Obstetrics & Gynecology:
Recurring Complications in Second Pregnancy
Lykke, Jacob Alexander MD1,2; Paidas, Michael J. MD2; Langhoff-Roos, Jens MD, DMSc1
From the 1Department of Obstetrics, Rigshospitalet, Copenhagen, Denmark; and 2Department of Obstetrics, Gynecology, and Reproductive Science, Yale Women and Children’s Center for Blood Disorders, Yale University School of Medicine, New Haven, Connecticut.
The authors thank Steen Rasmussen at the National Board of Health for assisting in the extraction of data.
Corresponding author: Jacob Alexander Lykke, MD, Department of Obstetrics, Rigshospitalet, Blegdamsvej 9, 2100 Kbh., Denmark; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To clarify the obstetric consequences in a second pregnancy after a first singleton pregnancy complicated by spontaneous preterm delivery or preeclampsia and stratified by the variation in fetal growth.
METHODS: In a registry-based cohort study, we identified women having a first and second singleton delivery in Denmark from 1978 to 2007 (n=536,419). The exposures and endpoints were preterm delivery, preeclampsia, fetal growth, placental abruption, and stillbirth after 20 weeks of gestation. We used χ2 and t test to compare differences between incidences on first and second pregnancies.
RESULTS: Compared with a spontaneous first delivery at term, a delivery between 32 and 36 weeks of gestation increased the risk of preterm delivery in the second pregnancy from 2.7% to 14.7% (odds ratio [OR] 6.12, 95% confidence interval [CI] 5.84–6.42) and the risk of preeclampsia from 1.1% to 1.8% (OR 1.60, 95% CI 1.41–1.81); a delivery before 28 weeks increased the risk of a second preterm delivery to 26.0% (OR 13.1, 95% CI 10.8–15.9) and a second pregnancy with preeclampsia to 3.2% (OR 2.96, 95% CI 1.80–4.88). A first delivery in preeclamptic women between 32 and 36 weeks, compared with delivery after 37 weeks, increased the risk of preeclampsia in a second pregnancy from 14.1% to 25.3% (OR 2.08, 95% CI 1.87–2.31) and a small for gestational age infant from 3.1% to 9.6% (OR 2.82, 95% CI 2.38–3.35). Compared with the mean, fetal growth 2 to 3 standard deviations below mean in the first pregnancy increased the risk of preeclampsia from 1.1% to 1.8% (OR 1.62, 95% CI 1.34–1.96) in the second pregnancy.
CONCLUSION: Spontaneous preterm delivery, preeclampsia, and fetal growth deviation tend to recur and predispose to each other in a second pregnancy. Severe complications further increase these risks.
LEVEL OF EVIDENCE: II
Preterm delivery, small for gestational age (SGA) offspring, preeclampsia, placental abruption, and stillbirth complicate up to 10–25% of first singleton pregnancies; the prevalence of these complications is lower in parous than in nulliparous women.1
These pregnancy complications are seemingly different in manifestation and are often regarded as separate disease entities. However, they frequently occur in the same pregnancy, and they seem to share much of their causation through a dysfunctional placenta.2–5 Also, a metabolic syndrome seems to be a pivotal component of these pregnancy complications6,7: Endothelial dysfunction,8,9 dyslipidemia,10,11 inflammation markers,12,13 and obesity14,15 have all been associated with these different pregnancy complications. On a genetic level, thrombophilia may also contribute to the pathophysiology of these.16 Thus, it seems plausible that each of these pregnancy complications could predispose to others in a subsequent pregnancy as well as a recurrence of the complication.
Previous studies have investigated the recurrence in a second pregnancy of preterm delivery,17–23 preeclampsia,24,25 SGA offspring,24 placental abruption,24,26 and stillbirth.24,27 Other studies have investigated the relation between one complication in the first pregnancy and the risk of developing a different complication in the subsequent consecutive pregnancy.24,28–31 However, none of these studies have investigated how the severity of these pregnancy complications affects the risk of recurrence or risk of other complications in a subsequent pregnancy.
