 86:658-663, 2006.
187. Hughes RC, Rowan JA: Pregnancy in women with type 2 diabetes: Who
takes metformin and what is the outcome? Diabet Med 23:318-322,
188. Glueck CJ, Wang P: Metformin before and during pregnancy and lactation
in polycystic ovary syndrome. Expert Opin Drug Saf 6:191-198, 2007.
991CHAPTER 46 Diabetes in Pregnancy
189. Arauz-Pacheco C, Parrott MA, Raskin P: The treatment of hypertension
in adult patients with diabetes. Diabetes Care 25:134-147, 2002.
190. Buttar HS: An overview of the inﬂuence of ACE inhibitors on fetal-
placental circulation and perinatal development. Mol Cell Biochem
191. Briggs GG, Nageotte MP: Fatal fetal outcome with the combined use of
valsartan and atenolol. Ann Pharmacother 35:859, 2001.
192. American Diabetes Association: Gestational diabetes mellitus. Diabetes
Care 27(Suppl 1):S88, 2004.
193. Naylor CD, Sermer M, Chen E, et al: Selective screening for gestational
diabetes mellitus. N Engl J Med 337:1591, 1997.
194. Metzger BE, Coustan DR: Summary and recommendations of the Fourth
International Workshop-Conference on Gestational Diabetes Mellitus.
The Organizing Committee. Diabetes Care 21(Suppl 2):B161, 1998.
195. Metzger BE, Buchanan TA, Coustan DR, et al: Summary and Recommen-
dations of the Fifth International Workshop-Conference on Gestational
Diabetes Mellitus. Diabetes Care 30:S251-S260, 2007.
196. American College of Obstetricians and Gynecologists (ACOG): Clinical
management guidelines for obstetrician-gynecologists. ACOG practice
bulletin no. 30, September 2001. Obstet Gynecol 98:525, 2001.
197. Mello G, Elena P, Ognibene A, et al: Lack of concordance between the 75-g
and 100-g glucose load tests for the diagnosis of gestational diabetes mel-
litus. Clin Chem 52:1679-1684, 2006.
198. Brody SC, Harris R, Lohr K: Screening for gestational diabetes: A summary
of the evidence for the U.S. Preventive Services Task Force. Obstet Gynecol
199. Dooley SL, Metzger BE, Cho NH, et al: The inﬂuence of demographic and
phenotypic heterogeneity on the prevalence of gestational diabetes melli-
tus. Int J Gynaecol Obstet 35:13, 1991.
200. Bobrowski RA, Bottoms SF, Micallef JA, Dombrowski MP: Is the 50-gram
glucose screening test ever diagnostic? J Matern Fetal Med 5:317, 1996.
201. Berkus MD, Langer O: Glucose tolerance test: degree of glucose abnormal-
ity correlates with neonatal outcome. Obstet Gynecol 81:344, 1993.
202. Langer O, Brustman L, Anyaegbunam A, et al: The signiﬁcance of one
abnormal glucose tolerance test value on adverse outcome in pregnancy.
Am J Obstet Gynecol 157:758, 1987.
203. McLaughlin GB, Cheng YW, Caughey AB: Women with one elevated 3-
hour glucose tolerance test value: Are they at risk for adverse perinatal
outcomes? Am J Obstet Gynecol 194:e16-e19, 2006.
204. Roberts AB, Court DJ, Henley P, et al: Fructosamine in diabetic pregnancy.
Lancet 2:998, 1983.
205. Roberts AB, Baker JR: Relationship between fetal growth and maternal
fructosamine in diabetic pregnancy. Obstet Gynecol 70:242, 1987
206. Page RC, Kirk BA, Fay T, et al: Is macrosomia associated with poor gly-
caemic control in diabetic pregnancy? Diabet Med 13:170, 1996.
