1) This study conducted a systematic review and meta-analysis of 23 studies to examine the effects of chronic kidney disease (CKD) on pregnancy outcomes and the effects of pregnancy on renal outcomes in women with CKD. 2) The results showed that women with CKD faced significantly higher risks of adverse pregnancy outcomes like preeclampsia, premature birth, and small-for-gestational-age babies compared to women without CKD. 3) However, the study found no evidence that pregnancy led to worsening of renal outcomes in women with CKD compared to non-pregnant women with CKD. Pregnancy did not appear to negatively impact kidney function or progression to kidney failure.

1. Moh’d Sharshir, MD
Nephrology Fellow

2. Introduction:
■ The prevalence of CKD in women of childbearing age ranges from 0.1% to 3%.
■ Furthermore, pregnancy is generally considered to be a risk factor for the
progression of CKD.

3. Introduction:
■ Previous systematic reviews indicated that the risk of adverse maternal and fetal
outcomes was higher in patients with CKD compared with those without CKD, but
the influence of pregnancy on renal outcomes was undetermined.
Piccoli GB, Conijn A, AttiniR, Biolcati M, Bossotti C, Consiglio V, Deagostini MC, Todros T: Pregnancy in chronic kidney disease: Need for a common language. J Nephrol 24: 282–299, 2011

4. Introduction:
■ Traditionally, it was considered that CKD progressively worsens in pregnant
women, especially with serious pathologic changes or renal insufficiency
before pregnancy (42–44).
■ Therefore, women with CKD were usually advised to avoid gestation,
except for recipients of renal transplants with stable renal function.

5. Introduction:
■ Here, they conducted a systematic review and meta-analysis of published cohort
studies and case control studies to obtain an overall estimate of the potential effect
of CKD and pregnancy on each other.

6. Materials and Methods:
■ They conducted and reported this
systematic review according to published
guidelines, using a prespecified protocol.
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group: Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. J Clin Epidemiol 62: 1006–1012, 2009

7. Eligibility Criteria:
■ They included cohort studies and case-control studies that reported maternal or
fetal outcomes in pregnant women with CKD and without CKD as a comparator
group who may or may not have had other comorbidities (e.g., diabetes mellitus) or
studies that reported renal outcomes in pregnant women with CKD and
nonpregnant women with CKD as a comparator group.

8. Eligibility Criteria:
■ Primary studies defined CKD as any of the following: abnormal serum creatinine
(SCr)/abnormal GFR and/or proteinuria with a specific primary or secondary kidney
disease.
■ CKD is classified into five stages.
■ Adverse maternal outcomes were defined by the primary study authors and
included preeclampsia, eclampsia, and maternal mortality.
■ Adverse fetal outcomes included premature births, small for gestational age (SGA),
low birth weight, neonatal mortality, and stillbirths.
■ Renal outcomes included incidence of ESRD requiring RRT, doubling of SCr, and
50% decrement of eGFR/creatinine clearance rate (CCr).

9. Eligibility Criteria:
■ They excluded studies of women with a history of autoimmune diseases
(SLE, ANCA-associated systemic vasculitis, or Sjögren syndrome),
hereditary kidney disease, kidney transplant, or maintenance dialysis, as
well as studies of women with AKI or a single kidney.

10. Search Strategy:
■ They searched the following electronic databases from the date of inception up to
November 2014: MEDLINE (Ovid, 1946–2014) and Embase (1988–2014).

11. Study Selection:
■ Full-text articles considered potentially relevant were retrieved.
■ To ensure accuracy, the articles were independently screened the full-text articles
for inclusion.
■ Disagreement over eligibility was resolved by discussion or with the help of another
reviewer.

12. Study Quality:
■ The evidential level of each outcome of the studies was determined in accordance
with the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) system and was conducted with GRADE profiler 3.6.
■ Publication bias was assessed by creating and examining funnel plots.
■ A sensitivity analysis was performed by omitting studies with the smallest number of
participants and investigating the influence on the overall meta-analysis estimate.

13. Statistical Analyses:
■ The data was independently abstracted in duplicate to increase accuracy and
reduce measurement bias.
■ Disagreements were resolved with the help of another reviewer.