We designed a registry-based study employing the Danish national registries to clarify the obstetric consequences in a second pregnancy after a first singleton pregnancy complicated by spontaneous preterm delivery, preeclampsia, and stratified by the variation in fetal growth. Specifically, we investigated 1) spontaneous preterm delivery at different gestational ages and the risk of subsequent preterm delivery, preeclampsia, SGA offspring, placental abruption, and stillbirth; 2) occurrence as well as severity of preeclampsia and the risk of subsequent preeclampsia, SGA offspring, placental abruption, and stillbirth; and 3) variation in fetal growth and the risk of subsequent SGA offspring, preeclampsia, placental abruption, stillbirth, and preterm delivery offspring in the second pregnancy.
MATERIALS AND METHODS
The National Patient Registry (NPR) collects information on all discharge diagnoses and all complications during pregnancy and delivery in Denmark since 1978.32 We extracted information on all singleton deliveries in Denmark from January 1, 1978, to October 1, 2007, which accrued 1,795,806 deliveries of 965,475 women. From this population, we defined a cohort consisting of women, who had a first delivery after the age of 15 years and a second delivery before the age of 50 years (n=550,805), excluding those with a cardiovascular diagnosis (n=11,969; 2.2%) or type 1 and 2 diabetes (n=2,179; 0.5%) preceding the second delivery, and women who died or emigrated within 3 months of the second delivery (n=46 and n=196). Thus, the cohort consisted of 536,419 women. The exposures and endpoints were preterm delivery, preeclampsia, fetal growth, placental abruption, and stillbirth after 20 weeks of gestation.
At delivery, gestational age is routinely recorded. Initially, gestational age was assessed by the last menstruation period; gradually, gestational age was determined by early second trimester ultrasonography from 1978 to 2007. We stratified preterm delivery into four groups by gestational age: 20 to 27 weeks, 28 to 31 weeks, 32 to 37 weeks; and deliveries after 37 weeks as the reference group. We defined a spontaneous delivery as a pregnancy without preeclampsia, SGA offspring, placental abruption, or stillbirth. Fetal growth was measured by the birth weight standardized for gender and gestational age33; SGA was defined as fetal growth 2 standard deviations (SDs) below the mean.
Implausible values of birth weight, gestational age, fetal growth, and the combination of these were reassigned as missing values; these were analyzed as separate groups. Missing values occurred more frequently in the earlier years.
Hypertensive pregnancy disorders, placental abruption, and stillbirth were assessed by the specific International Classification of Diseases, 8th and 10th Revision codes for these diagnoses (see the box, Diagnoses and International Classification of Diseases, 9th and 10th Revisions Codes). The hypertensive pregnancy disorders were stratified into gestational hypertension and preeclampsia (including eclampsia and hemolysis, elevated liver enzymes, low platelets syndrome). The definition of preeclampsia has changed criteria during the 30 study years,34 but the frequency of preeclampsia in the NPR has remained stable. The accuracy of the hypertensive diagnoses in the NPR has been manually validated several times, accruing specificities of more than 99% for all types, but sensitivities at 10% for gestational hypertension and 69% for preeclampsia.34
We used χ2 and t test to compare differences between incidences on first and second pregnancies. We used multivariate logistic models and included year of delivery, maternal age at first delivery, and years between first delivery and estimated time of conception in second pregnancy. After initial stratification, we included interaction links in a stepwise forward procedure using likelihood ratio statistics with an entry criterion of P<.05. All odds ratios (ORs) are presented with 95% confidence intervals (CIs). We used SPSS 16.0 for Macintosh (SPSS Inc., Chicago, IL) for all calculations. The study was approved by the Danish National Data Protection Agency.
The baseline characteristics are shown in Table 1. In general, the birth weight of the offspring was higher in the second pregnancy, and the prevalence of preterm delivery, SGA, hypertensive pregnancy disorders, placental abruption, and stillbirth were lower in the second pregnancy. Missing values were more frequent in the first pregnancy and in the earlier years.
Women with a spontaneous preterm delivery in their first pregnancy (Table 2) had increased risk of preterm delivery, preeclampsia, an SGA offspring, and placental abruption in the second pregnancy. These risks were inversely related to gestational age at their first delivery.