207. Nasrat H, Fageeh W, Abalkhail B, et al: Determinants of pregnancy
outcome in patients with gestational diabetes. Int J Gynaecol Obstet
208. Huter O, Brezinka C, Sölder E, et al: Postpartum diabetes screening: Value
of fructosamine determination [in German]. Zentralbl Gynakol 114:18,
209. Shah BD, Cohen AW, May C: Comparison of glycohemoglobin determina-
tion and the one-hour oral glucose screen in the identiﬁcation of gesta-
tional diabetes. Am J Obstet Gynecol 144:774, 1982.
210. Baxi L, Barad D, Reece EA, et al: Use of glycosylated hemoglobin as a
screen for macrosomia in gestational diabetes. Obstet Gynecol 64:347,
211. Artal R, Mosley GM, Dorey FJ: Glycohemoglobin as a screening test for
gestational diabetes. Am J Obstet Gynecol 148:412, 1984.
212. Agarwal MM, Hughes PF, Punnose J, et al: Gestational diabetes screening
of a multiethnic, high-risk population using glycated proteins. Diabetes
Res Clin Pract 51:67, 2001.
213. Moses R, Grifﬁths RD, Davis W: Gestational diabetes: Do all women need
to be tested? Aust N Z J Obstet Gynaecol 35:387, 1995.
214. American College of Obstetricians and Gynecologists (ACOG): Gesta-
tional diabetes. ACOG practice bulletin no. 30. Obstet Gynecol 98:525,
215. Coustan DR, Widness JA, Carpenter MW, et al: Should the ﬁfty-gram,
one-hour plasma glucose screening test for gestational diabetes be
administered in the fasting or fed state? Am J Obstet Gynecol 154:1031,
216. Sermer M, Naylor CD, Gare D, et al: Impact of time since last meal on the
gestational glucose challenge test. Am J Obstet Gynecol 171:607, 1994.
217. Major CA, Henry MJ, De Veciana M, et al: The effects of carbohydrate
restriction in patients with diet-controlled gestational diabetes. Obstet
Gynecol 91:600, 1998.
218. Crapo PA, Insel J, Sperling MA, et al: Comparison of serum glucose,
insulin and glucagon responses to different types of complex carbohydrate
in non–insulin-dependent diabetic patients. Am J Clin Nutr 34:184,
219. Churchill JA, Berrendes H, Nemore W, et al: Neuropsychological deﬁcits
in children of diabetic mothers: A report from the Collaborative Study of
Cerebral Palsy. Am J Obstet Gynecol 105:257, 1969.
220. Coetzee EJ, Jackson WPU, Berman PA: Ketonuria in pregnancy—with
special reference to calorie-restricted food intake in obese diabetics. Dia-
betes 29:177, 1980.
221. Parﬁtt VJ, Clark JD, Turner GM, et al: Use of fructosamine and glycated
haemoglobin to verify self blood glucose monitoring data in diabetic
pregnancy. Diabet Med 10:162, 1993.
222. Goldberg JD, Franklin B, Lasser D, et al: Gestational diabetes: Impact of
home glucose monitoring on neonatal birth weight. Am J Obstet Gynecol
223. Jovanovic-Peterson L: What is so bad about a prolonged pregnancy? J Am
Coll Nutr 10:1, 1991.
224. de Veciana M, Trail PA, Evans AT, et al: A comparison of oral acarbose and
insulin in women with gestational diabetes mellitus. Am J Obstet Gynecol
225. Cousins L, Rigg L, Hollingsworth D, et al: The 24-hour excursion and
diurnal rhythm of glucose, insulin and C peptide in normal pregnancy.
Am J Obstet Gynecol 136:483, 1980.
226. Parretti E, Mecacci F, Papini M, et al: Third-trimester maternal glucose
levels from diurnal proﬁles in nondiabetic pregnancies: Correlation with
sonographic parameters of fetal growth. Diabetes Care 24:1317, 2001.
227. Yogev Y, Ben-Haroush A, Chen R, et al: Diurnal glycemic proﬁle in obese
and normal weight nondiabetic pregnant women. Am J Obstet Gynecol
228. Lepore M, Pampanelli S, Fanelli C, et al: Pharmacokinetics and pharma-
codynamics of subcutaneous injection of long-acting human insulin
analog glargine, NPH insulin, and Ultralente human insulin and continu-
ous subcutaneous infusion of insulin lispro. Diabetes 49:2142, 2000.