14. Statistical Analyses:
■ The following data were extracted: title, author, year, journal, period of study,
country, type of study, number of cases, number of pregnancies, mean age, type of
study population, preeclampsia, gestational age, birth weight, preterm delivery,
cesarean section, other maternal complications, stillbirth/neonatal death, SGA,
other neonatal complications, the number of adverse renal outcome events,
baseline and follow-up BP, proteinuria, eGFR, and SCr.

15. Statistical Analyses:
■ They also calculated stillbirth, fetal death, and neonatal death together as
pregnancy failure because these outcomes were so serious that they led to failure
of pregnancy.

16. Statistical Analyses:
■ Summary estimates of the odds ratio (ORs) and 95% confidence intervals (95%
CIs) or mean difference and 95% CIs for continuous variables were obtained using
a random-effects model.
■ Heterogeneity across the included studies was analyzed using the I2 statistic.
■ They performed additional subgroup analyses by pooling estimates for subgroups
defined by the median, and the level of adjustment when these were reported.

17. Statistical Analyses:
■ The definition of macroproteinuria was PCR > 500 mg/g or urinary albumin-to-
creatinine ratio > 300 mg/g according to the Kidney Disease Improving Global
Outcomes 2012 CKD guideline, and the definition of microproteinuria was the level
of proteinuria below macroproteinuria.
■ All analyses were performed using Stata (release 11.0) or RevMan (release 5.2)
software.
■ A standard level (P< 0.05) of statistical significance was used in all analyses.

18. RESULTS

19. Study Selection and General Information:
■ They screened and evaluated 6372 citations, of which 143 were reviewed in full text.
■ Twenty-two were selected as relevant studies for our analysis, and one study that
was published as an American Society of Nephrology 2014 meeting abstract was
also added.

20. Study Selection and General Information:
■ Among 23 retrieved studies, 12 were prospective studies, 7 were retrospective
studies, and 4 did not mention whether they were retrospective or prospective.
■ Twelve studies were from European countries, five were from the United States,
four were from Asia, and two were from Brazil.
■ This meta-analysis of 23 selected studies including 504,826 pregnancies and 1514
pregnancies with CKD investigated the associations between pregnancy and CKD
outcomes as well as CKD and fetal/maternal outcomes during pregnancy.
■ Of the 23 studies (n=505,759 pregnancies), 14 of the reported adverse maternal or
fetal outcomes in pregnant women with CKD.

21. Study Selection and General Information:
■ The definition of CKD varied across the studies:
 Among 14 studies, 8 enrolled patients diagnosed with diabetic nephropathy (DN)
with proteinuria, 3 defined CKD according to the National Kidney Foundation Kidney
Disease Outcomes Quality Initiative definition, 1 defined CKD according to by
medical coding , and 1 defined CKD by biopsy.
 One study enrolled pregnant women with low kidney function defined as SCr >/=1.5
mg/dl.

23. Study Selection and General Information:
■ Six studies compared the maternal or fetal outcomes in pregnant women with CKD
with healthy pregnant women.
■ The remaining eight studies involving patients with DN had a control group with
comorbidities of diabetes with normal proteinuria and kidney function.
■ Four of 14 studies accounted for potential confounding factors such as proteinuria,
hypertension, systolic BP, and so forth (Tables 1 and 2).

26. Study Selection and General Information:
■ Of the 23 studies, 9 (n=1342) described the renal outcomes of pregnant women with CKD.
■ Mean follow-up was 8.6 years (range, 3–18 years) and median follow-up was 5 years
(interquartile range, 5–14.7 years).
■ Five studies enrolled pregnant women with IgA nephropathy, one study dealt with DN, and
three studies analyzed primary GN with various diagnoses.
■ The patients in the control groups were all nonpregnant women with matched age, type of
disease, and renal function.
■ Six of nine studies accounted for confounding factors such as proteinuria, mean arterial
pressure, eGFR, and so forth (Tables 3 and 4).

29. Effect of the Kidney Disease on Pregnancy:
■ Pregnancy outcomes in kidney disease varied among the studies.
■ They analyzed preeclampsia, premature birth, SGA/ low birth weight, cesarean
section, and failure of pregnancy (including stillbirth, fetal death, and neonatal
death) in pregnancies with CKD, according to former studies.

