Placental abruption complicates approximately 1% of deliveries.1 It is a life-threatening condition to the fetus,2,3 and is implicated in serious maternal complications4 as well as cardiovascular and cerebrovascular morbidity and mortality in both the women and their children later in life.5,6 Previous epidemiologic studies7 as well as studies evaluating histologic lesions in the placenta, cord, and membranes8 suggest that the clinical manifestations of abruption may be the result of a long-standing process with its origins extending to the early stages of pregnancy.
Preeclampsia is one of the strongest known risk factors for abruption,9 and abruption is associated with a three- to fourfold increased risk of fetal growth restriction.10 Together, these three conditions have similar pathophysiologic process, and these conditions have been termed the syndrome of ischemic placental disease.11 All three conditions are associated with excessively high risks of preterm delivery.12
We examined both first-trimester (pregnancy-associated plasma protein A [PAPP-A] and total and free β-hCG) and second-trimester (maternal serum alpha-fetoprotein [AFP] unconjugated estriol, and dimeric inhibin-A) serum analytes and their association with abruption. We also examined whether these serum analytes were associated with abruption risk within subsets of high-risk women, defined as those with ischemic placental disease (preeclampsia or fetal growth restriction). Finally, we examined whether multiple abnormal serum analytes were associated with a further increased risk of abruption. We hypothesized that, if the origins of abruption extend to the early stages of pregnancy, evidence for this must be seen with its association with first- and second-trimester maternal serum analytes.
MATERIALS AND METHODS
We performed a secondary analysis of data from the First and Second Trimester Evaluation of Risk, a multicenter prospective cohort study carried out in 1999–200213 (centers listed in Appendix 1, available online at http://links.lww.com/AOG/A923).13 The First and Second Trimester Evaluation of Risk study was designed to evaluate ultrasound and screening markers for predicting the risk of Down syndrome. Women carrying a viable singleton fetus between 10 3/7 weeks and 13 6/7 weeks of gestation,14 corresponding to fetal crown rump length measuring 36–79 mm, were recruited. Women carrying fetuses diagnosed with anencephaly or septated cystic hygroma were ineligible. Serum samples were obtained from participating women in the first and second trimesters, centrifuged, and shipped to Women and Infants Hospital, Providence, Rhode Island, for processing. The First and Second Trimester Evaluation of Risk study received ethics approval from the institutional review boards at Columbia University, New York, New York (the primary site), as well as from each of the participating sites. All women provided written informed consent to participate in the First and Second Trimester Evaluation of Risk study. Further details of the First and Second Trimester Evaluation of Risk study are provided elsewhere.13
In the First and Second Trimester Evaluation of Risk study, maternal peripheral blood was drawn in both the first and second trimesters with no results reported until the second trimester. Serum measurements of PAPP-A (enzyme-linked immunosorbent assay method) and free β-hCG (Immunoradiometric assay method) were performed in the first trimester between 10 3/7 weeks and 13 6/7 weeks of gestation.15 Second-trimester screening for maternal serum AFP and total hCG were measured using the Immulite method; unconjugated estriol by radioimmunoassay; and inhibin-A by Diagnostic Systems Laboratories. The assay sensitivities for total hCG, free β-hCG, and inhibin-A were 2 milli-international units/mL, 1 milli-international unit/mL, and 10 pg/mL, respectively. The inter- and intraassay coefficients of variation were less than 15% for all three analytes.16
Samples were collected in serum separator tubes and allowed to clot at room temperature for approximately 30–60 minutes and were then centrifuged at 3,000 rpm for 15 minutes and stored in the refrigerator (4°C) until shipping. Samples were shipped at ambient temperature by priority overnight to Women and Infants Hospital, Providence, Rhode Island, for processing.
Fetal growth restriction was defined as ultrasonographically estimated fetal weight below the 10th percentile for gestational age. All diagnoses of placental abruption as well as preeclampsia and fetal growth restriction were based on an obstetrician diagnosis, and the data were abstracted from obstetric charts by trained research coordinators.
First, we examined the distributions of serum analytes and categorized each analyte's multiple of the median as fifth or less, 6–10, 11–89, 90–94, and 95th percentiles or greater to conform to clinically meaningful cutoffs. Although the multiples of the median for many of the analytes were normally distributed, some were not. To avoid making incorrect inferences, we therefore chose to present the median (instead of the mean) multiples of the median throughout. These percentile cutoffs were derived from women without a diagnosis of abruption. Associations between the analytes and the risk of abruption were evaluated from log-linear regression models based on the log-binomial or Poisson distribution. From these models, we derived the risk ratio (RR) and 95% confidence interval (CI) before and after adjustment for confounders. The confounders included maternal age, primiparity, race–ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, and other race), single marital status, education (grouped as 8 or less, 9–12, 13–16, and 17 years or greater), smoking, alcohol and drug use during pregnancy, prepregnancy body mass index (BMI, calculated as weight (kg)/[height (m)]2), chronic hypertension and assisted reproduction technology. Assisted reproductive technology included one or more of ovulation induction, intrauterine insemination, in vitro fertilization, or gamete intrafallopian transfer.
