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Reprints: Yair J. Blumenfeld, MD, Assistant Professor, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, 193 Walker Hays Dr., Stanford University School of Medicine, Palo Alto, CA 94303.
Genetic Disease Screening Program, California Department of Public Health, Richmond, CADivision of Preventive Medicine and Public Health, Department of Epidemiology and Biostatistics, University of California, San Francisco, School of Medicine, San Francisco, CA
The objective of the study was to examine the association between placental abruption, maternal characteristics, and routine first- and second-trimester aneuploidy screening analytes.
Study Design
The study consisted of an analysis of 1017 women with and 136,898 women without placental abruption who had first- and second-trimester prenatal screening results, linked birth certificate, and hospital discharge records for a live-born singleton. Maternal characteristics and first- and second-trimester aneuploidy screening analytes were analyzed using logistic binomial regression.
Results
Placental abruption was more frequent among women of Asian race, age older than 34 years, women with chronic and pregnancy-associated hypertension, preeclampsia, preexisting diabetes, previous preterm birth, and interpregnancy interval less than 6 months. First-trimester pregnancy-associated plasma protein–A of the fifth percentile or less, second-trimester alpha fetoprotein of the 95th percentile or greater, unconjugated estriol of the fifth percentile or less, and dimeric inhibin-A of the 95th percentile or greater were associated with placental abruption as well. When logistic models were stratified by the presence or absence of hypertensive disease, only maternal age older than 34 years (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.0–2.0), pregnancy-associated plasma protein–A of the 95th percentile or less (OR, 1.9; 95% CI, 1.2–3.1), and alpha fetoprotein of the 95th percentile or greater (OR, 2.3; 95% CI, 1.4–3.8) remained statistically significantly associated for abruption.
Conclusion
In this large, population-based cohort study, abnormal maternal aneuploidy serum analyte levels were associated with placental abruption, regardless of the presence of hypertensive disease.
Placental abruption is largely a clinical diagnosis, suspected when gravidas present with vaginal bleeding or severe abdominal pain, often accompanied by uterine contractions or nonreassuring fetal heart rate patterns.
Serious adverse neonatal outcomes have been linked with placental abruption, most notably preterm birth, small-for-gestational-age weight, and even neonatal hypoxic ischemic encephalopathy and death in severe cases.
Adverse maternal outcomes have also been associated with placental abruption including increased rates of operative delivery, a need for blood transfusion, and hysterectomy.
Risk factors for placental abruption include chronic maternal medical conditions such as thyroid and hypertensive disease, fetal and placental etiologies such as multiple gestation and umbilical cord abnormalities, and obstetric factors such as preterm premature rupture of membranes (PPROM).
Noninvasive aneuploidy screening using maternal serum analyte and first-trimester nuchal translucency measurement has become a standard part of prenatal care for many pregnancies.
All serum aneuploidy analytes (pregnancy-associated plasma protein A [PAPP–A]), total human chorionic gonadotropin (hCG), alpha fetoprotein (AFP), unconjugated estriol (uE3), and dimeric inhibin-A (INH) are directly or indirectly associated with placental function and pregnancy maintenance.
Homodimeric pregnancy-associated plasma protein-A in normal human placenta of first and third trimester of pregnancy: biochemical and morphological observation.
Although abnormal analyte levels have been associated with placentation disorders, including preeclampsia and intrauterine growth restriction (IUGR), their association with placental abruption remains inconclusive.
First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (The FASTER Trial).
First-trimester serum analytes, biophysical tests and the association with pathological morphometry in the placenta of pregnancies with preeclampsia and fetal growth restriction.
Our objective was to examine the association between placental abruption, maternal characteristics, and routine first- and second-trimester aneuploidy screening analytes among a large population-based cohort of women undergoing prenatal screening for fetal aneuploidy.
Materials and Methods
The study sample was drawn from a cohort of 236,714 singleton pregnancies undergoing first- and second-trimester prenatal serum screening through the California Prenatal Screening Program administered by the Genetic Disease Screening Program (GDSP), with expected dates of delivery in 2009 and 2010. The sample was restricted to pregnancies that had a linked live birth and hospital discharge record in the birth cohort database maintained by the Office of Statewide Health Planning and Development (total with linked records = 140,577).
Pregnancies with fetal chromosomal abnormalities, neural tube defects, or abdominal wall defects were excluded (n = 361). To focus on placental abruption, pregnancies with other potential etiologies for vaginal bleeding were also excluded, including placenta previa and retained placenta without abruption (n = 2301). Of the 137,915 remaining pregnancies, 1017 experienced placental abruption and 136,898 did not (Figure 1).
