Background
The Eunice Kennedy Shriver National Institute of Child Health and Human Development Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be was established to investigate the underlying causes and pathophysiological pathways associated with adverse pregnancy outcomes in nulliparous gravidas.
Objective
This study aimed to study placental physiology and identify novel biomarkers concerning adverse pregnancy outcomes, including preterm birth (medically indicated and spontaneous), preeclampsia, small-for-gestational-age neonates, and stillbirth. We measured levels of placental proteins in the maternal circulation in the first 2 trimesters of pregnancy.
Study Design
Maternal serum samples were collected at 2 study visits (6–13 weeks and 16–21 weeks), and levels of 9 analytes were measured. The analytes we measured were vascular endothelial growth factor, placental growth factor, endoglin, soluble fms-like tyrosine kinase-1, A disintegrin and metalloproteinase domain-containing protein 12, pregnancy-associated plasma protein A, free beta-human chorionic gonadotropin, inhibin A, and alpha-fetoprotein. The primary outcome was preterm birth between 20 0/7 and 36 6/7 weeks of gestation. The secondary outcomes were spontaneous preterm births, medically indicated preterm births, preeclampsia, small-for-gestational-age neonates, and stillbirth.
Results
A total of 10,038 eligible gravidas were enrolled in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be cohort, from which a nested case-control study was performed comparing 800 cases with preterm birth (466 spontaneous preterm births, 330 medically indicated preterm births, and 4 unclassified preterm births), 568 with preeclampsia, 406 with small-for-gestational-age birth, and 49 with stillbirth with 911 controls who delivered at term without complications. Although levels of each analyte generally differed between cases and controls at 1 or 2 visits, the odds ratios revealed a <2-fold difference between cases and controls in all comparisons. Receiver operating characteristic curves, generated to determine the relationship between analyte levels and preterm birth and the other adverse pregnancy outcomes, resulted in areas under the receiver operating characteristic curves that were relatively low (range, 0.50–0.64) for each analyte. Logistic regression modeling demonstrated that areas under the receiver operating characteristic curves for predicting adverse pregnancy outcomes were greater using baseline clinical characteristics and combinations of analytes than baseline characteristics alone, but areas under the receiver operating characteristic curves remained relatively low for each outcome (range, 0.65–0.78).
Conclusion
We have found significant associations between maternal serum levels of analytes evaluated early in pregnancy and subsequent adverse pregnancy outcomes in nulliparous gravidas. However, the test characteristics for these analytes do not support their use as clinical biomarkers to predict adverse pregnancy outcomes, either alone or in combination with maternal clinical characteristics.
Why was this study conducted?
This study aimed to identify novel biomarkers of placental function concerning adverse pregnancy outcomes, including preterm birth (PTB), preeclampsia, small-for-gestational-age (SGA) birth, and stillbirth.
Key findings
Maternal serum levels of each analyte at first- and second-trimester study visits differed between cases with adverse pregnancy outcomes (APOs) and controls. In particular, decreased levels of placental growth factor and pregnancy-associated plasma protein A were associated with medically indicated PTB, preeclampsia, and SGA births. Test characteristics (eg, odds ratios and areas under the receiver operating characteristic curves) for these analytes do not support their use as clinical biomarkers to predict APOs.
What does this add to what is known?
Although this study confirmed the relationship between maternal serum levels of placental proteins and APOs, the findings did not support the use of these proteins in clinical protocols for identifying nulliparous patients at high risk of APOs.
Introduction
Most reproductive biologists agree that failed invasion by extravillous trophoblast cells into the maternal spiral arteries early in pregnancy reduces maternal blood flow into the placenta and induces functional and pathologic changes in the placenta that are observed frequently in those who have hypertensive disorders of pregnancy, small-for-gestational-age (SGA) neonates, and stillbirth. Many of these pregnancy complications result in medically indicated preterm births (PTBs). Furthermore, there is evidence that impaired trophoblast invasion into the maternal uterine vasculature early in pregnancy can result in placental dysfunction that leads to spontaneous PTB (SPTB; eg, preterm labor or preterm premature rupture of membranes [PPROM]). Unfortunately, reproductive biologists studying placental function have been stymied by the absence of animal models that recapitulate the human placenta and the inability to access placental tissue during human pregnancy, so the ability to identify placental dysfunction before these adverse outcomes occur has been limited.