Because the association between continuous variables (eg, age, BMI) and the outcome may portend a nonlinear relationship (eg, “U”-shaped), we evaluated nonlinearity by including a quadratic term (centered around the mean to avoid multicollinearity). The presence of nonlinearity was then assessed by comparing the residual deviance χ2 value between the model with and without the quadratic term; those with a P value <.1 were retained in the regression models. Although maternal age demonstrated a nonlinear relationship with abruption, BMI did not. Confounders were included in the final model if they either changed the confounder-adjusted (log) RR by at least 10% or were candidates with a priori interest.
In addition to the primary outcome, we performed two additional analyses. In the first, we examined the associations among the serum analytes and placental abruption within high-risk subsets. These subsets included women with ischemic placental disease, defined as those with abruption only or abruption with preeclampsia or fetal growth restriction or both. In the second analysis, we examined whether combinations of serum analytes were associated with abruption. For this analysis, we also determined the sensitivity, specificity, and positive and negative predictive values. Owing to small numbers, the 95% CIs for the test characteristics were estimated from the exact method based on binomial proportions.
From a total of 38,033 participants in the First and Second Trimester Evaluation of Risk study, we sequentially excluded women who delivered at less than 20 weeks of gestation (n=2,398) and women for whom a diagnosis of abruption was not recorded (n=143). The remaining 35,327 women constituted the analytic cohort.
Of the 35,327 eligible women, 250 (0.7%) had a recorded diagnosis of abruption. Compared with women without abruption, those with abruption tended to be slightly older, have higher risks of assisted reproduction technology methods, gestational diabetes, hypertensive disorders, fetal growth restriction, and preterm delivery (Table 1). These women were also more likely to have undergone assisted reproduction technology, have hypertensive disorders, diabetes, and deliver preterm (less than 37 weeks of gestation); the association with preterm delivery was the strongest (RR 10.2, 95% CI 8.0–13.0). Neonates born to women with abruption were delivered 3 weeks earlier and weighed, on average, more than 650 g less than those born to women without abruption. They, in turn, were at increased risk of both fetal growth restriction and perinatal death.
Women with abruption had abnormally low first-trimester PAPP-A levels (fifth percentile or less) compared with those without abruption (9.6% compared with 5.3%), yielding an adjusted RR of 1.9 (95% CI 1.2–2.8; Table 2). In the second trimester, abnormally high maternal serum AFP 95th percentile or greater was more common among abruption (9.6%) than nonabruption (5.1%) pregnancies (RR 1.9, 95% CI 1.3–3.0; Table 2). Among women with abruption, inhibin-A demonstrated a U-shaped nonlinear relationship with increased risks among women with both abnormally low (fifth percentile or less) and abnormally high (95th percentile or greater) inhibin-A levels. None of the other analytes was associated with abruption.
To evaluate whether the associations of the abnormal serum analytes and abruption were driven by co-occurring obstetric complications, we then examined the associations among women with abruption only and those with abruption and either preeclampsia or fetal growth restriction or both (Table 3). These analyses show that the abnormal analytes were associated with abruption as well as with abruption accompanied by ischemic placental disease.
Because abnormal PAPP-A, maternal serum AFP, and inhibin-A were the analytes associated with abruption (Table 2), we examined whether women with combinations of these analytes were associated with increased risk of abruption (Table 4). With PAPP-A, maternal serum AFP, and inhibin-A values being normal (11–89th percentile) as the reference, women with abnormal inhibin-A (either fifth or less or 95th percentiles or greater) and normal PAPP-A and maternal serum AFP were associated with increased risk of abruption. Similarly, those with abnormal maternal serum AFP and inhibin-A (both 95th percentiles or greater) and normal PAPP-A were associated with a fourfold (RR 4.0, 95% CI 1.5–10.8) increased risk of abruption. Abnormal PAPP-A (fifth percentile or less) but normal maternal serum AFP and inhibin-A were also associated with a 2.4-fold (95% CI 1.4–4.1) increased risk. Finally, when all three analytes were abnormal (PAPP-A fifth percentile or less), maternal serum AFP, and inhibin-A (both 95th percentiles or greater), the risk of abruption was the highest at 8.8 (95% CI 2.3–34.3). In fact, this RR was different from the RRs for other combinations of the analytes (P=.004). Although the specificity and negative predictive values for all combinations of the three analytes for placental abruption were close to perfect, the sensitivity and positive predictive values were very low (Table 5).
