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Is a history of preeclampsia associated with an increased risk of a small for gestational age infant in a future pregnancy? Anna Palatnik, MD; William A. Grobman, MD, MBA; Emily S. Miller, MD, MPH
BACKGROUND: A history of preeclampsia is associated with an increased risk of subsequent preeclampsia, but it is unclear whether women with prior preeclampsia are at increased risk of having a small-forgestational-age infant in their subsequent pregnancy, even if they do not develop preeclampsia. OBJECTIVE: The objective of this study was to evaluate whether women with preeclampsia in a prior pregnancy are at increased risk of having a pregnancy complicated by a small-for-gestational-age infant, even in the absence of recurrent preeclampsia. STUDY DESIGN: This was a secondary analysis of data from 2 multicenter, randomized controlled trials evaluating the role of aspirin in preeclampsia prevention in healthy nulliparas and women at high risk of preeclampsia (ie, with chronic hypertension or a history of preeclampsia). Women who developed preeclampsia in a subsequent pregnancy and women with pregestational diabetes or with a multiple gestation were excluded. The association between a history of preeclampsia and the subsequent birth of a small-for-gestational-age infant was determined in both a univariable and multivariable analysis.
I
t is well established that a pregnancy complicated by preeclampsia increases the risk of delivery of a small-for-gestational-age infant.1,2 The pathophysiology is attributable to an underlying propensity toward abnormal placentation.3 Abnormalities in the development of the placental vasculature lead to diminished uteroplacental-fetal blood flow, which ultimately results in fetal growth restriction.2-5 Once women have had preeclampsia, they are at increased risk of recurrent preeclampsia6 and the attendant risks of an small-for-gestational-age birth.2 However, it remains unclear whether the risk for an small-for-gestational-age birth also is elevated in women with a
Cite this article as: Palatnik A, Grobman WA, Miller ES. Is a history of preeclampsia associated with an increased risk of a small for gestational age infant in a future pregnancy? Am J Obstet Gynecol 2016;215:355.e1-6. 0002-9378/$36.00 ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2016.03.011
RESULTS: A total of 4052 women were included in the analysis: 2972 healthy nulliparas, 499 women with a history of preeclampsia, and 581 women with chronic hypertension. The frequency of delivery of a small-for-gestational-age infant significantly differed by clinical history (5.1% vs 9.2% vs 12.1% in healthy nulliparas, women with a history of preeclampsia, and women with chronic hypertension, respectively, P < .001). Compared with healthy nulliparas, a history of preeclampsia was associated with a significantly increased odds for a small-for-gestational-age infant, even if recurrent preeclampsia did not occur (adjusted odds ratio, 1.48, 95% confidence interval, 1.02e2.17). CONCLUSION: Even in the absence of recurrent preeclampsia, women with a history of preeclampsia are at a higher risk of delivering a small-forgestational-age infant in a subsequent pregnancy. Key words: preeclampsia, prior pregnancy, small-for-gestational-age
infant, subsequent preeclampsia
history of preeclampsia but without recurrent preeclampsia. Although the data point toward a higher risk of obstetric complications in women with a history of preeclampsia, including preterm birth, placental abruption, small-for-gestational-age infants and stillbirth, most studies examining this association grouped subsequent pregnancies, without a separate evaluation of the outcomes of successive pregnancies in the absence of recurrent preeclampsia.7-11 Therefore, our objective was to estimate the frequency of small-for-gestational-age births in women with prior preeclampsia in whom preeclampsia did not recur and to determine whether this frequency was elevated compared with nulliparas. We hypothesized that even in the absence of recurrent preeclampsia, women with a history of preeclampsia are at increased risk of a subsequent small-for-gestationalage birth.
Materials and Methods This was a secondary analysis of data from the following 2 multicenter,
randomized controlled trials conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network: 1) prevention of preeclampsia with low-dose aspirin in healthy nulliparous women12 and 2) low-dose aspirin to prevent preeclampsia in high-risk women.13 These trials examined whether lowdose aspirin therapy, initiated between 13 and 26 weeks, could reduce the incidence of preeclampsia compared with placebo. Because neither trial identified a significant reduction in the incidence of small-for-gestational-age infants in women randomized to aspirin, the present analysis included the entire study group without stratification by study arm. Also, in the present analysis, we excluded women who developed recurrent preeclampsia, had pregestational diabetes, or had a multiple gestation.14-16 A woman was defined as having a small-for-gestational-age infant based on a birth weight below the 10th percentile of normative birthweights for
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FIGURE
Flow chart detailing exclusion criteria applied to the present analysis
Palatnik. A history of preeclampsia and risk for SGA infant. Am J Obstet Gynecol 2016.