30. Effect of the Kidney Disease on Pregnancy:
■ Nine studies evaluated the occurrence of preeclampsia.
■ Overall, there were 14,993 events in 504,700 pregnancies.
■ The overall preeclampsia OR was 10.36 (95% CI, 6.28 to 17.09; P< 0.01; Figure 2)
in women with CKD compared with women without CKD.

31. Figure 2. | Overall odds ratios of the association of CKD and preeclampsia. 95% CI,
95% confidence interval.

32. Effect of the Kidney Disease on Pregnancy:
■ Ten studies reported 25,273 failures of pregnancy among 505,038 pregnancies.
■ Compared with the controls, patients with CKD with pregnancy had a significantly
higher rate of pregnancy failure (OR, 1.80; 95% CI, 1.03 to 3.13; P=0.04; Figure
3).

33. Figure 3. | Overall odds ratios of the association of CKD and failure of pregnancy (including stillbirth, fetal
death, and neonatal death). 95% CI, 95% confidence interval.

34. Effect of the Kidney Disease on Pregnancy:
■ The odds of premature birth, cesarean section, and SGA/low birth weight were also
higher in women with CKD, with ORs of 5.72 (95% CI, 3.26 to 10.03)
(Supplemental Figure 1), 4.85 (95% CI, 3.03 to 7.76) (Supplemental Figure 2),
and 2.67 (95% CI, 2.01 to 3.54) (Supplemental Figure 3).

35. Supplementary figure 1 Overall odds ratio (OR) of the association of CKD and
premature delivery.

36. Supplementary figure 2 Overall odds ratio (OR) of the association of CKD and small for
gestational age/low birth weight.

37. Supplementary figure 3 Overall odds ratio (OR) of the association of CKD and
cesarean section.

38. Effect of the Kidney Disease on Pregnancy:
■ Subgroup analysis showed that odds of preeclampsia (P=0.002), and premature
birth (P< 0.01) were higher in women with nondiabetic nephropathy than those
with DN (Figure 4).
■ The odds of preeclampsia (P=0.01) and premature delivery (P< 0.01) were higher
in women with macroproteinuria compared with those with microproteinuria
(Figure 4).
■ The identified between-study heterogeneity in failure of pregnancy (P=0.03) was
also caused by differences in sample size (Figure 4).

39. Figure 4. |
• Odds ratios of CKD on pregnancy complications
according to subgroups of publication year, sample size,
type of study population, and proteinuria.
• Microproteinuria indicates albuminuria 30–300 mg/24 h
or total proteinuria 150–500 mg/24 h, whereas
macroproteinuria indicates albuminuria >/=300 mg/24 h
or total proteinuria >/= 500 mg/24 h. 95% CI, 95%
confidence interval; DN, diabetic nephropathy; SGA,
small for gestational age.

40. Effect of the Kidney Disease on Pregnancy:
■ Most studies did not provide the full baseline data, such as BP, eGFR/CCr, and
SCr, which did not allow us to analyze whether these factors affected the
heterogeneity of pregnancy outcomes.

41. Effect of Pregnancy on Kidney Disease:
■ Eight studies reported 216 renal outcomes in 1268 participants.
■ Renal outcomes were defined as doubling of SCr levels, 50% decrement of
eGFR/CCr, or ESRD.
■ Compared with the control group, there was no difference in renal outcomes of
pregnant women with CKD (OR, 0.96; 95% CI, 0.69 to 1.35; P=0.83) (Figure 5).

42. Figure 5. | Overall odds ratios of the association of pregnancy and renal events (including doubling
of serum creatinine levels, 50% decrement of eGFR/CCr, and ESRD). 95% CI, 95% confidence
interval; CCr, creatinine clearance rate.

43. Effect of Pregnancy on Kidney Disease:
■ Only part of one study enrolled pregnant women with low kidney function (SCr
>1.2 mg/dl) before pregnancy.
■ There was also no significant difference in renal outcomes compared with the
control group (OR, 0.93; 95% CI, 0.17 to 5.15; Figure 5).
Rossing K, Jacobsen P, Hommel E, Mathiesen E, Svenningsen A, Rossing P, Parving HH: Pregnancy and progression of diabetic nephropathy. Diabetologia 45: 36–41, 20

44. Figure 5. | Overall odds ratios of the association of pregnancy and renal events (including doubling
of serum creatinine levels, 50% decrement of eGFR/CCr, and ESRD). 95% CI, 95% confidence
interval; CCr, creatinine clearance rate.

