Data Search TableKeywordParametersCINAHLPubMedMedline

Data Search Table
Keyword
Parameters
CINAHL
PubMed
Medline
PsychInfo
Cochrane
Pregnancy outcome for women aged 35 years & above
And middle-aged women
Not older adults
2015-2022
44
Preterm birth to advanced maternal age mothers
Or pregnant women aged 35 years & above
And quantitative study
2015-2022

135
(MH "Maternal Age 35 and Over") OR (MH "Childbirth,
Premature")
And a qualitative study
2005 – 2022
193
Prenatal care for advanced age women
2005-2020
37

366
©Copyright 2019 by The Medical Bulletin of
İstanbul Haseki Training and Research Hospital
The Medical Bulletin of Haseki published by Galenos Yayınevi.
AddressforCorrespondence/Yaz›flmaAdresi: Burcu
Dinçgez Çakmak, University of Health
Sciences, Bursa Yüksek İhtisas Training and Research Hospital,
Clinic of Gynecology and
Obstetrics, Bursa, Turkey
E-mail: [email protected] ORCID: orcid.org/0000-0002-2697-
7501
Received/Gelifl-Tarihi: 11 January 2019
Ac-cep-ted/Ka-bul-Ta-ri-hi: 18 February 2019
©Telif Hakkı 2019 İstanbul Haseki Eğitim ve Araştırma
Hastanesi
Haseki Tıp Bülteni, Galenos Yayınevi tarafından yayınlanmıştır.
DOI: 10.4274/haseki.galenos.2019.5003
Med Bull Haseki 2019;57:366-371
Perinatal Outcomes of Advanced and Extremely
Advanced Maternal Age Pregnancies
İleri ve Çok İleri Anne Yaşı Gebeliklerinin Perinatal Sonuçları
Aim: Advanced and extremely advanced maternal age (AMA,
EAMA) are known to be associated with increased perinatal
mortality and morbidity. We aimed to compare the perinatal
outcomes of pregnancy in women <35 and ≥35 years of age
and also to compare the outcomes between AMA and EAMA
pregnancies.

Methods: A total of 1202 patients, who had regular antenatal
follow-up and gave birth in our clinic between June 2016 and
December 2017, were included. The study group consisted of
632 patients aged ≥35 years and control group consisted of
570 patients aged <35 years. Then, the patients were divided
into two subgroups; patients aged 35-40 years (n=495) and
over 40 years (n=137). Socio-demographic features, delivery
characteristics and perinatal outcomes were obtained from the
medical records. Perinatal outcomes were compared between
patient and control groups and between subgroups.
Results: Gestational diabetes (GDM) (p<0.001), preeclampsia
(p<0.001), placenta previa (PP) (p=0.03) and intrauterine fetal
death (IFD) (p<0.001) were more common in AMA group than
in
controls. In subgroup analysis, cesarean section rate was higher
(p<0.001), IFD (p=0.04), PP (p<0.001), preeclampsia (p<0.001)
and GDM (p<0.001) were more common in EAMA group than
in AMA group.
Conclusion: Adverse perinatal outcomes are more common in
AMA and EAMA pregnancies. We suggest that close monitoring
of these pregnants in the antenatal period is crucial to avoid
adverse outcomes and to prevent perinatal mortality and
morbidities.
Keywords: Advanced maternal age, extremely advanced
maternal age, perinatal outcomes
Amaç: İleri ve çok ileri anne yaşı gebelikleri (İAY, ÇİAY)
artmış
perinatal mortalite ve morbidite ile ilişkilidir. Çalışmamızda, 35
yaşın altındaki ve üzerindeki gebeliklerin ve ayrıca İAY,
ÇİAY’nin
perinatal sonuçlarının karşılaştırılması amaçlanmıştır.

Yöntemler: Çalışmaya Haziran 2016 ve Aralık 2017 tarihinde
kliniğimizde takip edilen ve doğumu gerçekleştirilen 1202 hasta
dahil edildi. Çalışma grubu ≥35 yaşındaki 632 gebeden ve
kontrol
grubu <35 yaşındaki 570 gebeden oluşmaktaydı. Hasta grubu
da 35-40 yaş arasındaki gebeler (n=495) ve 40 yaşın üzerindeki
gebeler (n=137) olmak üzere iki alt gruba ayrıldı. Hastaların
sosyo-
demografik özellikleri, doğum özellikleri ve perinatal sonuçları
medikal dosyalarından kaydedildi. Perinatal sonuçlar hasta ve
kontrol grubu arasında ve ayrıca alt gruplar arasında
karşılaştırıldı.
Bulgular: Gestasyonel diyabet (p<0,001), preeklampsi
(p<0,001),
plasenta previa (p=0,03) ve intrauterin fetal ölüm (p<0,001)
ileri
maternal yaş grubunda kontrol grubuna göre istatistiksel anlamlı
olarak daha sıktı. Alt grup analizinde, sezaryen oranı daha
yüksek
iken (p<0,001), benzer şekilde intrauterin fetal ölüm (p=0.04),
plasenta previa (p<0,001), preeklampsi (p<0,001) ve
gestasyonel
diyabet (p<0,001) de çok ileri anne yaşı grubunda, ileri anne
yaşı
grubundan daha sık olarak tespit edildi.
Sonuç: İAY, ÇİAY’de olumsuz perinatal sonuçlar daha sık
görülmektedir. Antenatal dönemde bu hastaların yakın takibinin
bu olumsuz sonuçlardan korunmada ve perinatal mortalite ve
morbidite artışını önlemede kritik rolü olduğunu
düşünmekteyiz.
Anahtar Sözcükler: İleri anne yaşı, çok ileri anne yaşı, perinatal
sonuçlar

ÖzAbs tract
Burcu Dinçgez Çakmak, Betül Dündar, Ülkü Ayşe Türker
University of Health Sciences, Bursa Yüksek İhtisas Training
and Research Hospital, Clinic of Gynecology and Obstetrics,
Bursa, Turkey
Original Article / Özgün Araştırma
https://orcid.org/0000-0002-2697-7501
https://orcid.org/0000-0003-4383-4374
https://orcid.org/0000-0002-3393-6310
Dinçgez Çakmak et al. Advanced Maternal Age and Pregnancy
Outcomes
367
Introduction
Advanced maternal age (AMA) is defined as childbearing
in a woman over 35 years of age while extremely advanced
maternal age (EAMA) is defined as pregnancy in those over
40 years of age by the International Federation of Gynecology
and Obstetrics (1).
The incidence of AMA is reported to be 12.6% in
England, 33.4% in Norway, 11.4-19.1% in Taiwan and it
varies from 8.6% to 11.8% in our country. For EAMA, it
has been reported to be 4% in England (2,3). According
to the Civil Registration and Nationality Services of Turkey,
2.3% of all pregnancies were in women at EAMA in 2009
and this reached to 2.8% in 2014 (4).

Delayed childbearing has been an increasing trend
in developed countries due to social, financial and
educational status of women. Moreover, late miscarriages,
career goals, advanced assisted reproductive techniques
and ineffective contraception in multiparous women are
the main risk factors for AMA and EAMA (5-7).
AMA and EAMA are known to be associated with
increased maternal and fetal mortality and morbidity.
Previous studies reported that they were related with
hypertensive disorders of pregnancy, gestational diabetes
mellitus (GDM), postpartum hemorrhage, placenta previa
(PP), low birth weight, intrauterin growth restriction,
prematurity, macrosomia, low Apgar scores and increased
cesarean section rates (8-13). Although adverse perinatal
outcomes are more common in AMA and EAMA, these
outcomes could generally be avoided with advanced
neonatal care units and close monitoring of pregnants in
the antenatal period.
In this study, we aimed to compare the perinatal
outcomes of pregnancy in women under and over 35
years of age and also to compare the outcomes between
AMA and EAMA.
Methods
This is a retrospective observational case-control study,
conducted in a high-volume university-affiliated training
and research hospital between June 2016 and December
2017. Ethics committee approval is not required for
retrospective studies in our country but we commit that
this study complies with the declaration of Helsinki.
Informed consent was routinely obtained from patients
during their admission which includes the participation in
scientific studies.