Analyte results were derived from blood samples collected between a gestation of 10 weeks 0 days and 13 weeks 6 days in the first trimester, and a gestation of 15 weeks 0 days and 20 weeks 0 days in the second trimester. First-trimester analyte measurements included PAPP-A and hCG. Second-trimester analytes included AFP, hCG, uE3, and INH. Analyte levels were measured on automated equipment (Auto DELFIA; Perkin Elmer Life Sciences, Waltham, MA, and Applied Biosystems, Brea, CA), and results were entered directly into a state database along with patient information used to adjust multiple of the median (MoM) values associated with biomarker results and/or used in final result interpretation. All analyte MoMs were adjusted for gestational age, maternal weight (as a proxy for blood volume), race/ethnicity, smoking status, and preexisting diabetes. Data related to chromosomal, neural tube, and abdominal wall defects were obtained from the GDSP screening records and associated defect registries. Details regarding the program and associated registries have been described elsewhere.
) and prepregnancy weight provided in the linked vital statistics birth and hospital discharge records. The interpregnancy interval was calculated from previous live birth (month and year) as reported in linked records and estimated as months to conception of the index pregnancy. Given that the day of the previous live birth was not available, the first of the month was used for calculation purposes. Parity, previous cesarean section, and previous preterm birth were also obtained from linked birth and hospital discharge records as was diabetes status, the presence of hypertensive disorders including preexisting hypertension, gestational hypertension, hypertension unspecified, any preeclampsia, mild/unspecified preeclampsia, severe preeclampsia, eclampsia, and preeclampsia/eclampsia superimposed on preexisting hypertension.
Analyses utilized logistic regression to calculate odds ratios (ORs) and their 95% confidence intervals (CIs). To examine associations, maternal characteristics were grouped as follows: nonwhite race/ethnicity (by subgroup) vs white race/ethnicity, maternal age younger than 18 years or older than 34 years vs maternal age 18-34 years, maternal BMI underweight (<18.5 kg/m2), overweight (25.0–29.9 kg/m2), or obese (≥30 kg/m2) compared with normal BMI (18.5-24.9 kg/m2), mothers with a hypertensive disorder (by subgroup) vs mothers without a hypertensive disorder, diabetic mothers (by subgroup) vs nondiabetic mothers, smoking during pregnancy (by trimester) vs nonsmoking, nulliparous vs multiparous pregnancies, those with a previous cesarean section (by subgroup) vs those who had not, mothers who had a previous preterm birth vs those who had not, and mothers with an interpregnancy interval less than 6 months, 6-23 months, and 60 months or longer vs those with an interpregnancy interval of 24-59 months.
The relationship between biomarkers and placental abruption was measured by comparing biomarker MoM the fifth percentile or less or the 95th percentile or greater vs biomarker MoM between the sixth and 94th percentile.
Logistic models were built using backward-stepwise logistic regression wherein initial inclusion was determined by a threshold of P < .10 on initial crude analyses. Models were also stratified by the presence or absence of any hypertensive disorder.
All analyses were performed using Statistical Analysis Software (SAS) version 9.3 (SAS Institute, Cary, NC) and were based on data received by the GDSP program as of March 31, 2013. Methods and protocols for the study were approved by the Committee for the Protection of Human Subjects within the Health and Human Services Agency of the State of California.
Results
When analyzing the demographics of the cohort, Asian race (OR, 1.4; 95% CI, 1.1–1.7) and maternal age older than 34 years (OR, 1.4; 95% CI, 1.2–1.6) were more common among women with placental abruption. Women with placental abruption were also more likely to have 1 or more hypertensive disorders. Specifically, they were more than twice as likely to have pregestational hypertension (OR, 2.5; 95% CI, 1.6–3.8) and more than 3 times as likely to have preeclampsia or eclampsia (OR, 3.8; 95% CI, 3.1–4.6). Pregestational diabetes (OR, 2.0; 95% CI, 1.2–3.3), previous preterm birth (OR, 2.6; 95% CI, 1.4–4.7), and an interpregnancy interval less than 6 months (OR, 1.8; 95% CI, 1.2–2.7) were also more frequent among women with placental abruption (Table 1).
Table 1Maternal characteristics in pregnancies with and without placental abruption
Analyses of serum analytes indicated that first-trimester PAPP-A of the fifth percentile or less (OR, 1.6; 95% CI, 1.3–2.0), second-trimester AFP of the 95th percentile or greater (OR, 1.9; 95% CI, 1.4–2.4), uE3 of the fifth percentile or less (OR, 1.5; 95% CI, 1.2–1.9), and INH of the 95th percentile or greater (OR, 1.8; 95% CI, 1.4–2.3) were associated with an increased risk of placental abruption (Table 2).
