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Association between maternal characteristics, abnormal serum aneuploidy analytes, and placental abruption

Published:March 17, 2014DOI:https://doi.org/10.1016/j.ajog.2014.03.027

      Objective

      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.

      Key words

      See related editorial, page 89
      Placental abruption, or bleeding into the decidua basalis, complicates approximately 0.5% of all pregnancies.
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      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).
      Figure thumbnail gr1
      Figure 1Overview of sample selection
      aPlacental previa and retained placenta without abruption.
      Blumenfeld. Association between serum analytes and abruption. Am J Obstet Gynecol 2014.
      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.
      • Currier R.
      • Wu N.
      • Van Meter K.
      • Goldman S.
      • Lorey F.
      • Flessel M.
      Integrated and first trimester prenatal screening in California: program implementation and patient choice for follow-up services.
      • Jelliffe-Pawlowski L.L.
      • Shaw G.M.
      • Currier R.J.
      • et al.
      Association of early-preterm birth with abnormal levels of routinely collected first- and second-trimester biomarkers.
      Maternal body mass index (BMI) was calculated using height (height
      • Bolin M.
      • Åkerud H.
      • Cnattingius S.
      • Stephansson O.
      • Wikström A.K.
      Hyperemesis gravidarum and risks of placental dysfunction disorders: a population-based cohort study.
      ) 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
      VariableNo abruption

      (n = 136,898), %
      Placental abruption

      (n = 1017), %
      OR

      (95% CI)
      Race/ethnicity
       White, non-Hispanic39,857 (29.1)268 (26.4)Reference
       Hispanic66,984 (48.9)484 (47.6)1.1 (0.9–1.2)
       Black4125 (3.0)31 (3.1)1.1 (0.8–1.6)
       Asian14,792 (10.8)136 (13.4)1.4 (1.1–1.7)
      P < .05
       Other
      Includes Asian East Indian, Pacific Islander, Native American, Middle Eastern, and other race/ethnicity
      7799 (5.7)64 (6.3)1.2 (0.9–1.6)
      Maternal age, y
       ≤181089 (0.8)5 (0.5)0.7 (0.3–1.6)
       18-34101,074 (73.8)682 (67.1)Reference
       ≥3534,713 (25.4)330 (32.5)1.4 (1.2–1.6)
      P < .05
      Maternal weight
       Underweight (BMI <18.5 kg/m2)5062 (3.7)45 (4.4)1.1 (0.8–1.5)
       Normal weight (BMI 18.5-24.9 kg/m2)69,361 (50.7)547 (53.8)Reference
       Overweight32,633 (23.8)207 (20.4)0.8 (0.7–0.9)
      P < .05
       Obese22,970 (16.8)154 (15.1)0.9 (0.7–1.0)
      P < .10.
      Hypertensive disorders
       No hypertension128,136 (93.6)861 (84.7)Reference
       All hypertension8762 (6.4)156 (15.3)2.7 (2.2–3.1)
      P < .05
       Preexisting hypertension with no preeclampsia1379 (1.0)23 (2.3)2.5 (1.6–3.8)
      P < .05
       Gestational hypertension2860 (2.1)26 (2.6)1.2 (0.8–1.8)
       Preeclampsia/eclampsia4075 (3.0)103 (10.1)3.8 (3.1–4.6)
      P < .05
       Mild preeclampsia2329 (1.7)40 (3.9)2.6 (1.9–3.5)
      P < .05
       Severe preeclampsia1220 (0.9)54 (5.3)6.6 (5.0–8.7)
      P < .05
       Eclampsia73 (0.1)1 (0.1)2.0 (0.3–14.7)
      Diabetes
       No diabetes124,616 (91.0)915 (90.0)Reference
       All diabetes12,282 (9.0)102 (10.0)1.1 (0.9–1.4)
       Preexisting diabetes1072 (0.8)16 (1.6)2.0 (1.2–3.3)
      P < .05
       Gestational diabetes11,270 (8.2)88 (8.7)1.1 (0.9–1.3)
      Smoking1073 (0.8)8 (0.8)1.0 (0.5–2.0)
      Parity
       Nulliparous57,673 (42.1)426 (41.9)Reference
       Multiparous79,152 (57.8)591 (58.1)1.0 (0.9–1.1)
      Prior cesarean
       No prior cesarean116,291 (85.0)872 (85.7)Reference
       1 prior cesarean15,304 (11.2)111 (10.9)1.0 (0.8–1.2)
       ≥2 prior cesareans5218 (3.8)33 (3.2)0.8 (0.6–1.2)
      Previous PTB
       No previous of PTB136,316 (99.6)1006 (98.9)Reference
       Previous PTB582 (0.4)11 (1.1)2.6 (1.4–4.7)
      Includes Asian East Indian, Pacific Islander, Native American, Middle Eastern, and other race/ethnicity
      Interpregnancy interval, mo
       <61773 (1.3)22 (2.2)1.8 (1.2–2.7)
      Includes Asian East Indian, Pacific Islander, Native American, Middle Eastern, and other race/ethnicity
       6-2325,561 (18.7)188 (18.5)1.0 (0.9–1.2)
       24-5988,674 (64.8)616 (60.6)Reference
       >6019,879 (14.5)166 (16.3)1.2 (1.0–1.4)
      BMI, body mass index; CI, confidence interval; OR, odds ratio; PTB, preterm birth.
      Blumenfeld. Association between serum analytes and abruption. Am J Obstet Gynecol 2014.
      a P < .05
      b Includes Asian East Indian, Pacific Islander, Native American, Middle Eastern, and other race/ethnicity
      c P < .10.
      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
      VariableNo abruption