In this study, a total of 1202 patients, who had a regular
antenatal follow-up and gave birth in our clinic, were
included. The study group was composed of 632 patients
aged 35 years and over and control group was composed
of 570 patients younger than 35 years. Then, the patients
were divided into two subgroups as; patients aged 35-40
years (n=495) and patients over 40 years of age (n=137).
Patients with cardiac diseases, chronic hypertension, hypo-
hyperthyroidism, Diabetes mellitus, congenital uterine
anomalies, multiple pregnancies, hepatic and renal failure,
prior placental abnormalities, previous preterm birth,
recurrent pregnancy loss, hematological and auto-immune
diseases and alcohol or cigarette habits were excluded.
The patients’ gravidity, parity, delivery mode, gestational
age at delivery, birth weight, presence of premature rupture
of the membrane, PP, pre-eclampsia, GDM, intrauterine
pregnancy loss, Apgar scores at the first and fifth minutes,
presence of respiratory distress syndrome, sepsis, and
neonatal intensive care unit admission were obtained
from the medical records. The perinatal outcomes were
compared between patient and control groups and also
between subgroups.
Statistical Analysis
Statistical analyses were performed by using the SPSS
statistical software version 21.0 (Statistical Package for
the Social Sciences, Chicago, IL). The Kolmogorov-Smirnov
test was carried out to evaluate the normality of variables.
Normally distributed variables were expressed as mean
± standard deviation, non-normally distributed ones
as median and categorical variables were expressed as
percentage. For group comparison, the Mann-Whitney U

test was performed to compare non-normally distributed
parameters and the chi-square test for categorical
variables. A p value of less than 0.05 was considered
statistically significant.
Results
The mean age of the study participants was
31.55±11.63 years, median gravidity was 3 (1:7) and
the mean parity was 2 (1:7). The mean birth weight
was 3108.2±517.2 grams and gestational week at birth
was 37 (28:40). Assisted reproductive techniques were
performed in 69 patients (5.7%). Intrauterine fetal
death was determined in 34 (2.8%) patients, PP in 27
(2.2%), pre-eclampsia in 108 (8.9%), GDM in 75 (6.2%),
premature rupture of the membrane in 73 (6.1%),
preterm delivery before 34 weeks in 96 (7.9%) and
preterm delivery between 34 and 37 weeks in 76 (6.3%)
patients. A total of 563 patients (46.8%) underwent
cesarean section. In 27 neonates (2.2%) the 1-minute
Apgar score was <7 while 5-minute Apgar score was <7
in 17 (1.4%) neonates. While 110 (9.2%) infants were
small for gestational age (SGA), 25 (2.1%) were large
for gestational age (LGA). Respiratory distress syndrome
was detected in 47 (3.9%) babies and sepsis was
present in 32 (2.6%). One hundred and twenty-seven
(10.6%) neonates required neonatal intensive care unit
admission.
Outcomes
368

The demographic features and perinatal outcomes of
the study and control groups are demonstrated in Table
1. There was no difference between the two groups in
gestational week at delivery, birth weight, rate of assisted
reproductive techniques and adverse perinatal outcomes
such as an Apgar score of <7 at the first and fifth
minutes, SGA and LGA, presence of premature rupture
of the membranes, preterm delivery, respiratory distress
syndrome, neonatal sepsis and neonatal intensive care
unit admission. Pre-eclampsia (p<0.001), GDM (p<0.001),
PP (p=0.03) and intrauterine fetal death (p<0.001) were
more common and cesarean section rate was significantly
higher (p=0.02) in AMA group. Moreover, the number of
gravida and parity of this group was higher as compared
to controls.
The demographic features and perinatal outcomes
of AMA and EAMA groups are presented in Table 2. In
subgroup analysis, assisted reproductive techniques were
more common in EAMA group (p<0.001). Furthermore,
cesarean section rate was higher (p<0.001), intrauterine
fetal death (p=0.04), PP (p<0.001), pre-eclampsia
(p<0.001) and GDM (p<0.001) were more common in
EAMA group as compared to AMA group.
Discussion
The main findings of the study were as follows: 1)
Pre-eclampsia, GDM, PP and intrauterine fetal death were
more common and cesarean section rate was higher in
AMA group as compared to controls, 2) In EAMA group,
assisted reproductive techniques were more common as it
was expected and in addition to this, cesarean section rate
was higher, intrauterine fetal death, PP, pre-eclampsia and
GDM were more common as compared to AMA group.

Advanced aged pregnancies have been gradually
increasing all over the world during the last decades.
Women have a tendency to postpone their childbearing
due to their career goals and financial problems. Moreover,
increased use of assisted reproductive techniques and
effective birth control methods could be encountered as a
risk factor for these pregnancies (5,6).
Pregnancy at advanced ages may be unfavorable
owing to maternal and fetal complications. Recent
studies have demonstrated that AMA pregnancies are
associated with adverse perinatal outcomes such as
hypertensive disorders, GDM, preterm birth, placental
abnormalities, increased cesarean section rates, low birth
weight, macrosomia, low Apgar scores and perinatal
Table 1. Demographic features and perinatal outcomes of the
study group
Maternal age ≥35 years
(n=632)
Maternal age <35 years
(n=570)
p
Gravida-(n) 4 (2-7) 2 (1-4) <0.001
Parity-(n) 3 (1-7) 1 (1-4) <0.001
Gestational-week-at-birth-(week) 37 (28-40) 38 (34-40) 0.46
Birth-weight-(gram) 3155.1±575.2 3040.8±486.2 0.71
Assisted-reproductive-technique-(n,-%) 53 (8.4%) 16 (2.8%)

0.14
Intrauterine-fetal-death-(n,-%) 20 (3.2%) 14 (2.4%) <0.001
Placenta-previa-(n,-%) 18 (2.8%) 9 (1.6%) 0.03
Pre-eclampsia-(n,-%) 84 (13.3%) 24 (4.2%) <0.001
Gestational-diabetes-mellitus-(n,-%) 56 (8.9%) 19 (3.3%)
<0.001
Premature-rupture-of-membranes-(n,-%) 42 (6.6%) 31 (5.4%)
0.27
Cesarean-section-(n,-%) 336 (53.2%) 227 (39.8%) 0.02
Apgar-1st-min-<7-(n,-%) 16 (2.5%) 11 (1.9%) 0.54
Apgar-5th-min-<7-(n,-%) 11 (1.7%) 6 (1.1%) 0.68
Respiratory-distress-syndrome-(n,-%) 29 (4.6%) 18 (3.2%) 0.23
Neonatal-sepsis-(n,-%) 17 (2.7%) 15 (2.6%) 0.89
Neonatal-intensive-care-unit-admission-(n,-%) 68 (10.8%) 59
(10.4%) 0.74
Preterm-delivery-<34-weeks-(n,-%) 53 (8.4%) 43 (7.5%) 0.68
Preterm-delivery-<34-37-weeks-(n,-%) 41 (6.5%) 35 (6.1%)
0.71
Small-for-gestational-age-(n,-%) 64 (10.1%) 46 (8.1%) 0.17
Large-for-gestational-age-(n,-%) 16 (2.5%) 9 (1.6%) 0.43

n: Number
Outcomes
369
mortality (11). Furthermore, these adverse problems are
more apparent in EAMA pregnancies (13,14). It is known
that AMA and EAMA pregnancies are linked with adverse
perinatal outcomes, however, it is not clearly investigated
which adverse outcome is more tightly related with AMA
or EAMA.
Earlier studies reported an increased cesarean rate
in AMA pregnancies. In our study, we found increased
cesarean rate in AMA group as compared to controls,
consistent with the literature. The cesarean rate was 53.2%
in AMA group and 39.8% in control group. In a study by
Berkowitz et al. (15), the cesarean rate was higher in AMA
group and they claimed that this condition could probably
be related to increased pregnancy complications such as
hypertension, GDM and bleeding. Similar to our study, in
another study from Nigeria evaluating only primigravid
women, the cesarean rate was reported to be 58.1% in
women older than 35 years while it was 32.1% in those
younger than 35 years of age (16). Studies performed in
our country demonstrated significantly higher cesarean
rates for AMA pregnancies (17,18). Another interesting
finding of our study was the increased cesarean rate in
EAMA group as compared to AMA group. Likewise, Hsieh
et al. (13) reported an increased cesarean rate for both
AMA and EAMA groups and found a 1.6 fold increased

risk for AMA group and 2.6 fold for EAMA group. In
a study from Turkey by Cambaztepe et al. (19), the
cesarean rate was found to be statistically significantly
higher in EAMA group (65.7%) than in those aged 20-35
years (40.2%). Similarly, another study investigating the
pregnancy outcomes of EAMA pregnancies reported a
higher rate of cesarean section as compared to pregnancy
in women aged 18-39 years (1). We assume that these
higher cesarean rates could be related with increased
pregnancy complications especially in primigravid patients
and previous cesarean section and tubal ligation for
multiparous women who desire permanent contraception.
Due to repeated cesarean section, we found that PP was
more common in AMA and EAMA pregnancies. In a study
by Hsieh et al. (13), the prevalence of PP was 2.3% in
AMA and 2.6% in EAMA group while it was significantly
lower in <35 years with an incidence of 1%. Supporting
these results, Jacobsson et al. (20) claimed that women
over 40 years of age had nearly 4-fold increased risk of PP
as compared to those under 40 years of age.
GDM is the most common metabolic disorder in
pregnancy. Pancreatic beta cell function and insulin
sensitivity decline with age and this condition leads to
Table 2. Demographic features and perinatal outcomes of
advanced and extremely advanced maternal age pregnancies
Advanced Maternal Age
(n=495)
Extremely Advanced Maternal Age
(n=137)
p

Gravida-(n) 4 (2-5) 4 (2-7) 0.71
Parity-(n) 3 (1-5) 3 (1-7) 0.86
Gestational-week-at-birth-(week) 37 (32-40) 36 (28-39) 0.54
Birth-weight-(gram) 3270.47±634.2 2980.3±524.1 0.26
Assisted-reproductive-technique-(n,-%) 32 (6.5%) 21 (15.3%)
<0.001
Intrauterine-fetal-death-(n,-%) 14 (2.8%) 6 (4.4%) 0.04
Placenta-previa-(n,-%) 12 (2.4%) 6 (4.4%) <0.001
Pre-eclampsia-(n,-%) 56 (11.3%) 28 (20.4%) <0.001
Gestational-diabetes-mellitus-(n,-%) 35 (7.1%) 21 (15.3%)
<0.001
Premature-rupture-of-membranes-(n,-%) 33 (6.6%) 9 (6.6%)
0.91
Cesarean-section-(n,-%) 240 (48.5%) 96 (70.1%) <0.001
Apgar-1st-min-<7-(n,-%) 12 (2.4%) 4 (2.9%) 0.67
Apgar-5th-min-<7-(n,-%) 8 (1.6%) 3 (2.2%) 0.34
Respiratory-distress-syndrome-(n,-%) 23 (4.6%) 6 (4.4%) 0.58
Neonatal-sepsis-(n,-%) 13 (2.6%) 4 (2.9%) 0.49
Neonatal-intensive-care-unit-admission-(n,-%) 51 (10.3%) 17
(12.4%) 0.61