Table 2Screening marker measurements in pregnancies with and without placental abruption
Biomarker cut points for MoM percentiles (≤5th and >95th) were as follows: PAPP-A, 0.38 and 2.63; hCG (first trimester), 0.50 and 2.00; AFP, 0.60 and 1.79; hCG (second trimester), 0.41 and 2.28; uE3, 0.63 and 1.48; and INH, 0.54 and 2.14
Biomarker cut points for MoM percentiles (≤5th and >95th) were as follows: PAPP-A, 0.38 and 2.63; hCG (first trimester), 0.50 and 2.00; AFP, 0.60 and 1.79; hCG (second trimester), 0.41 and 2.28; uE3, 0.63 and 1.48; and INH, 0.54 and 2.14
Biomarker cut points for MoM percentiles (≤5th and >95th) were as follows: PAPP-A, 0.38 and 2.63; hCG (first trimester), 0.50 and 2.00; AFP, 0.60 and 1.79; hCG (second trimester), 0.41 and 2.28; uE3, 0.63 and 1.48; and INH, 0.54 and 2.14
Biomarker cut points for MoM percentiles (≤5th and >95th) were as follows: PAPP-A, 0.38 and 2.63; hCG (first trimester), 0.50 and 2.00; AFP, 0.60 and 1.79; hCG (second trimester), 0.41 and 2.28; uE3, 0.63 and 1.48; and INH, 0.54 and 2.14
Biomarker cut points for MoM percentiles (≤5th and >95th) were as follows: PAPP-A, 0.38 and 2.63; hCG (first trimester), 0.50 and 2.00; AFP, 0.60 and 1.79; hCG (second trimester), 0.41 and 2.28; uE3, 0.63 and 1.48; and INH, 0.54 and 2.14
Biomarker cut points for MoM percentiles (≤5th and >95th) were as follows: PAPP-A, 0.38 and 2.63; hCG (first trimester), 0.50 and 2.00; AFP, 0.60 and 1.79; hCG (second trimester), 0.41 and 2.28; uE3, 0.63 and 1.48; and INH, 0.54 and 2.14
AFP, alpha fetoprotein; BMI, body mass index; CI, confidence interval; INH, dimeric inhibin-A; MoM, multiple of the median; OR, odds ratio; PAPP-A, pregnancy-associated plasma protein A; uE3, unconjugated estriol.
Blumenfeld. Association between serum analytes and abruption. Am J Obstet Gynecol 2014.
a Biomarker cut points for MoM percentiles (≤5th and >95th) were as follows: PAPP-A, 0.38 and 2.63; hCG (first trimester), 0.50 and 2.00; AFP, 0.60 and 1.79; hCG (second trimester), 0.41 and 2.28; uE3, 0.63 and 1.48; and INH, 0.54 and 2.14
Multivariable models revealed that pregnancies with hypertensive disorders had the greatest odds of placental abruption (ORs, 2.5-5.9 and 95% CI, 1.2–7.9) (Table 3). Given the association between hypertensive disorders and placental abruption, final stepwise models were built for pregnancies with and without any hypertensive disorder. Although most risks persisted in adjusted models in pregnancies without hypertensive disorders, only maternal age older than 34 years (OR, 1.4; 95% CI, 1.0–2.0), PAPP-A of the fifth percentile or less (OR, 1.9; 95% CI, 1.2–3.1), and AFP of the 95th percentile or greater (OR, 2.3; 95% CI, 1.4–3.8) remained statistically significant in models analyzing pregnancies with concomitant hypertensive disorders. A BMI of 30 kg/m2 or greater was associated with a reduced risk for placental abruption in both groups (OR, 0.8; 95% CI, 0.7–1.0, and OR, 0.6; 95% CI, 0.4–0.9) (Figure 2, Figure 3).
Table 3Risk factors for placental abruption stratified by hypertensive disorder
In this large population-based study, we show that abnormal aneuploidy screening analytes are independent markers of placental abruption, including among patients with hypertensive disease. Although the greatest risk for placental abruption was observed in the pregnancies with hypertensive disorders (nearly 3- to more than 5-fold increased risk), first-trimester PAPP-A of the fifth percentile or less and second-trimester AFP of the 95th percentile or greater were associated with an increased risk for placental abruption for those with and without a hypertensive disorder.