      (n = 136,898), %
      Placental abruption

      (n = 1017), %
      OR

      (95% CI)
      First-trimester biomarkers
       PAPP-A (MoM percentile)
      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
      ≤5th6725 (4.9)78 (7.7)1.6 (1.3–2.0)
      P < .05
      6-94th124,034 (90.6)908 (89.3)Reference
      ≥95th6139 (4.5)31 (3.1)0.7 (0.5–1.0)
      P < .10.
       hCG (MoM percentile)
      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
      ≤5th6663 (4.9)48 (4.7)1.0 (0.7–1.3)
      6-94th124,327 (90.8)920 (90.5)Reference
      ≥95th5905 (4.3)49 (4.8)1.1 (0.8–1.5)
      Second-trimester biomarkers
       AFP (MoM percentile)
      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
      ≤5th7629 (5.6)68 (6.7)1.3 (1.0–1.6)
      P < .10.
      6-94th124,685 (91.1)888 (87.3)Reference
      ≥95th4584 (3.4)61 (6.0)1.9 (1.4–2.4)
      P < .05
       hCG (MoM percentile)
      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
      ≤5th7073 (5.2)58 (5.7)1.1 (0.9–1.5)
      6-94th124,391 (90.9)913 (89.8)Reference
      ≥95th5434 (4.0)46 (4.5)1.2 (0.9–1.6)
       uE3 (MoM percentile)
      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
      ≤5th6816 (5.0)74 (7.3)1.5 (1.2–1.9)
      P < .05
      6-94th124,816 (91.2)909 (89.4)Reference
      ≥95th5117 (3.7)31 (3.1)0.8 (0.6–1.2)
       INH (MoM percentile)
      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
      ≤5th7470 (5.5)60 (5.9)1.1 (0.9–1.5)
      6-94th124,545 (91.0)894 (87.8)Reference
      ≥95th4883 (3.6)63 (6.2)1.8 (1.4–2.3)
      P < .05
      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
      b P < .05
      c P < .10.
      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
      Characteristic(s)OR95% CI
      All placental abruption
       Age >34 y1.41.2–1.6
      P < .01
       Overweight (BMI 25.0-29.9)0.80.6–0.9
      P < .01
       Obese (BMI ≥30 kg/m2)0.70.6–0.9
      P < .01
       Preexisting hypertension (excluding preeclampsia)2.51.6–3.8
      P < .01
       Mild/unspecified preeclampsia2.61.9–3.5
      P < .01
       Severe preeclampsia5.94.4–7.9
      P < .01
       Preeclampsia/eclampsia superimposed on preexisting hypertension2.51.2–5.0
      P < .01
       Previous preterm birth2.81.6–4.7
      P < .01
       Interpregnancy interval <6 mo1.91.3–3.0
      P < .01
       First-trimester PAPP-A ≤5th percentile1.51.2–1.8
      P < .01
       First-trimester PAPP-A ≥95th percentile0.70.5–1.0
      P < .05.
       Second-trimester AFP ≥95th percentile1.71.3–2.2
      P < .01
       Second-trimester uE3 ≤fifth percentile1.31.0–1.6
      P < .05.
       Second-trimester INH ≥95th percentile1.41.0–1.8
      P < .05.
      Abruption without hypertensive disorder
       Asian race/ethnicity1.31.0–1.5
      P < .05.
       Age >34 y1.31.2–1.6
      P < .01
       Overweight (BMI 25.0-29.9 kg/m2)0.80.6–0.9
      P < .01
       Obese (BMI ≥30 kg/m2)0.80.7–1.0
      P < .05.
       Preexisting diabetes2.11.2–3.9
      P < .01
       Previous preterm birth2.81.6–5.2
      P < .01
       Interpregnancy interval <6 mo2.01.3–3.1
      P < .01
       First-trimester PAPP-A ≤5th percentile1.31.0–1.8
      P < .05.
       First-trimester PAPP-A ≥95th percentile0.70.4–1.0
      P < .05.
       Second-trimester AFP ≥95th percentile1.61.2–2.2
      P < .01
       Second-trimester uE3 ≤5th percentile1.31.0–1.8
      P < .05.
       Second-trimester INH ≥95th percentile1.41.0–2.0
      P < .05.
      Abruption with hypertensive disorder
       Age >34 y1.41.0–2.0
      P < .05.
       Obese (BMI ≥30 kg/m2)0.60.4–0.9
      P < .01
       First-trimester PAPP-A ≤5th percentile2.01.2–3.1
      P < .01
       Second-trimester AFP ≥95th percentile2.31.4–3.8
      P < .01
      AFP, alpha fetoprotein; BMI, body mass index; CI, confidence interval; INH, dimeric inhibin-A; 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 P < .01
      b P < .05.
      Figure thumbnail gr2
      Figure 2Abruption, maternal characteristics, and serum markers in pregnancies without hypertension
      Blumenfeld. Association between serum analytes and abruption. Am J Obstet Gynecol 2014.
      Figure thumbnail gr3
      Figure 3Abruption, maternal characteristics, and serum markers in pregnancies with hypertension
      Blumenfeld. Association between serum analytes and abruption. Am J Obstet Gynecol 2014.