Preterm-delivery-<34-weeks-(n,-%) 41 (8.3%) 12 (8.8%) 0.44
Preterm-delivery-<34-37-weeks-(n,-%) 30 (6.1%) 11 (8%) 0.21
Small-for-gestational-age-(n,-%) 51 (10.3%) 13 (9.5%) 0.38
Large-for-gestational-age-(n,-%) 11 (2.2%) 5 (3.6%) 0.11
n: Number
Outcomes
370
high DM and GDM prevalence in advanced ages (1,9,13).
Previous studies searching the relationship between GDM
and maternal age reported that GDM and pregestational
diabetes were more common in advanced-age pregnancies
(1,21,22). Moreover, maternal age was claimed to be one
of the independent predictors of GDM (9). Likewise, data
from our country demonstrated similar results. Gunduz et
al. (1) found that the prevalence of GDM was 12.5 fold
increased in women aged over 40 years than in controls.
Cambaztepe et al. (19) reported that the incidence of
GDM in pregnant women at EAMA and those aged 20-
35 years was 5.9% and 1.1%, respectively. In our study,
GDM was more common when it was compared between
pregnant women of advanced age and controls and also
between women at AMA and EAMA.
Pre-eclampsia is another medical problem associated
with AMA. In a study including 4193 patients with pre-
eclampsia and eclampsia in Taiwan, AMA was claimed to

be a risk factor for pre-eclampsia and 4.56 fold increased
risk for pre-eclampsia was reported in pregnant women
at AMA compared to pregnants younger than 35 years of
age (23). Similarly, Gunduz et al. (1) reported that women
at EAMA had 3.4 fold increased risk for pre-eclampsia
compared to those younger than 40 years. We found
that the prevalence of pre-eclampsia was higher both in
AMA and EAMA groups in our study. In accordance with
the literature, we suggest that the underlying mechanism
for the aforementioned complication is probably due to
uteroplacental vasculopathy. In their study investigating
62 autopsies, Naeye (24) demonstrated that the incidence
of sclerotic pathologies in myometrial arteries increased
with age. Furthermore, they reported that the incidence
of sclerotic lesions was 61% at ages 30-39 and 83% after
age 39. This vasculopathy may lead placental insufficiency
which is the main pathophysiological mechanism for pre-
eclampsia.
Another pathology that may lead to intrauterine fetal
death is placental insufficiency. As it was expected, the
risk of intrauterine fetal death was found to be higher
in pregnant women of AMA in previous studies (25,26).
Similarly, we found that the incidence of intrauterine fetal
death was higher not only in AMA group but also in EAMA
pregnancies. The other explanation for this increment
could be high fetal anomaly rates after 35 years of age.
Study-Limitations
This retrospective study reported data from a single
center reflecting the outcomes of pregnancies from
a limited geographic region. To clarify the importance
of advanced age on maternal and fetal outcomes,
randomized controlled trials including more than one
clinical center are required.

Conclusion
Adverse perinatal outcomes are more common in
pregnant women of AMA and EAMA. We suggest that
close monitoring of these pregnants in the antenatal
period is crucial to avoid these adverse outcomes and
to prevent possible maternal and fetal mortality and
morbidities.
Authorship-Contributions
Concept: B.D.Ç., B.D. Design: B.D., Ü.A.T. Data Collection
or Processing: Ü.A.T. Analysis or Interpretation: B.D.Ç., B.D.
Literature Search: Ü.A.T., B.D.Ç. Writing: B.D.Ç., B.D.
Conflict- of- Interest: The authors declare that they
have no conflict of interest.
Financial Disclosure: The authors declared that this
study received no financial support.
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G, Temmerman M. Pregnancy outcome in primiparae of
advanced maternal age. Eur J Obstet Gynecol Reprod Biol
2007;135:41-6.
22. Luke B, Brown MB. Elevated risks of pregnancy
complications
and adverse outcomes with increasing maternal age. Hum
Reprod 2007;22:1264-72.
23. Chen CL, Cheng Y, Wang PH, Juang CM. Review of pre-
eclampsia in Taiwan: a multi-institutional study. Zhonghua Yi
Xue Za Zhi (Taipei) 2000;63:869-75.
24. Naeye RL. Maternal age, obstetric complications, and the
outcome of pregnancy. Obstet Gynecol 1983;61:210-6.

25. Jolly M, Sebire N, Harris J, Robinson S, Regan L. The risks
associated with pregnancy in women aged 35 years or older.
Hum Reprod 2000;15:2433-7.
26. Göker Tamay A, Güvenal T, Özgür N, Oruç Koltan S,
Koyuncu
FM. Retrospective Analysis of Advanced Maternal Age
Pregnancies. Gynecol Obstet Reprod Med 2011;17:83-6.
Specialised antenatal clinics for women with a pregnancy at
high risk of preterm birth (excluding multiple pregnancy) to
improve maternal and infant outcomes (Review)
Whitworth M, Quenby S, Cockerill RO, Dowswell T
This is a reprint of a Cochrane review, prepared and maintained
by The Cochrane Collaboration and published in The Cochrane
Library
2011, Issue 9
http://www.thecochranelibrary.com
improve
maternal and infant outcomes (Review)
Copyright © 2011 The Cochrane Collaboration. Published by
John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com
T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
.
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . .
2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. .
3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
.
3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
.
9AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . .
9ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . .
10REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . .

12CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . .
. . . . . . . . . .
18DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . .
Analysis 1.1. Comparison 1 Specialised antenatal care versus
routine care, Outcome 1 Perinatal death. . . . . . 19
routine care, Outcome 2 Extremely preterm birth (< 28 weeks’
gestation). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
routine care, Outcome 3 Development of antenatal
complications - preterm labour. . . . . . . . . . . . . . . . . . . . . . . . .
. . . . 20
routine care, Outcome 4 Preterm birth - adjusted for cluster
design effect (ICC 0.002). . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. 21
routine care, Outcome 5 Sensitivity analysis. Preterm birth
(adjusted for cluster design effect using upper CI, ICC 0.0041).
. . . . . . . . . . . . . . . . 22
routine care, Outcome 6 Very preterm birth (birth before 34
weeks’ gestation). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23
routine care, Outcome 7 Gestation at birth. . . . . 23
routine care, Outcome 9 Caesarean section. . . . . 24
routine care, Outcome 13 Neonatal intensive care unit
admission. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
routine care, Outcome 19 Costs associated with care. . 25
routine care, Outcome 20 Costs associated with newborn
inpatient care (US $). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25
routine care, Outcome 21 Number of antenatal visits. 26
routine care, Outcome 27 Preterm birth - all studies,
unadjusted data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
27HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
.
27CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . .
. . . . . . . . .

28DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . .
28SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . .
28DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . .
. . . . . . . . . . . . . . . . .
28INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . .
iSpecialised antenatal clinics for women with a pregnancy at
improve
[Intervention Review]
improve maternal and infant outcomes
Melissa Whitworth1, Siobhan Quenby2, Ruth O Cockerill3,
Therese Dowswell4
1St Mary’s Hospital, Manchester, UK. 2Clinical Sciences
Research Institute, University of Warwick, Coventry, UK.
3Department of

Obstetrics, St Mary’s Hospital, Manchester, UK. 4Cochrane
Pregnancy and Childbirth Group, Department of Women’s and
Children’s
Health, The University of Liverpool, Liverpool, UK
Contact address: Melissa Whitworth, St Mary’s Hospital,
Central Manchester and Manchester Children’s University
Hospitals NHS
Trust, Hathersage Road, Manchester, M13 0JH, UK.
[email protected]
Editorial group: Cochrane Pregnancy and Childbirth Group.
Publication status and date: New, published in Issue 9, 2011.
Review content assessed as up-to-date: 24 July 2011.
Citation: Whitworth M, Quenby S, Cockerill RO, Dowswell T.
high risk
of preterm birth (excluding multiple pregnancy) to improve
maternal and infant outcomes. Cochrane Database of Systematic
Reviews
2011, Issue 9. Art. No.: CD006760. DOI:
10.1002/14651858.CD006760.pub2.
A B S T R A C T
Background
Amongst the risk factors for preterm birth, previous preterm

delivery is a strong predictor. Specialised clinics for women
with a history
of spontaneous preterm delivery have been advocated as a way
of improving outcomes for women and their infants.
Objectives
To assess using the best available evidence, the value of
specialised antenatal clinics for women with a pregnancy at
high risk of preterm
delivery when compared with ’standard’ antenatal clinics.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group’s
Trials Register (30 June 2011).
Selection criteria
All published, unpublished, and ongoing randomised controlled
trials (including cluster-randomised trials) examining
specialised
compared with standard antenatal clinic care for women with a
singleton pregnancy considered at high risk of preterm labour.
Data collection and analysis
Two review authors independently assessed trial quality and
extracted data.
Main results
We included three trials with 3400 women, all carried out in the