The human placenta is characterized by a villous structure that provides a large surface area for gas and nutrient exchange, and placental products are secreted mostly from the villous surface of the syncytiotrophoblast into the intervillous space and maternal circulation. To study placental physiology concerning adverse pregnancy outcomes (APOs) and to identify novel biomarkers of these outcomes, we measured levels of placental proteins in the maternal circulation in a large cohort of nulliparous gravidas during the first 2 trimesters of pregnancy. The 9 proteins we studied fall into 3 broad physiological categories: (1) angiogenesis, vascular endothelial growth factor (VEGF), placental growth factor (PlGF), endoglin (Eng), and soluble fms-like tyrosine kinase-1 (sFlt-1) ; (2) placental implantation and development, A disintegrin and metalloproteinase domain-containing protein 12 (ADAM12) and pregnancy-associated plasma protein A (PAPP-A) , ; and (3) established clinical markers of fetal aneuploidy, free beta-human chorionic gonadotropin (β-hCG), inhibin A, and alpha-fetoprotein (AFP). , Although AFP is not secreted by the placenta, elevated levels in second-trimester maternal serum have been associated with APOs, likely in association with excessive placental permeability. ,
The Eunice Kennedy Shriver National Institute of Child Health and Human Development established the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) to investigate the underlying causes and pathophysiological pathways associated with APOs (eg, PTB, hypertensive disorders of pregnancy, SGA neonates) in nulliparous gravidas. More than 10,000 gravidas with singleton pregnancies were enrolled in nuMoM2b, which combined detailed demographic and medical information, clinical parameters, ultrasound measurements, genetics, biomarker measurements in biologic fluids, and psychosocial and behavioral measures in both prespecified and exploratory analyses to identify pregnant gravidas at risk of APOs. , , Maternal peripheral blood samples were collected from all nuMoM2b participants during the first and second trimesters of pregnancy. This analysis aimed to determine the use of placental analytes in maternal serum to predict APOs, including PTB (medically indicated and spontaneous), preeclampsia, SGA neonates, and stillbirth.
Methods
Nulliparous gravidas with a viable singleton pregnancy were recruited during their first trimester of pregnancy into the nuMoM2b observational prospective cohort at 8 institutions across the United States. The data-coordinating and analysis center was RTI International (Research Triangle Park, NC). Each site’s local governing institutional review board approved the nuMoM2b protocol and procedures ( ClinicalTrials.gov ; Identifier: NCT01322529).
Participants were enrolled in the nuMoM2b cohort between 6 0/7 and 13 6/7 weeks of gestation (first study visit). Gestational dating was based on a documented ultrasound crown-rump length measurement by a certified nuMoM2b sonographer at the first study visit, and potential participants were considered eligible for enrollment if they had no previous pregnancy that lasted ≥20 weeks of gestation based on self-report and review of available medical records.
Participants were evaluated at 3 study visits during pregnancy and again at delivery. Peripheral maternal blood samples were collected at all 3 study visits: first study visit (6 0/7 to 13 6/7 weeks of gestation), second study visit (16 0/7 to 21 6/7 weeks of gestation), and third study visit (22 0/7 to 29 6/7 weeks of gestation). We collected 4 to 8 cc maternal blood in serum separating tubes, centrifuged the samples, and stored 0.5 cc serum aliquots at −70°C within 2 hours after collection. Samples were transported on dry ice to analytical laboratories (provided below) for subsequent batch analyses. For the current study, we measured placental analyte levels in maternal serum samples collected at the first 2 study visits, because earlier pregnancy biomarkers are more likely to yield effective strategies for preventing APOs.