229. Langer O: Maternal glycemic criteria for insulin therapy in gestational
diabetes mellitus. Diabetes Care 21(Suppl 2):B91, 1998.
230. Holcberg G, Tsadkin-Tamir M, Sapir O, et al: Transfer of insulin lispro
across the human placenta. Eur J Obstet Gynecol Reprod Biol 115:117-
231. Bhattacharyya A, Brown S, Hughes S, et al: Insulin lispro and regular
insulin in pregnancy. QJM 94:255, 2001.
232. Hermansen K, Vaaler S, Madsbad S, et al: Postprandial glycemic control
with biphasic insulin aspart in patients with type 1 diabetes. Metabolism
233. Bode B, Weinstein R, Bell D, et al: Comparison of insulin aspart with
buffered regular insulin and insulin lispro in continuous subcutaneous
insulin infusion: A randomized study in type 1 diabetes. Diabetes Care
234. Cypryk K, Sobczak M, Pertynska-Marczewska M, et al: Pregnancy com-
plications and perinatal outcome in diabetic women treated with Humalog
(insulin lispro) or regular human insulin during pregnancy. Med Sci
Monit 10:PI29-PI32, 2004.
235. Di Cianni G, Volpe L, Ghio A, et al: Maternal metabolic control and peri-
natal outcome in women with gestational diabetes mellitus treated with
lispro or aspart insulin: Comparison with regular insulin. Diabetes Care
236. Mathiesen ER, Kinsley B, Amiel SA, et al: Maternal glycemic control and
hypoglycemia in type 1 diabetic pregnancy: A randomized trial of insulin
992 CHAPTER 46 Diabetes in Pregnancy
aspart versus human insulin in 322 pregnant women. Diabetes Care
237. Pettitt DJ, Ospina P, Kolaczynski JW, Jovanovic L: Comparison of an
insulin analog, insulin aspart, and regular human insulin with no insulin
in gestational diabetes mellitus. Diabetes Care 26:183, 2003.
238. Gillies PS, Figgitt DP, Lamb HM: Insulin glargine. Drugs 59:253, 2000.
239. Price N, Bartlett C, Gillmer M: Use of insulin glargine during pregnancy:
A case-control pilot study. BJOG 114:453-457, 2007.
240. Woolderink JM, van Loon AJ, Storms F, et al: Use of insulin glargine
during pregnancy in seven type 1 diabetic women. Diabetes Care 28:2594,
241. Hofmann T, Horstmann G, Stammberger I: Evaluation of the reproductive
toxicity and embryotoxicity of insulin glargine (LANTUS) in rats and
rabbits. Int J Toxicol 21:181, 2002.
242. Gabbe SG, Holing E, Temple P, et al: Beneﬁts, risks, costs, and patient sat-
isfaction associated with insulin pump therapy for the pregnancy compli-
cated by type 1 diabetes mellitus. Am J Obstet Gynecol 182:1283, 2000.
243. Simmons D, Thompson CF, Conroy C, et al: Use of insulin pumps in
pregnancies complicated by type 2 diabetes and gestational diabetes in a
multiethnic community. Diabetes Care 24:2078, 2001.
244. Gimenez M, Conget I, Nicolau J, et al: Outcome of pregnancy in women
with type 1 diabetes intensively treated with continuous subcutaneous
insulin infusion or conventional therapy. A case-control study. Acta Dia-
betol 44:34-37, 2007.
245. Hieronimus S, Cupelli C, Bongain A, et al: Pregnancy in type 1 diabetes:
Obstet Fertil 33:389-394, 2005.
246. Lapolla A, Dalfra MG, Masin M, et al: Analysis of outcome of pregnancy
in type 1 diabetics treated with insulin pump or conventional insulin
therapy. Acta Diabetol 40:143-149, 2003.