USA. All focused on specialised clinics for women at high risk
of
preterm birth. Gestational age at delivery, preterm delivery, or
both were primary outcomes in all studies. The interventions in
the
three trials differed.
Overall there was very little data on our prespecified outcomes.
For most outcomes a single study provided data, hence there
was not
the statistical power to detect any possible differences between
groups. There was no clear evidence that specialised antenatal
clinics
reduce the number of preterm births.
1Specialised antenatal clinics for women with a pregnancy at
improve
mailto:[email protected]
Authors’ conclusions
Specialised antenatal clinics are now an accepted part of care in
many settings, and carrying out further randomised trials may
not be

possible. Any future research in this area should include
psychological outcomes and should focus on which aspects of
service provision
are preferred by women. Such research could underpin further
service development in this area.
P L A I N L A N G U A G E S U M M A R Y
improve outcomes for women and babies
Women who have had a previous preterm birth are at increased
risk of having another premature birth. Babies who are born
before
the 37th week of pregnancy, and particularly those born before
the 34th week, are at greater risk of suffering problems at birth
and
of disability in childhood. ’Specialised’ antenatal clinics have
been suggested for women at high risk of a preterm birth as a
way of
improving health outcomes for the women and their infants.
This review of three randomised controlled trials involving
3400 women
in the USA found that there was no reduction in the number of
preterm births in women attending specialised antenatal clinics.
The
results were difficult to interpret, as the trials were conducted

in slightly different ways and offered slightly different care.
The trials were
all conducted in the 1980s, before the introduction of many of
the screening tests currently offered in specialised antenatal
clinics such
as ultrasound assessment of cervical length. There was no
information available on the effect of specialised antenatal care
on maternal
wellbeing or long-term outcome.
B A C K G R O U N D
Preterm birth occurs in up to 6% to 10% of all births and is as -
sociated with perinatal mortality and morbidity (Lumley 2003).
Nearly half of all preterm births are due to preterm labour.
Preterm
birth is associated with emotional and economic costs to both
the
family and society (Petrou 2001). Once congenital anomalies
are
excluded, preterm birth is responsible for the majority of
neonatal
deaths and is the major cause of disability in childhood (Hack
1999). The majority of mortality and morbidity occurs with ex-
tremely preterm birth (defined as birth before 28 weeks’

gestation).
However, whilst the incidence of death and long-term handicap
is relatively low in those born after 32 weeks, they make up
over
80% of all preterm deliveries and therefore this group of infants
has a significant impact upon the burden that preterm birth
makes
on public health (Kramer 2000). Despite research over the past
few decades, no decrease in the incidence of preterm birth has
oc-
curred, although there have been improved survival and
outcomes
for premature infants.
Amongst the risk factors for preterm birth, previous preterm de-
livery is a strong predictor and the earlier the birth the more
likely
it is to be repeated at the same gestation (Hoffman 1984). Other
risk factors include cervical weakness, cervical trauma, and
stress
(El-Bastawissi 1999; Iams 2004; Ruis 2003). Specialised clinics
for
women with a history of spontaneous preterm delivery have

been
advocated, with non-randomised cohort data suggesting
improved
perinatal outcomes with the provision of intensive antenatal ed-
ucation, continuity of carer and individualised care (Bienstock
2001). Such specialised clinics may also see women with
previous
preterm prelabour rupture of the membranes, previous late mis-
carriage (16 weeks 0 days to 23 weeks 6 days of gestation), or
prior
cervical surgery. Prediction of risk may utilise ultrasound
assess-
ment of cervical length and the presence of fetal fibronectin in
cer-
vico-vaginal secretions. The package of care offered in such
clinics
may include promising prophylactic interventions for labour
pre-
vention including progesterone, clindamycin or cervical
cerclage
(Althuisius 1998; Da Fonesca 2003; Ugwumadu 2003).
However,
stress has been associated with enhanced risk of preterm

delivery
and there is evidence that, whilst some pregnant women
welcome
referral to a specialist clinic during pregnancy, others
experience it
as unsettling (Jackson 2006).
The aim of this review is to assess, using the best available evi -
dence, the value of such specialised antenatal clinics for women
with a pregnancy at high risk of preterm birth when compared
with ’standard’ antenatal clinic attendance. The primary
outcomes
relate to maternal and neonatal morbidity, and maternal and
peri-
natal mortality. In women with multiple pregnancy, who have
an
increased risk of premature delivery, specialised clinics have
been
advocated in an attempt to improve perinatal outcomes. The
value
of specialised antenatal care for women with a multiple
pregnancy

improve
when compared with ’standard’ antenatal care is the subject of a
different Cochrane review (Dodd 2007).
O B J E C T I V E S
To assess, using the best available evidence, the value of
specialised
antenatal clinics for women with a pregnancy at high risk of
preterm delivery when compared with ’standard’ antenatal
clinics.
M E T H O D S
Criteria for considering studies for this review
Types of studies
All published, unpublished, and ongoing randomised controlled
trials including cluster-randomised trials. We have included
quasi-
randomised controlled trials.

Types of participants
Pregnant women with a singleton pregnancy considered by the
trial authors to be at high risk of preterm labour.
Types of interventions
’Specialised’ antenatal clinics (as defined by trial authors) com-
pared with ’standard’ antenatal clinic care (as defined by trial
au-
thors).
Types of outcome measures
Primary outcomes
1. Perinatal death (defined as stillbirth after trial entry, or
death of a liveborn infant up to seven days of age).
2. Extremely preterm birth (defined as birth less than 28
weeks’ gestation).
Secondary outcomes
Secondary outcomes relate to pregnancy outcomes,
complications, satisfaction and costs
Pregnancy outcomes
1. Development of antenatal complications (including

preterm labour (actual or suspected), preterm prelabour ruptured
membranes, intrauterine growth restriction (estimated fetal
weight less than 10th centile for gestational age)).
2. Preterm birth (defined as birth before 37 weeks’ gestation).
3. Very preterm birth (defined as birth before 34 weeks’
gestation).
4. Gestation at birth.
5. Instrumental vaginal birth.
6. Infection requiring intravenous antibiotics.
7. Mode of birth.
8. Postnatal depression.
9. Breastfeeding.
Complications for infants
1. Neonatal intensive care unit admission.
2. Respiratory distress syndrome.
3. Parameters of birth asphyxia (neonatal irritability, neonatal
seizures, neonatal hypotonia, abnormal level of consciousness,
neonatal apnoea, tube feeding greater than 48 hours).

4. Complications of prematurity.
5. Disability at childhood follow-up (including deafness,
blindness, neurodisability or cerebral palsy).
Measures of satisfaction
1. Women’s satisfaction.
Costs
1. Costs associated with ’specialised’ antenatal care versus
’standard’ care.
2. Number of antenatal visits.
3. Number of antenatal admissions and length of admission.
4. Length of maternal postnatal stay.
5. Length of stay in neonatal intensive care unit.
6. Infant length of hospital stay.
We have included outcomes in the analysis if data were
available ac-
cording to original allocation and reasonable measures were
taken
to minimise observer bias. Only outcomes with available data
ap-

pear in the analysis tables. In order to minimise the risk of bias,
we have based the conclusions solely on the pre-stated
outcomes.
Search methods for identification of studies
We searched the Cochrane Pregnancy and Childbirth Group’s
Tri-
als Register by contacting the Trials Search Co-ordinator (30
June
2011).
improve
The Cochrane Pregnancy and Childbirth Group’s Trials Register
is maintained by the Trials Search Co-ordinator and contains
trials
identified from:
1. quarterly searches of the Cochrane Central Register of
Controlled Trials (CENTRAL);

2. weekly searches of MEDLINE;
3. weekly searches of EMBASE;
4. handsearches of 30 journals and the proceedings of major
conferences;
5. weekly current awareness alerts for a further 44 journals
plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL, MEDLINE, and
EMBASE, the list of handsearched journals and conference pro-
ceedings, and the list of journals reviewed via the current
aware-
ness service can be found in the ‘Specialized Register’ section
within the editorial information about the Cochrane Pregnancy
and Childbirth Group.
Trials identified through the searching activities described
above
are each assigned to a review topic (or topics). The Trials
Search
Co-ordinator searches the register for each review using the
topic
list rather than keywords.