Compared with a delivery after 37 weeks, a first delivery between 32 and 36 weeks increased the risk of recurrence of preterm delivery in the second pregnancy from 2.7% to 14.7% (OR 6.12, 95% CI 5.84–6.42); a first delivery before 28 weeks increased this risk to 26.0% (OR 13.1, 95% CI 10.8–16.0). Decreasing gestational age in the first spontaneous preterm birth implied an increased risk of preeclampsia, SGA, and placental abruption in the second pregnancy, and the increases were of similar magnitude.
In women with preeclampsia in a first pregnancy, early gestational age at delivery increased the risk of recurrent preeclampsia, SGA offspring, placental abruption, and stillbirth in the second pregnancy (Table 3). Women with preeclampsia who delivered after 37 weeks of gestation had a 14.1% overall risk of developing preeclampsia in the second pregnancy; this risk increased to 37.9% in preeclamptic women who delivered before 28 weeks (OR 3.90, 95% CI 2.50–6.05).
Lower-than-average fetal growth in a first pregnancy not complicated by preterm delivery, hypertensive disorders, placental abruption, or stillbirth increased the risk of SGA offspring, preterm delivery, preeclampsia, placental abruption, and stillbirth in the second pregnancy (Table 4). Fetal growth 0.5 to 1 SD below the mean increased the risk of an SGA offspring in the second pregnancy from 1.5% to 3.6% (OR 2.40, 95% CI 2.27–2.53); fetal growth below 3 SD increased the risk to 22.2% (OR 19.3, 95% CI 15.9–23.4). Fetal growth between 1 and 1.5 SD below the mean increased the risk of preeclampsia in the second pregnancy from 1.1% to 1.3% (OR 1.18, 95% CI 1.07–1.30); fetal growth between 2 and 3 SD below the mean increased the risk to 1.8% (OR 1.62, 95% CI 1.34–1.96).
A higher than average fetal growth in the first pregnancy did not overall significantly increase the risk of preeclampsia or stillbirth in the second pregnancy (Table 4). However, a fetal growth up to 2 SD above the mean in the first pregnancy was associated with a lower-than-average risk of preterm delivery and placental abruption in the second pregnancy.
The present study illustrates the link between pregnancy complications across two pregnancies. A first spontaneous preterm delivery is a risk factor for the recurrence of preterm delivery as well as the development of preeclampsia, SGA offspring, and placental abruption in a second pregnancy. Previous studies have investigated the recurrence of preterm delivery, and our findings are in accordance with these.17–22 Furthermore, we have demonstrated the presence of a “dose–response relationship,” with increased risks after lower gestational age at a first delivery.
We did not find a significant increase in risk of stillbirth after a first spontaneous preterm delivery. Smith et al28 previously found a twofold increase after a first spontaneous preterm delivery. However, the authors did not control for placental abruption, and their definition of small for gestational age was below the 10th percentile; these differences could explain the discrepancy in the associations found. Surkan et al29 also found an adjusted twofold increase in risk of stillbirth after preterm delivery before 32 weeks of gestation.
Women with preeclampsia have increased risk of recurrence of the preeclampsia as compared with women with spontaneous deliveries. Preeclampsia in pregnancies associated with preterm delivery imposed an even higher risk of developing preeclampsia in the second pregnancy. This suggests that the severity of preeclampsia, reflected in the degree of associated prematurity, is an important clinical predictor for a subsequent pregnancy35; previous studies agree with these findings.24,25 Also, we found this severity of preeclampsia to be associated with the risk of developing SGA offspring, placental abruption, and stillbirth in the second pregnancy; these latter associations could be driven by their primary complications in the first preeclamptic pregnancies. However, we did not control for this because these complications are secondary events with respect to the preeclampsia and thus are markers of disease severity.
Even marginally low fetal growth (still categorized as appropriate for gestational age) increases the risk of SGA offspring as well as preeclampsia in the second pregnancy, thereby contributing to the hypothesis of a common cause,3 Rasmussen et al36 found the same relation in a Norwegian population. Additionally, we found increased risks of placental abruption, stillbirth, and preterm delivery in the second pregnancy; however, these risks could be driven by the increased risk of preeclampsia in the same pregnancy. Adjusting for preeclampsia in the second pregnancy attenuated these odds ratios only slightly (data not shown). In contrast, we found that fetal growth 1 to 2 SD above the mean in the first pregnancy had a protective effect on the risk of preterm delivery and placental abruption (although not significant) in the second pregnancy.