247. Caruso A, Lanzone A, Bianchi V, et al: Continuous subcutaneous insulin
infusion (CSII) in pregnant diabetic patients. Prenat Diagn 7:41, 1987.
248. McFarland MB, Langer O, Conway DL, et al: Dietary therapy for gesta-
tional diabetes: How long is long enough? Obstet Gynecol 93:978, 1999.
249. Crowther CA, Hiller JE, Moss JR, et al: Effect of treatment of gestational
diabetes mellitus on pregnancy outcomes. N Engl J Med 352:2477-2486,
250. Pirc LK, Owens JA, Crowther CA, et al: Mild gestational diabetes in preg-
nancy and the adipoinsular axis in babies born to mothers in the ACHOIS
randomised controlled trial. BMC Pediatr 7:18, 2007.
251. Jovanovic-Peterson L, Bevier W, Peterson CM: The Santa Barbara County
Health Care Services Program: Birth weight change concomitant with
screening for and treatment of glucose-intolerance of pregnancy: A poten-
tial cost-effective intervention? Am J Perinatol 14:221, 1997.
252. Buchanan TA, Kjos SL, Montoro MN, et al: Use of fetal ultrasound to
select metabolic therapy for pregnancies complicated by mild gestational
diabetes. Diabetes Care 17:275, 1994.
253. Zucker P, Simon G: Prolonged symptomatic neonatal hypoglycemia
associated with maternal chlorpropamide therapy. Pediatrics 42:824,
254. Piacquadio K, Hollingsworth DR, Murphy H: Effects of in-utero exposure
to oral hypoglycaemic drugs. Lancet 338:866, 1991.
255. Towner D, Kjos SL, Leung B, et al: Congenital malformations in pregnan-
cies complicated by NIDDM. Diabetes Care 18:1446, 1995.
256. Kolterman OG: Glyburide in non-insulin-dependent diabetes: An update.
Clin Ther 14:196, 1992.
257. Koren G: Glyburide and fetal safety: Transplacental pharmacokinetic con-
siderations. Reprod Toxicol 15:227, 2001.
258. Elliott BD, Langer O, Schenker S, et al: Insigniﬁcant transfer of
glyburide occurs across the human placenta. Am J Obstet Gynecol 165:807,
259. Elliott BD, Schenker S, Langer O, et al: Comparative placental transport
of oral hypoglycemic agents in humans: A model of human placental drug
transfer. Am J Obstet Gynecol 171:653, 1994.
260. Langer O, Conway DL, Berkus MD, et al: A comparison of glyburide and
insulin in women with gestational diabetes mellitus. N Engl J Med
261. Langer O, Yogev Y, Xenakis EM, et al: Insulin and glyburide therapy:
Dosage, severity level of gestational diabetes, and pregnancy outcome. Am
J Obstet Gynecol 192:134-139, 2005.
262. Lim JM, Tayob Y, O’Brien PM, Shaw RW: A comparison between the
pregnancy outcome of women with gestation diabetes treated with glib-
enclamide and those treated with insulin. Med J Malaysia 52:377381,
263. Chmait R, Dinise T, Moore T: Prospective observational study to establish
predictors of glyburide success in women with gestational diabetes melli-
tus. J Perinatol 24:617-622, 2004.
264. Langer O: Oral anti-hyperglycemic agents for the management of gesta-
tional diabetes mellitus. Obstet Gynecol Clin North Am 34:255-274,
265. Coustan DR: Pharmacological management of gestational diabetes: An
overview. Diabetes Care 30:S206-S208, 2007.
266. Moore TR: Glyburide for the treatment of gestational diabetes: A critical
appraisal. Diabetes Care 30:S209-S213, 2007.
267. Jacobson GF, Ramos GA, Ching JY, et al: Comparison of glyburide and
insulin for the management of gestational diabetes in a large managed
care organization. Am J Obstet Gynecol 193:118-124, 2005.
268. Conway DL, Gonzales O, Skiver D: Use of glyburide for the treatment of
gestational diabetes: The San Antonio experience. J Matern Fetal Neonatal
Med 15:51-55, 2004.