We did not apply any language restrictions.
Data collection and analysis
Selection of studies
Two review authors independently assessed for inclusion all the
studies we identified as a result of the search strategy. We
resolved
any disagreement through discussion.
Data extraction and management
We designed a form to extract data. For eligible studies, at least
two review authors extracted the data using the agreed form. We
resolved discrepancies through discussion. We entered data into
Review Manager software (RevMan 2011) and checked for
accu-
racy.
When information regarding any of the above was unclear, we
attempted to contact authors of the original reports to provide
further details.
Assessment of risk of bias in included studies
Two review authors independently assessed risk of bias for each

study using the criteria outlined in the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2011). We
resolved
any disagreement by discussion.
(1) Sequence generation (checking for possible selection
bias)
We have described for each included study the method used to
generate the allocation sequence and assessed whether it should
have produced comparable groups.
We assessed the method as:
• low risk of bias (any truly random process, e.g. random
number table; computer random number generator);
• high risk of bias (any non-random process, e.g. odd or even
date of birth; hospital or clinic record number); or
• unclear risk of bias.
(2) Allocation concealment (checking for possible selection
bias)
We have described for each included study the method used to
conceal the allocation sequence and determined whether
interven-

tion allocation could have been foreseen in advance of, or
during
recruitment, or changed after assignment.
We assessed the methods as:
• low risk of bias (e.g. telephone or central randomisation;
consecutively numbered sealed opaque envelopes);
• high risk of bias (open random allocation; unsealed or non-
opaque envelopes, alternation; date of birth);
(3) Blinding (checking for possible performance bias)
We have described for each included study the methods used, if
any, to blind study participants and personnel from knowledge
of which intervention a participant received. With an interven-
tion such as the provision of specialised clinics blinding women
and clinic staff to group allocation is not generally feasible, it
may
however be possible, for some outcomes, to blind outcome
asses-
sors. We considered studies to be at lower risk of bias if
outcome

assessment was blinded or if we judged that the lack of blinding
would have been unlikely to have affected the results. We
assessed
blinding separately for different outcomes or classes of
outcomes.
• low, high, or unclear risk of bias for outcome assessors.
(4) Incomplete outcome data (checking for possible attrition
bias through withdrawals, dropouts, protocol deviations)
We have described for each included study, and for each
outcome
or class of outcomes, the completeness of data including
attrition
and exclusions from the analysis. We have stated whether
attrition
and exclusions were reported, the numbers included in the
analysis
at each stage (compared with the total randomised participants),
reasons for attrition or exclusion where reported, and whether
missing data were balanced across groups or were likely to be
related to outcomes. We assessed methods as:

improve
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es/PREG/frame.html
es/PREG/frame.html
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es/PREG/frame.html
es/PREG/frame.html
• low risk of bias;
• high risk of bias;
(We had intended to exclude data from the analysis where loss
to
follow-up for a particular outcome was greater than 20%;
however,
in two of the included trials information about exclusions and

attrition was not clear, so we have included all outcome data as
reported by study authors.)
(5) Selective reporting bias
We have described for each included study how we investigated
the possibility of selective outcome reporting bias and what we
found.
• low risk of bias (where it was clear that all of the study’s pre -
specified outcomes and all expected outcomes of interest to the
review were reported);
• high risk of bias (where not all the study’s pre-specified
outcomes were reported; one or more reported primary
outcomes were not pre-specified; outcomes of interest were
reported incompletely and so could not be used; study failed to
include results of a key outcome that would have been expected
to have been reported);
(6) Other sources of bias

We have described for each included study any important
concerns
we had about other possible sources of bias.
We assessed whether each study was free of other problems that
could put it at risk of bias:
• low risk of other bias;
• high risk of other bias;
• unclear risk of other bias.
(7) Overall risk of bias
We have made explicit judgements about whether studies are at
high risk of bias, according to the criteria given in the
Handbook
(Higgins 2011). With reference to (1) to (6) above, we assessed
the likely magnitude and direction of the bias and whether we
considered it is likely to impact on the findings. We planned to
explore the impact of the level of bias through undertaking
sensi-
tivity analyses - see Sensitivity analysis.
Measures of treatment effect
Dichotomous data

For dichotomous data, we have presented results as summary
risk
ratio with 95% confidence intervals.
Continuous data
For continuous data, we have used the mean difference if out-
comes were measured in the same way between trials. We used
the
standardised mean difference to combine trials that measured
the
same outcome, but used different methods.
Unit of analysis issues
Cluster-randomised trials
We have included one cluster-randomised trial in the analyses
along with individually-randomised trials. We adjusted the stan-
dard error for results from this study using the methods
described
in the Handbook (Higgins 2011). No estimate of the intraclus-
ter correlation co-efficient (ICC) was provided for this trial and
so we used a published ICC from another trial of antenatal care
(Piaggio 2001). As we used an ICC from another source, we
have

conducted sensitivity analyses to investigate the effect of
variation
in the ICC. Where we identified both cluster-randomised and
individually-randomised trials examining the same outcomes,
we
synthesised the relevant information. We considered it
reasonable
to combine the results from both, provided that there was little
heterogeneity between the study designs, and the interaction be-
tween the effect of intervention and the choice of randomisation
unit was considered to be unlikely.
Dealing with missing data
For included studies, we have noted levels of attrition. We
planned
to explore the impact of including studies with high levels of
miss-
ing data in the overall assessment of treatment effect by using
sen-
sitivity analysis; but in this version of the review, with so few
stud-
ies contributing data, we did not think further analysis would
shed

any further light on findings. In updates of the review, if more
data
are added, we will carry out sensitivity analysis excluding data
from
studies (or for particular outcomes) where there are high levels
of
missing data.
For all outcomes, we have carried out analyses, as far as
possible,
on an intention-to-treat basis, i.e. we attempted to include all
par-
ticipants randomised to each group in the analyses, and
analysed
all participants in the group to which they were allocated,
regard-
less of whether or not they received the allocated intervention.
The denominator for each outcome in each trial is the number
randomised minus any participants whose outcomes were known
to be missing.
improve

Assessment of heterogeneity
We assessed statistical heterogeneity in each meta-analysis
using
the T², I² and Chi² statistics. We have regarded heterogeneity as
substantial if I² is greater than 30% and either T² is greater than
zero, or there is a low P value (less than 0.10) in the Chi² test
for
heterogeneity.
Assessment of reporting biases
If there were 10 or more studies in the meta-analysis we
planned to
investigate reporting biases (such as publication bias) using
funnel
plots. In this version of the review, insufficient studies
contributed
data and we did not generate funnel plots. In updates, if more
data become available we will assess funnel plot asymmetry
visu-

ally, and use formal statistical tests; for continuous outcomes
we
will use the test proposed by Egger 1997, and for dichotomous
outcomes we will use the test proposed by Harbord 2006. If we
detect asymmetry in any of these tests or by a visual
assessment,
we will perform exploratory analyses to investigate it.
Data synthesis
We have carried out statistical analysis using the Review
Manager
software (RevMan 2011). We have used fixed-effect meta-
analysis
for combining data where it was reasonable to assume that
studies
were estimating the same underlying treatment effect: i.e. where
trials examined the same intervention, and the trials’
populations
and methods were judged sufficiently similar. Where we
suspected
clinical heterogeneity, or if we detected substantial statistical
het-
erogeneity, we have used random-effects meta-analysis to
produce

an overall summary if an average treatment effect across trials
was
considered clinically meaningful.
Where we have used random-effects analyses, we have
presented
results as the average treatment effect with 95% confidence
inter-
val, and the estimates of T² and I².
Subgroup analysis and investigation of heterogeneity
We planned to carry out the following subgroup analyses:
1. parity (nulliparous versus multiparous women);
2. type of care received (that is, time that specialised care
commenced; number of antenatal visits; use of ultrasound);
3. use of cervical length measurements (transvaginal
ultrasound versus no transvaginal ultrasound).
We planned to restrict subgroup analyses to primary outcomes.
We planned to assess differences between subgroups by inspec-
tion of the subgroups’ confidence intervals; with non-
overlapping
confidence intervals suggesting a statistically significant

difference
in treatment effect between the subgroups. In view of the small
number of studies contributing data we did not think there
would
be sufficient information for any particular subgroup to explore
possible subgroup differences and so in this version of the
review
we did not perform these additional analyses. If further studies
are
added in updates, we will consider carrying out further
analyses.
Sensitivity analysis
We planned to carry out sensitivity analyses to evaluate the
effect
of trial quality. In this version of the review, so few trials con-
tributed data that we did not think sensitivity analysis would
help
in the interpretation of results. One outcome included data from
a cluster-randomised trial, and for this outcome we carried out
a sensitivity analysis where we varied the value of the ICC
using
a more conservative value (upper 95% confidence interval for a

published ICC (Piaggio 2001)).
R E S U L T S
Description of studies
See: Characteristics of included studies; Characteristics of
excluded
studies.
Results of the search
Using the search strategy, we identified 15 reports describing
the
methods and findings from seven randomised trials (several of
the
studies resulted in multiple publications). We have included
three
of these trials in the review and have excluded four.
Included studies
All three included trials were carried out in the USA. All trials
fo-
cused on specialised clinics for women at high risk of preterm
birth,
and gestational age at delivery, preterm delivery, or both, were
pri-

mary outcomes in all studies. The interventions in the three
trials
differed slightly. In a study in Ohio (Iams 1989), women
attended
clinics and had cervical examinations weekly between 20 and 36
weeks’ gestation and were advised on the signs and symptoms
of
labour onset. In the Pennsylvania trial (Main 1989), women at-
tended weekly or twice-weekly clinics from 22 weeks’
gestation;
and again women were educated on the early signs of labour and
had cervical assessment. In the West Los Angeles 1994 trial,
clinics
rather than women were randomised (five experimental clinics
and
three control). Women attending experimental clinics had fort-
nightly visits and had three classes on preterm birth prevention.
In addition, in a nested study, women were randomised to one
of four secondary interventions (bed rest, psychosocial support,
oral progestin or a placebo). Participants in both experimental
and
control clinics received psychosocial and nutritional screening

and
were offered crisis intervention. We have set out further details
on
these studies in the Characteristics of included studies tables.
improve
Excluded studies
We excluded four studies: three because the samples included
women with multiple pregnancies and separate results were not
reported for singletons (Collaborative Group 1993; Goldenberg
1990; Pittsburgh 1989); finally, the study by Beazley 2001 was
reported in a brief abstract, we were not able to assess risk of
bias,
and it was not clear how many women were randomised to in-
tervention and control groups. We have provided further infor-
mation on these studies in the Characteristics of excluded