In summary, our data shows that spontaneous preterm delivery, preeclampsia, low fetal growth, placental abruption, and stillbirth in a first and second pregnancy are interrelated, which suggests that they all may be features of a common syndrome—a “placenta-associated syndrome”2: Each of these pregnancy complications in a first pregnancy predispose to the others in the second pregnancy. Still, each of them is more predictive of a recurrence of the same disorder; this illustrates that although we theorize the presence of a common syndrome, elusive factors may be playing different roles in each of the disorders.
Recently, the balance of angiogenic and antiangiogenic factors, ie, endoglin, soluble fms-like tyrosine kinase-1, vascular endothelial growth factor, and placental growth factor have been associated with different strengths with each of the complications.37–39 Further histologic evidence suggests that placentas from pregnancies complicated by preeclampsia, SGA, or abruption frequently show signs of ischemia in the form of lesions.40 In addition, maternal constitution, ie, high body mass index, predisposes more to preeclampsia than to spontaneous preterm delivery7,41; however, even spontaneous preterm delivery is related to a preexisting metabolic syndrome.10 Summarizing, a dysfunction of the endothelium, both the placental and the maternal, seems to be paramount in the development a placenta-associated syndrome; this is also reflected in the subsequent increased cardiovascular morbidity in women with pregnancy complications.42
The strengths and limitations of the present study are constituted in the registry-based design of the study. The data were collected in a prospective manner and thus recall bias is not present. The size of the population enabled us to investigate rare exposures and outcomes in a homogeneous, nonselected, and low-risk population and still have the statistical power to detect small dose–response effects.
The validity of the preeclampsia diagnosis in the NPR is acceptable: a sensitivity of 69% and specificity at 99%.34 The underreporting of gestational hypertension, ie, a sensitivity of 10%, may have an effect on the association between preterm delivery and low fetal growth in a first pregnancy and subsequent preeclampsia, abruption, and stillbirth in a second pregnancy: If the underreporting of gestational hypertension is biased to the nonpathologic first pregnancies, ie, there was more underreporting in pregnancies ending at term and with average fetal growth, this should bias our results toward null, and thus our results will be underestimated.
The operational definition of spontaneous preterm delivery—a pregnancy uncomplicated by SGA offspring, hypertensive disorders, placental abruption, and stillbirth—does not allow us to tell whether these women experienced true preterm labor, preterm premature rupture of membranes, undiagnosed abruption, or chorioamnionitis or whether they underwent induction of labor due to various complications; however, Ananth et al22 have in a U.S. population demonstrated that preeclampsia, SGA, and abruption constituted more than 54% of the diagnoses leading to medically indicated preterm birth. Also, we excluded implausible values of birth weight, gestational age, and fetal growth to prevent bias from misreporting in the NPR. Thus, we do not believe that major confounding is present. Possibly, cesarean delivery in a first pregnancy could be a confounder due to the scar of the uterus.
Unfortunately, we were not able to control for body mass index, gestational diabetes, smoking, socioeconomic status, race or ethnicity, change in partner, or other factors that were not registered in the NPR. Provided these factors are stable over the two pregnancies, the lack of control for these factors should have minimal effect on the association found: Smith et al28 did indeed find minimal confounding effect of these factors. Also, we were not able to control for any prophylactic interventions in the second pregnancy43; however, any efficient intervention should bias our estimates toward the null.
In conclusion, women delivering spontaneously preterm, having preeclampsia, or having SGA offspring are vulnerable from an obstetric point of view. They not only have increased risk of recurrence of the same pregnancy complication, but also are susceptible for other pregnancy complications in the next pregnancy; the more severe the complication as determined by gestational age or fetal growth deviation in the first pregnancy, the higher the risk of these complications in the second pregnancy. Based on the results of the present study, we may individualize the surveillance, prophylaxis or treatment in pregnant women with a previous pregnancy complication.
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