singletons at the time of the original trials.17 Preeclampsia was defined as hypertension (defined as a systolic blood pressure of 140 mm Hg or a diastolic blood pressure of 90 mm Hg on 2 occasions 4 hours apart) plus proteinuria (either 300 mg per 24 hours or 2þ or more by dipstick on 2 or more occasions 4 hours apart). Obstetric history was categorized as follows: 1) nulliparous women without chronic comorbidities (healthy nulliparas); 2) women with a history of preeclampsia but no other chronic comorbidities; and 3) women with chronic hypertension. The last group was included to estimate whether women with a history of preeclampsia have a comparable risk for having a small-for-gestational-age infant as women with chronic hypertension. Secondary maternal outcomes examined included frequency of placental abruption (diagnosed in the presence of vaginal bleeding with uterine tenderness and confirmed by placental pathology) and postpartum hemorrhage requiring blood transfusion. Secondary neonatal outcomes examined included gestational age at delivery and the frequencies of Apgar score <7 at 5 minutes, intensive care unit admission, and perinatal death (defined as any fetal or neonatal death after 23 weeks of gestation).
All analyses were performed with Stata version 12.0 (StataCorp, College Station, TX). All tests were two tailed and P < .05 was used to define statistical significance. Univariable comparisons were conducted with c2, Fisher exact, or one-way analysis of variance, as appropriate. Multivariable logistic regression was used to estimate the independent association between a history of preeclampsia (without recurrent preeclampsia) and delivery of a small-forgestational-age infant in a subsequent pregnancy. Potential confounding variables were entered into the regression equation if they differed between groups in univariable analysis at a level of P < .05. This study used publicly available deidentified data and was considered exempt by the Institutional Review Board at Northwestern University.
Results A total of 5638 women were enrolled in the original trials. After exclusion of women with pregestational diabetes (n ¼ 462), women with multifetal gestation (n ¼ 678), and women who developed preeclampsia in a current pregnancy (n ¼ 446), 4052 women remained eligible for analysis. Of these, 2972 (73.3%) were healthy nulliparous women, 499 (12.3%) had a prior pregnancy complicated by preeclampsia, and
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ajog.org 581 (14.3%) women had chronic hypertension (Figure). Maternal and neonatal characteristics of the study population, stratified by obstetric history, are depicted in Table 1. Women in all 3 risk groups differed in age, body mass index, race/ethnicity, education, marital status, tobacco use, and the presence of gestational diabetes. Pregnancy outcomes are shown in Table 2. Compared with healthy nulliparas, the frequency of a small-forgestational-age infant was significantly higher among women with a history of preeclampsia and was similar to the frequency of a small-for-gestational-age infant in pregnancies complicated by chronic hypertension. Mean birthweight also was significantly lower among women with a history of preeclampsia compared with healthy nulliparas. Other neonatal secondary outcomes such as preterm delivery, perinatal death, Apgar score <7 at 5 minutes, and neonatal intensive care unit admission were more frequent among women with a history of preeclampsia compared with healthy nulliparas. The frequency of placental abruption was higher among women with history of preeclampsia compared with the healthy nulliparous women. These observed adverse neonatal and maternal adverse outcomes were similar between the healthy nulliparous women and those with chronic hypertension. There were no differences in postpartum hemorrhage requiring transfusion or maternal deaths between the groups. Compared with healthy nulliparas, after adjusting for potential confounding variables in a multivariable regression, a history of preeclampsia was significantly more likely to be associated with a delivery of a small-for-gestational-age infant (Table 3). Similarly, the risks of preterm delivery (odds ratio, 2.25, 95% confidence interval, 1.69e3.00) and neonatal intensive care unit admission (odds ratio, 1.71, 95% confidence interval, 1.23e2.39) also were significantly increased among women with a history of preeclampsia. After a multivariable analysis, the other maternal and neonatal outcomes were not significantly
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TABLE 1
Maternal and neonatal clinical characteristics of the study population stratified by risk group Healthy nulliparas (n ¼ 2972)
Characteristics Maternal age, y 2
Body mass index, kg/m
History of preeclampsia (n ¼ 499)
Chronic hypertension (n ¼ 581)
20.5 4.6
24.5 5.3
29.7 6.4
<.001
23.6 4.8
27.7 7.7
32.8 9.2
<.001 <.001
Race/ethnicity Non-Hispanic white
539 (18.1)
122 (24.5)
164 (28.2)
Hispanic white
940 (31.6)
20 (4.0)
59 (10.2)
Non-Hispanic black
1441 (48.5)
356 (71.3)
352 (60.6)
Hispanic black
29 (1.0)
0 (0.0)
2 (0.3)
Other
22 (0.8)
1 (0.2)
4 (0.7)
Total years of regular school
P value
10.9 2.8
11.9 1.9
11.9 2.7
<.001 <.001
Marital status Married
594 (20.0)
156 (31.3)
224 (38.7)
Single
2318 (78.2)
291 (58.3)
291 (50.3)
54 (1.8)
52 (10.4)
64 (11)
334 (11.3)
77 (15.5)
103 (17.7)
<.001
82 (2.9)
42 (8.5)
98 (17.2)
<.001
Aspirin use during pregnancy
1488 (50.1)
253 (50.7)
300 (51.6)
.601
Male sex of infant
1503 (50.6)
243 (48.7)
292 (50.2)
.527
Divorced/separated/widowed Tobacco use in pregnancy Gestational diabetes
All data are presented as mean SD or n (percentage). Palatnik. A history of preeclampsia and risk for SGA infant. Am J Obstet Gynecol 2016.