studies
tables.
Risk of bias in included studies
Allocation
In the study by Iams 1989 there was little information on study
methods; the way the randomisation sequence was generated
and
methods used to conceal allocation were not clear. In the Main
1989 trial, allocation was by a quasi-randomised method. The
West Los Angeles 1994 study was a cluster-randomised trial;
eight
clinics were randomised using a blocked technique.
Blinding
Blinding women and care providers to treatment group is
difficult
to achieve with an intervention involving different models of
care.
Women would be aware of their more frequent attendance and
so would clinic staff. In the cluster-randomised trial,
randomisa-
tion at the clinic level would be likely to reduce bias associated

with contamination. This study also examined additional inter -
ventions, and within the nested study in experimental clinics, it
would be difficult to blind women and staff to these additional
interventions (e.g. bed rest) although one of the four groups re -
ceived a placebo. It is not clear whether lack of blinding
represents
a serious source of bias in these studies.
Incomplete outcome data
Rates of attrition and exclusion in the control and experimental
groups were not clearly set out in two studies (Iams 1989; Main
1989). In the Main 1989 study, there appeared to be little loss to
follow-up for the primary outcome (preterm birth), although
there
were relatively high levels of missing data for neonatal
outcomes as
approximately 20% of infant case-notes were not reviewed. In
the
West Los Angeles 1994 study, loss to follow up was less than
10%;
however, even small losses may be important in studies
examining

a relatively infrequent outcome, especially if loss is not
balanced
across groups, as those most vulnerable to poor outcomes may
be
over-represented amongst those who are not followed up.
Selective reporting
Without access to study protocols, it is difficult assess selective
reporting bias. All three studies reported the number of preterm
births, although other key outcomes (for example, perinatal
death
and extreme prematurity) were not reported. It is not clear
whether
or not this information was collected.
Other potential sources of bias
We have noted in the Characteristics of included studies tables
other possible sources of bias, and any factors which we thought
affected our interpretation of results. One of the included
studies
was a cluster randomised trial; in the trial report results had not
been adjusted for cluster design effect. In order to pool results
from

this trial with those from trials where women were randomised,
where sufficient information was available to allow us to do so,
we used the generic inverse variance method and adjusted the
standard error of results from the cluster randomised-trial to
take
account of design effect.
Effects of interventions
Specialised antenatal clinics versus routine care:
three studies with 3400 women
Primary outcomes
Perinatal death (defined as stillbirth after trial entry, or death
of a liveborn infant up to seven days of age)
Perinatal death was reported in one of the included studies with
outcome data for 302 infants (Main 1989). There was no
evidence
of a significant difference between groups; overall, there were
13
deaths, seven in the treatment group and six in the control group
(risk ratio (RR) 1.25, 95% confidence interval (CI) 0.43 to
3.62).

Extremely preterm birth (defined as birth less than 28 weeks’
gestation)
This outcome was reported in one study with data for 376
women
(Main 1989). There was no clear evidence of a difference
between
women attending specialist clinics compared with those
receiving
routine care (RR 0.77, 95% CI 0.26 to 2.25).
improve
Secondary outcomes
Antenatal complications
The number of women being admitted with antenatal compli-
cations (including preterm labour (actual or suspected), preterm
prelabour ruptured membranes, intrauterine growth restriction

(estimated fetal weight less than 10th centile for gestational
age))
was reported in one study (370 women) (Iams 1989). There was
no statistically significant difference between groups (RR 1.29,
95% CI 0.90 to 1.86).
Preterm birth (birth before 37 weeks’ gestation)
All three included studies provided data for this outcome (3400
women). One of the studies used a cluster-randomisation tech-
nique and so the standard error has been adjusted (West Los
Angeles 1994). When data from the three studies were pooled,
it appeared that there were fewer preterm births in the treatment
group compared with controls, but the difference between
groups
was not statistically significant (RR 0.87, 95% CI 0.69 to 1.08
(adjusted data, inverse variance method Analysis 1.4)). For this
outcome, we carried out a sensitivity analysis whereby, for the
cluster-randomised trial, we used the upper 95% CI for the ICC
(most conservative value); in this analysis, while the weight of
the

cluster-randomised trial was reduced, this adjustment made very
little difference to results (RR 0.87, 95% CI 0.69 to 1.11 (ad-
justed data, inverse variance method Analysis 1.5 )). (In
Analysis
1.27 we have set out the original data for the three studi es;
again
results were similar and although the 95% CI was narrower the
difference between groups still did not reach statistical
significance
(unadjusted RR 0.85, 95% CI 0.70 to 1.03).)
Very preterm birth (before 34 weeks)
One study contributed data to this outcome and there was no
evidence of differences between groups (RR 1.05, 95% CI 0.50
to 2.21) (Main 1989).
Other secondary outcomes
There was no significant evidence of differences between
women
attending specialised clinics and women receiving routine care
for any of the following secondary outcomes: gestational age at
birth (Analysis 1.7); caesarean section (Analysis 1.9); or
neonatal

intensive care unit admission (Analysis 1.13).
There were no data reported for our remaining secondary out-
comes.
Costs of care and process variables
Two studies examined the costs associated with care (Main
1989;
West Los Angeles 1994). However, in one of these studies
(West
Los Angeles 1994), a sub-sample of approximately 10% of the
total sample only was included in the cost-analysis (280/2705
women). Further, in this study there was no adjustment for
cluster
design effect and in the data and analyses tables we have
therefore
presented unadjusted data for cost outcomes.
When data from the Main 1989 and West Los Angeles 1994
stud-
ies were pooled there was no significant evidence that
specialised
clinics and routine management differed in terms of the total
cost

of care for women (Analysis 1.19).
The cost of newborn infant care was examined in the West Los
Angeles 1994 trial and appeared to be reduced in infants of
women
attending the experimental clinics compared with controls.
How-
ever, results were not simple to interpret. The authors suggest
that
the cost difference was due to a combination of fewer preterm
births in the experimental group, a lower relative rate of
delivery
at less than 32 weeks’ gestation, and lower mean costs for
infants
of comparable gestations (Analysis 1.20). They did not
comment
on what interventions were required by babies in the different
groups or whether the two groups had different rates of steroid
administration which may have impacted on neonatal condition
at delivery.
In the West Los Angeles 1994 study women in the control group
had fewer antenatal clinic visits with a mean of 4.9 clinic atten-

dances compared with a mean of 6.6 for women in the
experimen-
tal group (mean difference 1.7, 95% CI 0.72 to 2.68) (Analysis
1.21).
D I S C U S S I O N
Summary of main results
Overall there was very little data on our pre-specified outcomes.
For most outcomes a single study provided data, hence there
may
have been insufficient statistical power to detect any possible
differ-
ences between groups. There was no clear evidence that
specialised
antenatal clinics reduce the number of preterm births. Perinatal
death was reported in only one of the included studies and there
was no evidence of a significant difference between groups. .
Overall completeness and applicability of
evidence
Interpreting the findings of this review is not straightforward.
Preterm birth is a multi-factorial disorder and hence a complex
intervention such as a package of antenatal care is a logical

solution
to preventing its recurrence. The antenatal care needs to be
aimed
improve
at managing diverse contributing factors such nutritional
deficien-
cies, smoking cessation, dental hygiene, infection, cervical
weak-
ness, pro-thrombotic tendency, psycho-social stress and
excessive
uterine contractility. The review includes only three trials,
which
tackled potential contributing factors to varying degrees, and
the
same outcomes were not reported for all trials. Furthermore, the
three trials varied in the nature of the services provided as part
of

the specialised antenatal clinic. Two studies included repeat
digi-
tal cervical assessment (RDCA) in the treatment arm (Iams
1989;
Main 1989I). Whilst there is no evidence that RCDA is effective
as a routine intervention in the antenatal clinic as a screening
test
for the risk of preterm birth in average risk pregnancies, it has
not
been thoroughly evaluated as a component of a complex
interven-
tion such as a specialist antenatal clinic, targeting preterm birth
(Alexander 2010). This makes interpretation of our results more
difficult. In addition, the trials were all conducted in the 1980s
prior to the introduction of many of the screening tests currently
offered in specialised antenatal clinics e.g. fetal fibronectin
testing
and ultrasound assessment of cervical length. There is cl ear evi-
dence that antenatal steroids improve neonatal survival and
reduce
neonatal morbidity (Roberts 2006), hence the ability to
accurately

predict preterm labour in a specialised clinic would ensure that
women received the steroids prior to delivery. The problem is
that
at present the current predictive tests (cervical length
monitoring
and fetal fibronectin) are not sufficiently specific to make them
cost effective (Honest 2009).
Quality of the evidence
The quality of the evidence in these three trials was mixed, and
the methods used to conceal allocation were at high or unclear
risk of bias in the two trials where women were randomised
(Iams
1989; Main 1989). In the cluster-randomised trial findings were
not adjusted for cluster design effect; and while we attempted to
take account of possible design effects for some outcomes we
did
not have sufficient information to adjust the cost data reported
in
the West Los Angeles 1994 trial. Missing data were a concern in
two of the included trials; even small losses may be important
in