      Comment

      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.
      • Lockwood C.J.
      • Kayisli U.A.
      • Stocco C.
      • et al.
      Abruption-induced preterm delivery is associated with thrombin-mediated functional progesterone withdrawal in decidual cells.
      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.
      • Ranta J.K.
      • Raatikainen K.
      • Romppanen J.
      • Pulkki K.
      • Heinonen S.
      Decreased PAPP-A is associated with preeclampsia, premature delivery and small for gestational age infants but not with placental abruption.
      Immunohistochemical studies have localized PAPP-A to cytotrophoblasts, and in vitro studies have linked PAPP-A with differentiation of cytotrophoblasts into syncytiotrophoblasts.
      • Guibourdenche J.
      • Frendo J.L.
      • Pidoux G.
      • et al.
      Expression of pregnancy-associated plasma protein A (PAPP-A) during human villous trophoblast differentiation in vitro.
      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.
      • Newby D.
      • Dalgliesh G.
      • Lyall F.
      • Aitken D.A.
      Alphafetoprotein and alphafetoprotein receptor expression in the normal human placenta at term.
      • Perkes E.A.
      • Baim R.S.
      • Goodman K.J.
      • Macri J.N.
      Second-trimester placental changes associated with elevated maternal serum alpha-fetoprotein.
      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.
      • Smith G.C.
      • Shah I.
      • Crossley J.A.
      • et al.
      Pregnancy-associated plasma protein A and alpha-fetoprotein and prediction of adverse perinatal outcome.
      Using linked birth records, we were also able to confirm previously described risk factors for placental abruption including maternal age and hypertensive disorders.
      • Han C.S.
      • Schatz F.
      • Lockwood C.J.
      Abruption-associated prematurity.
      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.
      • De Weger F.J.
      • Hukkelhoven C.W.
      • Serroyen J.
      • te Velde E.R.
      • Smits L.J.
      Advanced maternal age, short interpregnancy interval, and perinatal outcome.
      The mechanism linking short IPI and adverse outcomes remains unclear but may be related to a depletion of maternal nutrients.
      • Shachar B.Z.
      • Lyell D.J.
      Interpregnancy interval and obstetrical complications.
      Additional theories include inflammatory processes such as endometritis or other pelvic infections extending from the previous birth to the index pregnancy.
      • Shachar B.Z.
      • Lyell D.J.
      Interpregnancy interval and obstetrical complications.
      The association between PPROM and short IPI among women with previous PPROM supports this theory.
      • Shachar B.Z.
      • Lyell D.J.
      Interpregnancy interval and obstetrical complications.
      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.
      • Alanis M.C.
      • Goodnight W.H.
      • Hill E.G.
      • Robinson C.J.
      • Villers M.S.
      • Johnson D.D.
      Maternal super-obesity (body mass index > or = 50) and adverse pregnancy outcomes.
      • Becker T.
      • Vermeulen M.J.
      • Wyatt P.R.
      • Meier C.
      • Ray J.G.
      Maternal obesity and the risk of placental vascular disease.
      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.
      • Bujold E.
      • Roberge S.
      • Lacasse Y.
      Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis.
      • Reberge S.
      • Nicolaides K.H.
      • Demers S.
      • Villa P.
      • Bujold E.
      Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: a meta-analysis.
      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.
      • Bujold E.
      • Roberge S.
      • Lacasse Y.
      Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis.
      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.
      • Pariente G.
      • Wiznitzer A.
      • Sergienko R.
      • Mazor M.
      • Holcberg G.
      • Sheiner E.
      Placental abruption: critical analysis of risk factors and perinatal outcomes.
      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.

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