different between groups based on obstetric history (data not shown). Because the original trial used an older birthweight reference for the definition of small for gestational age,17 we performed a sensitivity analysis, defining small for gestational age using a more recent US reference for birthweight percentiles.18 Using this more contemporary definition, in the univariable analysis, the rate of small for gestational age was 4.0%, 7.4%, and 10.3% among healthy nulliparas, women with a history of preeclampsia, and women with chronic hypertension, respectively (P < .001). A multivariable logistic regression demonstrated results similar to the original analysis, with an adjusted odds ratio for small for gestational age of 1.6 (95% confidence interval, 1.04e2.51) and 2.4 (95% confidence interval, 1.47e3.86) among women with a history of preeclampsia and women with chronic hypertension, respectively, compared with healthy nulliparas.
Comment In this secondary analysis, we found that the frequency of having a small-forgestational-age infant was significantly higher in women with a history of preeclampsia but without recurrent preeclampsia compared with low-risk nulliparous women. Prior studies have reported conflicting results regarding the association between a history of preeclampsia and the risk of small for gestational age in a subsequent pregnancy.9,10,19-21 Two studies reported a positive association between a history of preeclampsia and a small-forgestational-age infant in a subsequent pregnancy but included women with recurrent preeclampsia in the analysis.9,10 The 3 additional studies that excluded women with recurrent preeclampsia and focused on isolated small for gestational age have reported conflicting results. Makkonen et al19 and Lain et al20 did not find a higher frequency of small-forgestational-age infants among women
with a history of preeclampsia. Both of these studies had a relatively limited sample size of women with a history of preeclampsia (n ¼ 12919 and n ¼ 13020) limiting their power to detect potentially significant differences in the risk of small for gestational age. In contrast, Wikström et al,21 who looked at a large Swedish cohort, found that women with a history of preeclampsia in whom preeclampsia did not recur had an elevated risk of a small-forgestational-age infant in a subsequent pregnancy. Our demonstration of a 48% increased odds of small-for-gestationalage infants among women with a history of preeclampsia are in line with those of Wikström et al.21 The biological plausibility for these findings is based on placental implantation.22 Restricted endovascular invasion of the placenta is associated with both preeclampsia and fetal growth restriction, leading to a small-for-gestationalage infant, as well as other adverse
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TABLE 2
Pregnancy outcomes stratified by risk group
Outcomes
Healthy nulliparas (n ¼ 2972) 150 (5.1)
P valuea
History of preeclampsia (n ¼ 499)
P valueb
<.001
46 (9.2)
.134
Chronic hypertension (n ¼ 581)
P valuec
Neonatal Small for gestational age neonate
38.7 3.0
70 (12.1)
<.001
37.7 3.6
.014
Preterm delivery <37 wks
263 (9.3)
<.001
98 (19.9)
.031
145 (25.4)
Apgar score <7 at 5 min
272 (9.2)
.002
25 (5.0)
.400
36 (6.2)
Neonatal intensive care unit admission
258 (8.7)
.008
62 (12.4)
.013
104 (17.9)
Placental abruption
12 (0.4)
.008
7 (1.4)
.408
5 (0.9)
.026
Postpartum hemorrhage requiring transfusion
11 (0.4)
—
4 (0.8)
—
5 (0.9)
.176
2 (0.1)
—
1 (0.2)
—
0 (0.0)
.466
Gestational age at delivery
37.1 4.2
<.001 <.001 <.001 .001 <.001
Maternal
Maternal death All data are presented as mean SD or n (percentage).