studies examining relatively infrequent outcomes, as those most
vulnerable to poor outcomes may be over-represented amongst
those who are not followed up.
Potential biases in the review process
We are aware of potential biases in the reviewing process; and
we took steps to minimise bias (e.g. two authors independently
assessed study eligibility, carried out data extraction and
assessed
risk of bias).
A U T H O R S ’ C O N C L U S I O N S
Implications for practice
Since the publication of the trials included in this review (1989
to
1994) there have been further meta-analyses of trials of
individual
treatments that were effective at preventing preterm birth:
proges-
terone (Barros 2010; Honest 2009; Rode 2009); smoking cessa-
tion (Barros 2010); eradication of asymptomatic bacteriuria
(Iams
2010); appropriate use of cerclage (Iams 2010I); and calcium

sup-
plementation (Hofmeyr 2010). Implementation of evidence from
clinical trials is notoriously slow and incomplete (Bodribb
2010).
Hence, it may be that a future trial of specialised antenatal
clinic
would show evidence of benefit because of improved implemen-
tation of these interventions that have been more recently shown
to be effective.
Importantly, it is not known whether preventing preterm birth
reduces neonatal morbidity and mortality as it may be that re-
taining a fetus in an unfavourable intrauterine environment has
a detrimental effect on in utero development. Hence, any future
trials need to report both short and long-term neonatal outcomes
(Kenyon 2008).
Implications for research
As specialised antenatal clinics for women with a pregnancy at
high risk of preterm delivery are now an accepted part of
antenatal
services in many areas, it will be difficult to carry out further

randomised studies. However, the trials included in the review
included no information on psychological outcomes for women.
Some studies have suggested that whilst some pregnant women
welcome referral to a specialist clinic during pregnancy, others
experience it as unsettling (Jackson 2006). Any future research
in
this area should examine which aspects of service provision are
preferred by women. Such research could underpin further
service
development in this area.
A C K N O W L E D G E M E N T S
As part of the pre-publication editorial process, this review has
been
commented on by two peers (an editor and referee who is
external
to the editorial team), a member of the Pregnancy and
Childbirth
Group’s international panel of consumers and the Group’s
Statis-
tical Adviser.

improve
R E F E R E N C E S
References to studies included in this review
Iams 1989 {published data only}
Iams JD, Johnson FF. Effect of a preterm birth prevention
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Orleans, Louisiana, USA. 1989:387.
Main 1989 {published data only}
∗ Main DM, Gabbe SG, Richardson D, Strong S. Can
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Obstetrics and Gynecology 1985;151:892–8.
Main DM, Richardson DK, Hadley CB, Gabbe SG.
Controlled trial of a preterm labor detection program:

efficacy and costs. Obstetrics & Gynecology 1989;74:873–7.
West Los Angeles 1994 {published data only}
Hobel CJ, Bemis RL. West Area Los Angeles prematurity
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Hobel CJ, Bragonier R, Ross M, Bear M, Bemis R, Mori
B. West Los Angeles premature prevention program:
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∗ Hobel CJ, Ross MG, Bemis RL, Bragonier JR, Bear M,
Mori B. West Los Angeles preterm birth prevention project
(LAPPP): program impact. American Journal of Obstetrics
and Gynecology 1992;166:363.
Hobel CJ, Ross MG, Bemis RL, Bragonier JR, Nessim
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American Journal of Obstetrics and Gynecology 1994;170:
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Ross MG, Sandhu M, Bemis R, Nessim S, Bragonier JR,
Hobel C. The West Los Angeles preterm birth prevention
project: II. cost-effectiveness analysis of high-risk pregnancy
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Ross MG, Sandhu M, Bemis R, Nessim S, Bragonier JR,
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References to studies excluded from this review
Beazley 2001 {published data only}
Beazley D, Mercer B, Meyer N, Carr T. The Memphis
preterm birth project: prediction and prevention of preterm
birth in extremely high risk women [abstract]. American
Journal of Obstetrics and Gynecology 2001;185(6 Suppl):S86.
Collaborative Group 1993 {published data only}
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a preterm birth prevention program. American Journal of

Obstetrics and Gynecology 1993;169:352–66.
Creasy RK. United States multicenter preterm birth
prevention program. Prevention of Preterm Birth 1986;138:
187–204.
Goldenberg 1990 {published data only}
Goldenberg RL, Davis RO, Copper RL, Corliss DK,
Andrews JB, Carpenter AH. The Alabama Preterm Birth
Prevention Project. Obstetrics & Gynecology 1990;75:933–9.
Pittsburgh 1989 {published data only}
Mueller-Heubach E. Results of a three-year prospective
controlled randomized trial of preterm birth prevention at
the University of Pittsburgh. Advances in the Prevention of
Low Birthweight: an International Symposium; 1988 May
8-11; Cape Cod, Massachusetts, USA. 1988:61–6.
Mueller-Heubach E, Reddick D, Barnett B, Bente R.
Preterm birth prevention: evaluation of a prospective
controlled randomized trial. American Journal of Obstetrics
and Gynecology 1989;160:1172–8.

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D, Van Giejn HP. Cervical incompetence prevention
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length. Ultrasound in Obstetrics & Gynecology 1998;12:
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Barros 2010
Barros FC, Bhutta ZA, Batra M, Hansen TN, Victora
CG, Rubens CE, GAPPS Review Group. Global report
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Egger M, Smith GD, Schneider M, Minder C. Bias in
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Hack 1999
Hack M. Consideration of the use of health status,
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intensive care practice. Pediatrics 1999;103(1 Suppl E):
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Harbord 2006
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Systematic Reviews of Interventions Version 5.1.0 [updated
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the occurrence of preterm birth. Clinical Obstetrics and
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Hofmeyr 2010
Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L. Calcium
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Honest H, Forbes CA, Durée KH, Norman G, Duffy SB,
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Iams J. Cervical incompetence. Maternal-Fetal Medicine.
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Jackson 2006
Jackson CJ, Bosio P, Habiba M, Waugh J, Kamal P, Dixon-
Woods M. Referral and attendance at a specialist antenatal
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Kenyon 2008
Kenyon S, Pike K, Jones DR, Brocklehurst P, Marlow N,
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Kramer M, Demissie K, Yang H, Platt RW, Sauve R, Liston
R. The contribution of mild and moderate preterm birth to
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Lumley J. Defining the problem: epidemiology of preterm
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Roberts 2006
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Rode L, Langhoff-Roos J, Andersson C, Dinesen J,
Hammerum MS, Mohapeloa H, et al.Systematic review
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Ruis RJ, Fullerton J, Dudley DJ. The interrelationships
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∗ Indicates the major publication for the study
improve

C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Iams 1989
Methods Randomised controlled trial of routine antepartum care
versus routine antepartum care
plus a preterm birth prevention clinic in which symptoms and
signs of labour were taught
and the cervix examined at weekly visits between 20 and 36
weeks’ gestation
Participants 370 pregnant women considered high risk for
preterm birth based on use of the Creasey
Scoring system (Creasy 1980). Women were selected from 2829
women attending pre-
natal clinic at the Department of Obstetrics and Gynecology,
Ohio State University,
Ohio
Interventions Preterm birth prevention clinic in which
symptoms and signs of labour were taught and

the cervix examined at weekly visits between 20 and 36 weeks’
gestation
Outcomes Preterm labour diagnosed before 37 weeks’ gestation
when cervical changes accompanied
persistent uterine contractions despite bedrest and intravenous
hydration, or, if the cervix
was already 2 cm dilated and/or 50% effaced, when 8
contractions/hour persisted despite
bedrest and parenteral hydration
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Insufficient information about the se-
quence generation process to permit judge-
ment of risk of bias
Allocation concealment (selection bias) Unclear risk
Insufficient information about the se-

Blinding (performance bias and detection
bias)
All outcomes
Unclear risk Insufficient information about the se-
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk No reporting of attrition or exclusions.
Selective reporting (reporting bias) Unclear risk Insufficient
information about the se-
ment of risk of bias.
Other bias Unclear risk Does not explicitly state that only
single-
ton pregnancies were included in the study.
improve

Iams 1989 (Continued)
No comment is made on what cut-off was
used for the Creasy scoring system to de-
fine women as of high risk of preterm birth
(Creasy 1980).
Main 1989
Methods Randomised controlled trial of routine antepartum care
versus a preterm labour detection
clinic in which women were seen on a weekly or biweekly basis,
the cervix examined at
each visit and education provided regarding subtle signs of
labour
Participants All women were from the obstetric clinic of the
University of Pennsylvania Hospital,
USA. 376 black women considered at high risk for preterm birth
based on a Papiernik-
Creasey Scoring system value of 10 or more (Creasy 1980). 178
control patients and

198 women assigned to preterm labour detection clinic
Interventions Attendance at a preterm labour detection clinic on
a weekly or biweekly basis from
22 weeks’ gestation. Cervical assessment by 1 of 3 physicians at
each visit. Education
provided by a nurse specialist regarding subtle signs of labour
Outcomes Gestational age at delivery, birthweight, preterm
PROM, inpatient costs, outpatient costs
Notes Higher rate of accrual into the intervention group due to:
(1) high-risk women who par-
ticipated in the Preterm Labour Detection Clinic in earlier
pregnancies being uniformly
assigned to it in subsequent pregnancy; (2) higher elective
abortion and transfer of care
rates in control group
Risk of bias
bias)
High risk Consecutive numbers of a random num-
bers table were used to allocate the first

479 participants whilst the second sam-
ple of 464 women was divided into groups
by birthday (even versus odd day of the
month)
Allocation concealment (selection bias) High risk Date of birth
used for allocation of half of
participants.
bias)
All outcomes
Low risk Neither the physicians or the control pa-
tients were made aware they were at high
risk of preterm birth. Not possible to blind
participants attending the preterm labour
detection clinic due to the frequency of at-
tendance
improve