The main finding of this secondary analysis of data from the multicenter, First and Second Trimester Evaluation of Risk prospective cohort study is that abnormal values in three maternal serum analytes, PAPP-A in the first trimester and maternal serum AFP and inhibin-A in the second trimester, are associated with increased risk of abruption. Abnormal values of all three analytes are associated with increased risk of isolated abruption as well as abruptions that co-occur with ischemic placental disease. Women with abnormal values of all three analytes appear are almost at ninefold increased risk of abruption. However, given the low sensitivity and positive predictive values, none of these analytes was predictive of abruption.
Some limitations of the study deserve attention. In particular, associations pertaining to the combination of analytes on abruption risk were not adjusted for confounding variables owing to small cell sizes or instances in which some of the reported RRs were accompanied by fairly wide 95% CIs. Although misclassification of abruption is likely, this misclassification would have been nondifferential with respect to the results of the serum analytes. Moreover, we did not know whether women with abruption in this study experienced abruption in any of their previous pregnancies or if women in the nonabruption group had prior abruption.
The strengths of the study include the prospective nature of the First and Second Trimester Evaluation of Risk cohort, standardized data collection across the centers, and all data being manually checked by a data coordination center. Abnormal serum analytes were not utilized to modify the obstetric management or guide any interventions to prevent the outcome of interest from occurring, so these associations reflect real-life scenarios in contemporary obstetric practice.
Data on the associations between low PAPP-A and abruption is conflicting. Dugoff et al17 examined the associations of two first-trimester serum analytes, PAPP-A, and β-hCG, in relation to obstetric complications, including abruption, in the First and Second Trimester Evaluation of Risk cohort. They showed that the odds of abruption among women with abnormally low PAPP-A (fifth percentile or less of the multiples of the median) was 1.8 (95% CI 1.2–2.8); no association was reported for free β-hCG.
A large study of 137,915 women in California reported that PAPP-A 5th percentile or less was associated with a 1.6-fold (95% CI 1.3–2.0) increased risk of abruption.18 In contrast, a hospital-based study in Finland19 reported no association between low PAPP-A (less than 1.0 multiple of the median) and abruption (odds ratio 1.09, 95% CI 0.42–2.82). Similarly, another study from Greece by Pilalis et al20 reported that the prevalence risks of abruption were similar between women with and without low first-trimester PAPP-A. Finally, a third study from Israel21 also did not find an association between low PAPP-A (0.25 multiple of the median or less) and abruption. These latter studies were perhaps driven by the very few number of abruption cases (17 in the Finland study, seven in the Greece study, and two in the Israel study). Pregnancy-associated plasma protein A has also been shown to be associated with increased risks of other placental dysfunction disorders,22,23 including stillbirth. In fact, in a multicenter study of 7,934 women, first-trimester PAPP-A fifth percentile or less was associated with a more than 60-fold (hazard ratio 60.5, 95% CI 6.1–597.0) increased risk of stillbirth as a result of abruption.24
The mechanisms for elevated maternal serum AFP with a structurally normal fetus include disruption of the fetal–maternal–placental barrier, placental vascular damage from early subclinical abruption, or fetal–placental ischemia.25 The associations between high maternal serum AFP and abruption remains inconclusive with two studies showing increased risk26,27 and another demonstrating no association.28
Inhibin is a glycoprotein that is produced by the placenta. Concentrations of circulating dimeric inhibin-A rapidly rise in early pregnancy, fall after 12 weeks of gestation, remain low in the second trimester, and gradually increases in the latter half of pregnancy.29,30 Previous studies did not report associations of inhibin-A both at fifth or less and 95th percentiles or greater in relation to abruption.
Although our data suggest increased risk of abruption among women with abnormal PAPP-A, maternal serum AFP, and inhibin-A levels, the combination of these abnormal analytes substantially increases abruption risk. Despite the strong associations among these three analytes and abruption, we cannot recommend these multiple maternal serum markers as a population-based screening tool given the low sensitivity of these serum analytes in predicting abruption.31
Prediction of abruption has remained an obstetric challenge regarding prediction and prevention. We hope that future studies aimed at developing prediction models for abruption based on maternal early pregnancy serum biomarkers coupled with a Doppler velocimetry profile of the uterine and umbilical arteries or other biomarkers or demographic factors may yield clinically important insights.
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