Maternal serum levels of placental analytes were measured at 2 laboratories: Translational Core Laboratory at Children’s Hospital of Philadelphia (Philadelphia, PA) and Eurofins NTD, LLC (Melville, NY). Of note, 2 analytes were measured by enzyme-linked immunosorbent assays (ELISA) at the Children’s Hospital laboratory: Eng (human endoglin assay; R&D Systems, Minneapolis, MN), and ADAM12 (human ADAM12 ELISA; R&D Systems, Minneapolis, MN). Moreover, 2 analytes were measured by electrochemiluminescence assays (ECL) at the Children’s Hospital laboratory: VEGF (human VEGF-A electrochemiluminescence assay; Merck Sharp & Dohme, Kenilworth, NJ), and sFlt-1 (human Flt-1 electrochemiluminescence assay; Merck Sharp & Dohme, Kenilworth, NJ). Furthermore, 5 analytes were measured by lanthanide-based time-resolved fluorometry (TRF) at the Eurofins NTD laboratory: PlGF, PAPP-A, inhibin, β-hCG, and AFP. The TRF assays are New York State Department of Health–approved and use the AutoDELFIA system (PerkinElmer, Waltham, MA). Briefly, the TRF assays are “sandwich-type” immunoassays using a monoclonal antibody (mAb) immobilized on the bottom of a microtitration strip plate. As the analyte is captured, mAb labeled with Europium (tracer) binds to different sites on the molecules. The addition of an inducer causes the release of the respective tracer conjugated Europium into the solution, and the fluorescent-specific signals are proportional to the concentration of analyte targeted in the sample. Levels of each analyte were measured once by ELISA, ECL, or TRF—97.53% of assays yielded numeric results in range, 2.42% of assays yielded results above or below standard ranges, and only 0.05% of assays did not yield numeric results.
The primary outcome of this analysis was PTB between 20 0/7 and 36 6/7 weeks of gestation. The secondary outcomes were subsets of PTBs, including SPTB and medically indicated PTB, and APOs that frequently are associated with PTB, including preeclampsia, SGA birth, and stillbirth. Definitions for preeclampsia, SGA birth, stillbirth, and SPTB in the nuMoM2b cohort have been published. Preeclampsia included eclampsia, preeclampsia with and without severe features, and superimposed preeclampsia. Those with preeclampsia or nonproteinuric gestational hypertension (GHTN) followed by PTB were analyzed as an additional outcome group. Antepartum GHTN was defined as new-onset hypertension of ≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure on 2 occasions at least 6 hours apart at >20 0/7 weeks of gestation and before labor and delivery. SGA births were defined as neonates with birthweight <5th percentile for gestational age at delivery based on Alexander birthweight curves. , , Stillbirth was a fetal death at an estimated gestational age of ≥20 0/7 weeks of gestation with Apgar scores of 0 at 1, 5, and 10 minutes with no other signs of life by direct observation. SPTBs were defined as deliveries at 20 0/7 to 36 6/7 weeks of gestation resulting from preterm labor or PPROM. Medically indicated PTBs were those resulting from labor induction or cesarean delivery for maternal or fetal indication in the absence of preterm labor or PPROM.
Biospecimen sample selection for analysis was performed using a case-subcohort design. Specifically, available biospecimens from the first and second study visits from all participants delivered at or after 20 weeks of gestation with PTB, preeclampsia, stillbirth, or SGA birth were selected for laboratory analysis as “case” samples. “Control” samples were selected from available biospecimens on the subset of participants delivered at or after 20 weeks of gestation without any of the aforementioned APOs. Geographic region and institution were not considered when selecting controls. The sample size for the controls was determined by the available funds remaining for visit 1 and visit 2 assays of the biomarkers. The budget allowed for the assay of 4800 samples across the 2 visits. The control samples were randomly selected using a sampling frequency, f =12%, after selecting the APO samples. Finally, a random selection of the APO cases was identified using the sampling frequency, f =12%. This random selection of cases combined with the controls defined each random subcohort.