Main 1989 (Continued)
All outcomes
High risk Insufficient reporting of attrition/exclu-
sions: there were missing data (approxi-
mately 20%) for neonatal outcomes as not
all infant case notes were examined
Selective reporting (reporting bias) Unclear risk Insufficient
information about the se-
Other bias Unclear risk Women included in study during more
than one pregnancy.
West Los Angeles 1994
Methods Eight West Los Angeles County prenatal clinics
randomised to be either experimental or

control clinics. Women in experimental clinics offered a
programme of more frequent
visits, preterm birth prevention education, psychosocial and
nutritional screening and
crisis intervention. Women in control clinics offered routine
county care plus psychoso-
cial and nutritional screening and crisis intervention
Participants 1774 high-risk patients in experimental clinics and
880 control clinic patients. Majority
of patients were Hispanic
Interventions Women in control clinics offered visits at 4-week
intervals up to 30 weeks’ gestation, 2-
week intervals from 30-35 weeks’ gestation, and then weekly
until delivery. Psychosocial
and nutritional screening and crisis intervention also offered.
Women in experimental
clinics offered visits at 2-week intervals, 3 classes regarding
preterm birth prevention,
psychosocial and nutritional screening and crisis intervention.
Participants were ran-
domised to 1 of 4 secondary interventions (bed rest, social
work, Provera or Provera-
matched control) or to no additional intervention

Outcomes Preterm birth rate, costs of antenatal care, inpatient
preterm labour, delivery and postpar-
tum care, and newborn care. For continuous outcomes (costs
and number of antenatal
visits) means and standard errors were reported. We calculated
standard deviations in
order to include these data in the data and analyses tables
Notes
Risk of bias
bias)
Unclear risk Cluster randomised therefore not applica-
ble; “these clinics were randomized with a
restricted block (grouped by size and per-
cent black) randomized scheme to identify
the clinic as either experimental (five clin-
ics) or control (three clinics)”

improve
West Los Angeles 1994 (Continued)
Allocation concealment (selection bias) Unclear risk Cluster
randomised therefore not applica-
ble.
bias)
All outcomes
High risk Women randomised based on which clinic
they attended.
All outcomes
Unclear risk All high-risk women accounted for in a flow
chart. 5%-7% of women assessed as high
risk lost to follow-up

Other bias Low risk
PROM: preterm rupture of membranes
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Beazley 2001 Study design: randomised prospective trial.
Intervention: weekly contact with a nurse versus routine care.
Participants: 218 women at high risk of preterm birth
Outcomes: preterm birth before 37 weeks’ gestation and
spontaneous preterm birth before 37 weeks’
gestation
Published in abstract form only. Not clear how many patients
were in control and intervention groups
therefore analysis not possible. No decrease in the incidence of
preterm birth or spontaneous preterm
birth in the intervention group (43% vs 41%, 35% vs 30%
respectively)
Collaborative Group 1993 Study design: multi-centre
randomised controlled trial.
Intervention: preterm labour prevention programme with
additional visits, education about the signs
of preterm labour and cervical assessment at routine visits vs
routine care.

Participants: 2395 women considered at high risk of preterm
delivery.
Outcomes: spontaneous preterm birth by 36 and 37 completed
weeks with and without PPROM, very
low birthweight (< 1500 g at birth), low birthweight (< 2500 g
at birth).
Women with multiple pregnancies included in all the analyses.
Creasy publication of data from a cohort
of the women included in the Collaborative Group on Preterm
Birth Prevention publication
Goldenberg 1990 Study design: multi-centre randomised
controlled trial.
Intervention: preterm labour prevention programme with weekly
visits, education about the signs of
preterm labour and cervical assessment at routine visits vs
routine care. Control women seen in different
clinics from intervention patients.
delivery.
Outcomes: spontaneous preterm birth at less than 37 completed
weeks, very low birthweight (< 1500
improve

(Continued)
g at birth), low birthweight (1500-2499 g at birth), spontaneous
preterm PROM rate.
Women with multiple pregnancies included in all the analyses
Pittsburgh 1989 Study design: randomised controlled trial.
Intervention: preterm labour prevention programme with weekly
visits, education about the signs of
preterm labour and cervical assessment at each visit vs routine
care
delivery out of 5457 women screened.
Outcomes: spontaneous preterm birth at less than 37 completed
weeks.
Women with multiple pregnancies included in all the analyses
vs: versus
improve

D A T A A N D A N A L Y S E S
Comparison 1. Specialised antenatal care versus routine care
Outcome or subgroup title
No. of
studies
No. of
participants Statistical method Effect size
1 Perinatal death 1 302 Risk Ratio (M-H, Fixed, 95% CI) 1.25
[0.43, 3.62]
2 Extremely preterm birth (< 28
weeks’ gestation)
1 376 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.26, 2.25]
3 Development of antenatal
complications - preterm labour

4 Preterm birth - adjusted for
cluster design effect (ICC
0.002)
3 Risk Ratio (Fixed, 95% CI) 0.87 [0.69, 1.08]
4.1 Individually randomised
trials
4.2 Cluster randomisation 1 Risk Ratio (Fixed, 95% CI) 0.81
[0.58, 1.14]
5 Sensitivity analysis. Preterm
birth (adjusted for cluster
design effect using upper CI,
ICC 0.0041)
5.1 Individually randomised
trials
5.2 Cluster randomisation 1 Risk Ratio (Fixed, 95% CI) 0.81
[0.54, 1.22]

6 Very preterm birth (birth before
34 weeks’ gestation)
7 Gestation at birth 1 2654 Mean Difference (IV, Fixed, 95%
CI) -0.10 [-0.30, 0.10]
8 Infection requiring intravenous
antibiotics
9 Caesarean section 1 376 Risk Ratio (M-H, Fixed, 95% CI)
1.11 [0.76, 1.62]
10 Postnatal depression 0 0 Risk Ratio (M-H, Fixed, 95% CI)
0.0 [0.0, 0.0]
11 Breastfeeding 0 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0,
0.0]
12 Instrumental vaginal birth 0 0 Risk Ratio (M-H, Fixed, 95%
CI) 0.0 [0.0, 0.0]
13 Neonatal intensive care unit
admission
14 Respiratory distress syndrome 0 0 Risk Ratio (M-H, Fixed,
95% CI) 0.0 [0.0, 0.0]

15 Parameters of birth asphyxia 0 0 Risk Ratio (M-H, Fixed,
95% CI) 0.0 [0.0, 0.0]
16 Complications of prematurity 0 0 Risk Ratio (M-H, Fixed,
95% CI) 0.0 [0.0, 0.0]
17 Disability at childhood follow-
up
18 Women’s satisfaction 0 0 Risk Ratio (M-H, Fixed, 95% CI)
0.0 [0.0, 0.0]
19 Costs associated with care 2 604 Mean Difference (IV,
Fixed, 95% CI) -16.67 [-367.00,
335.67]
20 Costs associated with newborn
inpatient care (US $)
1 290 Mean Difference (IV, Fixed, 95% CI) -2196.0 [-4322.06,
-
69.94]
21 Number of antenatal visits 1 290 Mean Difference (IV,
Fixed, 95% CI) 1.70 [0.72, 2.68]
22 Number of antenatal
admissions

0 0 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
improve
23 Length of antenatal admissions 0 0 Mean Difference (IV,
Fixed, 95% CI) 0.0 [0.0, 0.0]
24 Length of maternal postnatal
stay
25 Length of stay in neonatal
intensive care unit
26 Infant length of stay in hospital 0 0 Mean Difference (IV,
Fixed, 95% CI) 0.0 [0.0, 0.0]
27 Preterm birth - all studies,
unadjusted data

27.1 Individual randomisation 2 746 Risk Ratio (M-H, Fixed,
95% CI) 0.90 [0.67, 1.21]
27.2 Cluster randomisation 1 2654 Risk Ratio (M-H, Fixed, 95%
CI) 0.81 [0.62, 1.06]
routine care, Outcome 1 Perinatal death.
Review: Specialised antenatal clinics for women with a
pregnancy at high risk of preterm birth (excluding multiple
pregnancy) to improve maternal and infant outcomes
Comparison: 1 Specialised antenatal care versus routine care
Outcome: 1 Perinatal death
Study or subgroup Treatment Control Risk Ratio Weight Risk
Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Main 1989 7/146 6/156 100.0 % 1.25 [ 0.43, 3.62 ]
Total (95% CI) 146 156 100.0 % 1.25 [ 0.43, 3.62 ]
Total events: 7 (Treatment), 6 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.40 (P = 0.69)
Test for subgroup differences: Not applicable
0.01 0.1 1 10 100

Favours treatment Favours control
improve
routine care, Outcome 2 Extremely preterm
birth (< 28 weeks’ gestation).
Review: Specialised antenatal clinics for women with a
pregnancy at high risk of preterm birth (excluding multiple
pregnancy) to improve maternal and infant outcomes
Comparison: 1 Specialised antenatal care versus routine care
Outcome: 2 Extremely preterm birth (< 28 weeks’ gestation)
Study or subgroup Treatment Control Risk Ratio Weight Risk
Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Main 1989 6/198 7/178 100.0 % 0.77 [ 0.26, 2.25 ]
Total (95% CI) 198 178 100.0 % 0.77 [ 0.26, 2.25 ]

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