Our finding of an association between low PAPP-A level and elevated AFP level even among hypertensive women is particularly interesting, given the underlying mechanisms leading to both abruption and abnormal analyte levels. Placental abruption, although often a third-trimester clinical diagnosis, likely results from pathological processes that begin as early as the first trimester, including shallow endovascular trophoblast invasion of the decidua and spiral artery thrombosis.
PAPP-A is known to be an insulin-like growth factor (IGF)-binding protein metalloproteinase whose presence results in increased availability of IGF. IGF is believed to play a role in fetal growth by mediating trophoblast invasion into the decidua and regulating steroidogenesis and glucose and amino acid transport in the chorionic villi.
Immunohistochemical studies have localized PAPP-A to cytotrophoblasts, and in vitro studies have linked PAPP-A with differentiation of cytotrophoblasts into syncytiotrophoblasts.
AFP originates in the fetal liver and crosses the placenta. Elevated AFP in the second trimester in the absence of abdominal wall or neural tube defects may indicate pathological transfer of fetal derived AFP across the placenta via area of damaged villi.
Low maternal serum levels of PAPP-A in the first trimester and high levels of AFP in the second trimester have been previously found to be independent events and likely result from different aspects of placental dysfunction; however, their combination has been more strongly associated with adverse pregnancy outcomes such as IUGR, preterm birth, and stillbirth.
Using linked birth records, we were also able to confirm previously described risk factors for placental abruption including maternal age and hypertensive disorders.
Our finding of a short interpregnancy interval (IPI) association is of particular interest because this variable is potentially modifiable. A short IPI has been linked with other adverse outcomes such as preterm birth and low birthweight.
Additional theories include inflammatory processes such as endometritis or other pelvic infections extending from the previous birth to the index pregnancy.
In our study, maternal obesity was associated with a protective effect for placental abruption. This effect has been noted by others and appears to be in paradox to other obstetric risks that have been linked with obesity, including preeclampsia.
Identifying pregnancies at risk for placental abruption via abnormal analyte levels may be of clinical use beyond counseling. Recent studies have identified low-dose aspirin as a possible method of reducing placenta-mediated adverse outcomes including preeclampsia and IUGR.
An abnormal first-trimester PAPP-A level as a marker of abnormal placentation is worth noting because studies suggest the benefit of aspirin in reducing pregnancy risk may be limited to initiation prior to 16 weeks' gestation.
Our study is not without limitations. First, we are limited by the particular reporting and coding in the data set. For example, both the smoking rates and prior preterm birth rates in the data set are lower than previously published studies (Table 1). The overall low rates of smoking (less than 1%) may be indicative of low reporting rates among patients in our cohort, and we may have been underpowered to appropriately assess the effect of smoking.
Along the same lines, placental abruption is a clinical diagnosis and the criteria for coding may not have been uniform in our study cohort. However, it is unlikely that women without placental abruption were coded as having abruption, and the prevalence of placental abruption in our study cohort appears to be consistent with that reported in other studies.
Another limitation is the lack of knowledge regarding whether providers were biased by the presence of abnormal analyte results. It is possible that antenatal management may have been altered such as via aspirin therapy.
Despite these limitations, the major strengths of our study are its size and the fact that the serum analyte measurements were performed using uniform methods in a single laboratory. Moreover, we were able to stratify our findings based on concomitant hypertensive disease and found an association between abnormal analyte levels, even among women with hypertensive disorders, suggesting a possible independent pathophysiological mechanism of abnormal placentation between the two.
In conclusion, abnormal aneuploidy screening analyte levels were found to be independently associated with placental abruption, even among patients with hypertensive disease. Caregivers of women with abnormal analyte results may use these data to counsel and manage patients accordingly. These data also highlight the utility of serum analyte programs beyond aneuploidy detection.
References
Riihimäki O.
Metsäranta M.
Ritvanen A.
et al.
Increased prevalence of major congenital anomalies in births with placental abruption.
Homodimeric pregnancy-associated plasma protein-A in normal human placenta of first and third trimester of pregnancy: biochemical and morphological observation.
First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (The FASTER Trial).
First-trimester serum analytes, biophysical tests and the association with pathological morphometry in the placenta of pregnancies with preeclampsia and fetal growth restriction.
This study was supported in part by grants from the March of Dimes Prematurity Center, Stanford University School of Medicine, Stanford, CA.
The authors report no conflict of interest.
Cite this article as: Blumenfeld YJ, Baer RJ, Druzin ML, et al. Association between maternal characteristics, abnormal serum aneuploidy analytes, and placental abruption. Am J Obstet Gynecol 2014;211:144.e1-9.
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