269. Kremer CJ, Duff P: Glyburide for the treatment of gestational diabetes.
Am J Obstet Gynecol 190:1438, 2004.
270. Chmait R, Dinise T, Moore T: Prospective observational study to establish
predictors of glyburide success in women with gestational diabetes melli-
tus. J Perinatol 24:617-622, 2004.
271. Rochon M, Rand L, Roth L, Gaddipati S: Glyburide for the management
of gestational diabetes: Risk factors predictive of failure and associated
pregnancy outcomes. Am J Obstet Gynecol 195:1090-1094, 2006.
272. Yin OQ, Tomlinson B, Chow MS: CYP2C9, but not CYP2C19, polymor-
phisms affect the pharmacokinetics and pharmacodynamics of glyburide
in Chinese subjects. Clin Pharmacol Ther 78:370-377, 2005.
273. Jaber LA, Antal EJ, Slaughter RL, Welshman IR: Comparison of pharma-
cokinetics and pharmacodynamics of short- and long-term glyburide
therapy in NIDDM. Diabetes Care 17:1300-1306, 1994.
274. Yogev Y, Ben Haroush A, Chen R, et al: Undiagnosed asymptomatic hypo-
glycemia: Diet, insulin, and glyburide for gestational diabetic pregnancy.
Obstet Gynecol 104:88-93, 2004.
275. Legro RS, Barnhart HX, Schlaff WD, et al: Clomiphene, metformin, or
both for infertility in the polycystic ovary syndrome. N Engl J Med
276. Vandermolen DT, Ratts VS, Evans WS, et al: Metformin increases the
ovulatory rate and pregnancy rate from clomiphene citrate in patients
with polycystic ovary syndrome who are resistant to clomiphene citrate
alone. Fertil Steril 75:310-315, 2001.
277. Coetzee EJ, Jackson WP: Metformin in management of pregnant insulin-
independent diabetics. Diabetologia 16:241, 1979.
278. Hellmuth E, Damm P, Molsted-Pedersen L: Oral hypoglycaemic agents in
118 diabetic pregnancies. Diabet Med 17:507, 2000.
279. Metzger BE: Diet and medical therapy in the optimal management of
gestational diabetes mellitus. Nestle Nutr Workshop Ser Clin Perform
Programme 11:155-165; discussion 165-169, 2006.
280. Rowan JA, on behalf of the Metformin in Gestational Diabetes Trial: A
trial in progress: Gestational diabetes: Treatment with metformin com-
pared with insulin (the Metformin in Gestational Diabetes [MiG] trial).
Diabetes Care 30:S214-S219, 2007.
281. Bertini AM, Silva JC, Taborda W, et al: Perinatal outcomes and the use of
oral hypoglycemic agents. J Perinat Med 33:519, 2005.
282. Sacks DA, Chen W: Estimating fetal weight in the management of macro-
somia. Obstet Gynecol Surv 55:229, 2000.
283. Chauhan SP, West DJ, Scardo JA, et al: Antepartum detection of macro-
somic fetus: Clinical versus sonographic, including soft-tissue measure-
ments. Obstet Gynecol 95:639, 2000.
284. O’Reilly-Green C, Divon M: Sonographic and clinical methods in the
diagnosis of macrosomia. Clin Obstet Gynecol 43:309, 2000.
993CHAPTER 46 Diabetes in Pregnancy
285. Sokol RJ, Chik L, Dombrowski MP, et al: Correctly identifying the
macrosomic fetus: Improving ultrasonography-based prediction. Am J
Obstet Gynecol 182:1489, 2000.
286. Landon MB: Prenatal diagnosis of macrosomia in pregnancy complicated
by diabetes mellitus. J Matern Fetal Med 9:52, 2000.
287. Combs CA, Rosenn B, Miodovnik M, et al: Sonographic EFW and
macrosomia: Is there an optimum formula to predict diabetic fetal
macrosomia? J Matern Fetal Med 9:55, 2000.