45. Effect of Pregnancy on Kidney Disease:
■ Subgroup analysis indicated that there was no significant difference according to
type of participants, CKD stage, baseline systolic BP, baseline proteinuria, and
level of SCr, publication year, sample size, and follow-up year (Figure 6).

46. Figure 6. | Odds ratios of pregnancy on renal out comes
according to subgroups of sample size, publication year,
follow-up year, type of study population, CKD classification,
baseline serum creatinine, baseline systolic BP, and baseline
proteinuria. 95% CI, 95% confidence interval; A, albuminuria
(mg/24 h); DN, diabetic nephropathy; SBP, systolic BP; SCr,
serum creatinine; T, total proteinuria (g/24 h).

47. Effect of Pregnancy on Kidney Disease:
■ Four studies reported the eGFR/CCr at the end of follow-up point (452
participants).
■ There was no significant difference in eGFR/CCr at the end of studies between
pregnant groups and nonpregnant groups (mean difference 2.91 ml/min; 95% CI,
22.42 to 8.24; P=0.28; Figure 7).

48. Figure 7. | Outcome of eGFR/CCr in women with CKD after pregnancy compared with non-pregnancy. 95% CI, 95%
confidence interval; CCr, creatinine clearance rate. IV, method of analysis was inverse variance.

49. Risk of Bias within Studies:
■ The GRADE evaluation indicated that the outcomes of preeclampsia and
premature delivery had high-quality evidence.
■ However, the quality of the evidence on SGA/ low birth weight was low, and failure
of pregnancy, cesarean section, and renal events were very low

50. Discussion:
■ The key finding of the systematic review of 216 renal events in 1268 participants
was that there was no significant difference in renal outcomes in pregnant women
compared with nonpregnant women who had CKD.
■ This association was uniformly consistent across subgroups characterized by
type of kidney disease, grade of CKD, systolic BP, and urinary proteins, which are
traditionally considered important risk factors for the decline of renal function.
 in this meta-analysis, there was no significant difference in renal outcomes between
pregnant women with stage 1–3 CKD and those without pregnancy.

51. Discussion:
■ They also observed that adverse pregnancy events, including preeclampsia,
premature birth, SGA/low birth weight, and cesarean section, were remarkably
higher in women with CKD than in women without CKD.
■ In particular, risks of failure of pregnancy, including stillbirth, fetal death, and
neonatal death were higher in pregnant women with CKD.

52. Discussion:
■ The odds of adverse pregnancy outcomes were different for various renal
diseases.
 The odds of premature delivery and preeclampsia were significantly higher in
women with nondiabetic nephropathy compared with those with DN.

53. Discussion:
■ They found that the odds of preeclampsia and premature delivery were higher in
women with macroproteinuria compared with women with microproteinuria.

54. Discussion:
■ Higher rates of successful pregnancy outcomes in women with DN have been
reported with treatment with angiotensin-converting enzyme inhibitors combined
with strict metabolic control for at least 6 months before gestation (42).
■ Therefore, measuring proteinuria is important before or early in pregnancy,
because proteinuria could predict patients at high risk for complications (43).

55. Discussion/ strengths :
■ This review had a number of strengths:
 They compared not only maternal and fetal outcomes between women with and
without CKD but also CKD progression in women with CKD who did or did not
become pregnant.

56. Discussion/ limitations :
■ There were several limitations in this meta-analysis:
 First, the data recorded in our study were not robust, because most related studies
were performed in a single center with limited numbers of participants and overall
low methodologic quality.
 Second, there was insufficient data to assess the degree of risk at various levels of
albuminuria and SCr/ eGFR on adverse pregnant outcomes.
 Third, there were only a few studies that assessed the association between renal
pathology and pregnancy outcome.
 Finally, we could not evaluate the effect of pregnancy on patients with stage 4 CKD
because of a lack of relevant studies.

57. CONCLUSIONS

58. The risks of adverse maternal and fetal outcomes in pregnancy are
higher for women with CKD versus pregnant women without CKD.
However, pregnancy was not a risk factor for progression of renal
disease in women with CKD before pregnancy.