P value for post-hoc analysis of comparison between low-risk nulliparous and a history of preeclampsia groups; b P value for post-hoc analysis of comparison between a history of preeclampsia and chronic hypertension groups; c P value for the overall analysis of variance. Palatnik. A history of preeclampsia and risk for SGA infant. Am J Obstet Gynecol 2016. a
TABLE 3
Multivariable regressions for the outcome of neonatal SGA Crude odds ratio
Variables
Adjusted odds ratio
95% Confidence interval
P value
Risk group Low-risk nulliparous women
1.00
1.00
Referent
Women with history of preeclampsia
1.91
1.48
1.02e2.17
.042
Women with chronic hypertension
2.58
1.97
1.28e3.03
.002
1.05
1.03
1.00e1.06
.036
1.01
0.98
0.96e1.00
.072
Non-Hispanic white
1.00
1.00
Referent
Hispanic white
0.66
1.03
0.61e1.74
.903
Maternal age, y 2
Body mass index, kg/m Race/ethnicity
—
Non-Hispanic black
1.48
1.86
1.27e2.72
.001
Hispanic black
0.55
0.89
0.12e6.78
.910
Other
1.32
1.60
0.36e7.14
.537
Smoked during pregnancy
2.21
2.08
1.50e2.90
<.001
Gestational diabetes
0.98
0.68
0.37e1.23
.200
Total years of regular school
1.04
0.99
0.93e1.05
.793
Married
1.00
1.00
Referent
Single
1.01
0.94
0.66e1.34
.728
Divorced/separated/widowed
2.50
1.37
0.79e2.38
.266
Marital status
Palatnik. A history of preeclampsia and risk for SGA infant. Am J Obstet Gynecol 2016.
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pregnancy outcomes such as placental abruption, preterm delivery, and stillbirth.7-9 Thus, women with a history of preeclampsia appear to be at increased risk of recurrent placental dysfunction that may manifest not only as a recurrence of the initial presentation but also as a different complication in a future pregnancy. In our study, women with a history of preeclampsia but without recurrent preeclampsia were at increased risk for a small-for-gestational-age infant and preterm delivery in a subsequent pregnancy. We did not observe an increased risk for placental abruption or stillbirth in our analysis; however, our sample size was not large enough to detect significant differences in these relatively uncommon outcomes. Our findings may have implications for screening for fetal growth restriction in women with a history of preeclampsia. At present, routine third-trimester growth ultrasound to screen for fetal growth restriction is not recommended.23,24 Instead, women are selected for a third-trimester growth ultrasound based on maternal and fetal risk factors for fetal growth restriction or if there is a discrepancy between uterine size and clinical dates.23,24
ajog.org Currently a history of preeclampsia is not a routine indication to obtain thirdtrimester ultrasound in a subsequent pregnancy if it is not complicated by another condition that would be an indication for sonographic surveillance.23-25 Our data, which suggest an increase in risk for developing fetal growth restriction in women with prior preeclampsia that is not dissimilar to the increase in women with chronic hypertension, raise the question as to whether women with such a history should receive routine sonographic growth surveillance as well. The limitations of this analysis should be noted. First, we did not have information on prior obstetrical history in terms of birthweight and smallfor-gestational-age infants. Therefore, it is not certain whether the relationship between prior preeclampsia and subsequent isolated small for gestational age is true only for women with a history of preeclampsia who also had a prior small-for-gestational-age birth. Second, we did not have information on the severity of prior preeclampsia. If the prior pregnancy was complicated by preeclampsia with severe features or preeclampsia that was diagnosed prior to 37 weeks, the risks for adverse pregnancy outcomes, including fetal growth restriction in a future pregnancy may be higher than women with a less severe manifestation of their preeclampsia.10,20 However, stratification based on severity of prior disease was not possible with the available data. Finally, we were limited in our patient selection by the population of the original trials, and this also may have affected the results. For example, the original trial for prevention of preeclampsia in lowrisk women included healthy nulliparas women, and thus, we used them as a control group, as opposed to a group of healthy parous women. However, because parous women without a history of preeclampsia would be expected to have an even lower risk of small for gestational age compared with nulliparous women, we anticipate that the use of healthy parous patients as a control group would only further support our observed findings.
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On the other hand, our study adds to the existing literature by examining a large sample of women with a history of preeclampsia by analyzing prospectively collected data and, most importantly, by analyzing only women without recurrent preeclampsia in their subsequent pregnancy. A unique feature of our analysis is our multigroup comparison. We compared women with a history of preeclampsia not only with low-risk nulliparous women, as has been done in prior studies,9,10,9-21 but also with women with chronic hypertension, which is an established risk factor for placental insufficiency and adverse pregnancy outcomes, including small for gestational age.24 We found that the frequency of small-for-gestational-age infants among women with a history of preeclampsia was similar to the frequency of small for gestational age among women with chronic hypertension. This similarity should stimulate further investigation into the validity of this association and the potential benefits of routine sonographic surveillance of growth based on preeclampsia history alone. n Acknowledgment We acknowledge the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Maternal-Fetal Medicine Units Network, and the Protocol Subcommittee for making this database publicly available.
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Author and article information From the Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL. Received Jan. 12, 2016; revised Feb. 25, 2016; accepted March 7, 2016. Presented in the poster format at the 36th annual meeting of the Society for Maternal-Fetal Medicine, Atlanta, GA, Feb. 1e6, 2016. Corresponding author: Anna Palatnik, MD. anatlivs@ gmail.com