288. Hackmon R, Bornstein E, Ferber A, et al: Combined analysis with
amniotic ﬂuid index and estimated fetal weight for prediction of severe
macrosomia at birth. Am J Obstet Gynecol 196:333.e1-e4, 2007.
289. Hedriana H, Moore TR: Comparison of single vs multiple growth sonog-
raphy in predicting birthweight. Am J Obstet Gynecol 170:1600, 1994.
290. Parry S, Severs CP, Sehdev HM, et al: Ultrasonographic prediction of fetal
macrosomia: Association with cesarean delivery. J Reprod Med 45:17-22,
291. Chauhan SP, Lynn NN, Sanderson M, et al: A scoring system for detection
of macrosomia and prediction of shoulder dystocia: A disappointment.
J Matern Fetal Neonatal Med 19:699-705, 2006.
292. Weeks JW, Pitman T, Spinnato JA: Fetal macrosomia: Does antenatal pre-
diction affect delivery route and birth outcome? Am J Obstet Gynecol
293. Rouse DJ, Owen J: Prophylactic cesarean delivery for fetal macrosomia
diagnosed by means of ultrasonograph—a Faustian bargain? Am J Obstet
Gynecol 181:332, 1999.
294. Rayburn WF, Sokkary N, Clokey DE, et al: Consequences of routine deliv-
ery at 38 weeks for A-2 gestational diabetes. J Matern Fetal Neonatal Med
295. Kjos SL, Henry OA, Montoro M, et al: Insulin-requiring diabetes in preg-
nancy: A randomized trial of active induction of labor and expectant
management. Am J Obstet Gynecol 169:611, 1993.
296. American College of Obstetricians and Gynecologists (ACOG): Fetal
macrosomia. ACOG practice bulletin no. 22, 2000.
297. Gonen R, Bader D, Ajami M: Effects of a policy of elective cesarean deliv-
ery in cases of suspected fetal macrosomia on the incidence of brachial
plexus injury and the rate of cesarean delivery. Am J Obstet Gynecol
298. Conway DL, Langer O: Elective delivery of infants with macrosomia in
diabetic women: Reduced shoulder dystocia versus increased cesarean
deliveries. Am J Obstet Gynecol 178:922, 1998.
299. Herbst MA: Treatment of suspected fetal macrosomia: A cost-effectiveness
analysis. Am J Obstet Gynecol 193:1035-1039, 2005.
300. Mimouni F, Tsang RC: Pregnancy outcome in insulin-dependent diabetes:
Temporal relationships with metabolic control during speciﬁc pregnancy
periods. Am J Perinatol 5:334-338, 1988.
301. Balsells M, Corcoy R, Adelantado JM, et al: Gestational diabetes mellitus:
Metabolic control during labour. Diabetes Nutr Metab 13:257, 2000.
302. McKinney PA, Parslow R, Gurney KA, et al: Perinatal and neonatal deter-
minants of childhood type 1 diabetes: A case-control study in Yorkshire,
UK. Diabetes Care 22:928, 1999.
303. Schrezenmeir J, Jagla A: Milk and diabetes. J Am Coll Nutr 19(Suppl):176S,
304. Pettitt DJ, Forman MR, Hanson RL: Breastfeeding and incidence of non–
insulin-dependent diabetes mellitus in Pima Indians. Lancet 350:166,
305. Gimeno SG, de Souza JM: IDDM and milk consumption: A case-control
study in Sao Paulo, Brazil. Diabetes Care 20:1256, 1997.
306. Neubauer SH, Ferris AM, Chase CG, et al: Delayed lactogenesis in
women with insulin-dependent diabetes mellitus. Am J Clin Nutr 58:54,
307. van Beusekom CM, Zeegers TA, Martini IA, et al: Milk of patients
with tightly controlled insulin-dependent diabetes mellitus has normal
macronutrient and fatty acid composition. Am J Clin Nutr 57:938,
308. Webster J, Moore K, McMullan A: Breastfeeding outcomes for women
with insulin dependent diabetes. J Hum Lact 11:195, 1995.