Demographic and baseline clinical characteristics were described using means and standard deviations or counts and percentages. Comparisons were performed using chi-square tests for categorical variables and analysis of variance methods for continuous variables.
The median and interquartile range for each analyte on the original scale were assessed for each APO group and controls by study visit. The comparison of analyte distributions between an APO group and controls was performed using Wilcoxon rank-sum tests.
Analyte results were assessed for normality at each visit. Those analyte results that showed a lack of normality were transformed using an optimal power transformation, across visits, that was determined using the Box-Cox algorithm. The transformed analyte results from both visits were regressed onto gestational age to generate studentized residuals. The studentized residuals allow for the study of the associations between APOs and analyte results while accounting for changes in analyte levels depending on gestational age.
The transformed and studentized analyte results were independently assessed for association with each APO at each visit using appropriate controls from the random subcohort (eg, PTBs compared with no PTB=random subcohort minus PTB cases). The results were summarized using odds ratios (ORs) and areas under the receiver operating characteristic curves (AUCs) from logistic regression, each with 95% confidence intervals.
To determine which analytes were most important in predicting APOs and whether the most important analytes provide prediction beyond baseline clinical characteristics, we performed model selection for each APO using cross-validation regression with the least absolute shrinkage and selection operator (LASSO) method. This was repeated for visit 1, visit 2, and visit 1 and visit 2 together. Potential variables included the transformed and studentized analyte results that were allowed as independent selections or through interactions with gestational age. To determine which combination of analytes best predicted an APO above baseline characteristics, each LASSO model included the baseline characteristic prediction as an offset. The baseline characteristics in the prediction were maternal age, self-identified race and ethnicity, early pregnancy body mass index (BMI), smoking status during the 3 months before pregnancy, pregestational diabetes mellitus, and chronic hypertension. LASSO model results were summarized using AUCs from logistic regression for the baseline characteristics and baseline characteristics plus the selected analyte variables.
Finally, consideration was given to sonographic findings of a cervical length of ≤25 mm and bilateral resistance index in the uterine arteries of ≥0.59, both measured at visit 2. , Data were summarized using AUCs from logistic regression for the baseline characteristics, plus the selected analyte variables plus cervical length; the baseline characteristics, plus the selected analyte variables plus resistance index; and the baseline characteristics, plus the selected analyte variables plus both sonographic measures.
All tests were performed using a nominal significant alpha level of .05 (2-sided). No correction was made for multiple comparisons. Analyses were performed using SAS (version 9.4; (SAS Institute, Cary, NC) and R (version 3.6.2; https://www.r-project.org/ ).
Results
A total of 10,038 eligible gravidas were consented and enrolled into the nuMoM2b cohort between October 2010 and September 2013, and delivery outcomes after 20 0/7 weeks of gestation and adequate maternal serum for analyses were available for 9222 participants ( Figure 1 ). There were 800 PTBs (466 SPTBs, 330 medically indicated PTBs, and 4 unclassified PTBs), 568 cases of preeclampsia, 406 SGA births, and 49 stillbirths. In addition, there were 62 cases of GHTN among those who also had a PTB. There was a modest overlap among these APOs—57 participants had both preeclampsia and SGA births, 25 participants had both SPTBs and preeclampsia, and 13 participants had both SPTBs and SGA births. Overall in the nested case-control study, there was a total of 1502 cases (some cases had >1 APO, and a total of 800 delivered preterm) and 911 controls who delivered at term without complications.
Demographic characteristics were compared between the 1502 participants with APOs (cases) and the 911 participants without APO (controls) ( Table 1 ). Controls were more likely to be non-Hispanic White and have more years of education. Cases were more likely to smoke and have a higher BMI, chronic hypertension, and pregestational diabetes mellitus.
| Descriptive characteristics | Sample population | P value a | |
|---|---|---|---|
| Case | Control | ||
| (n=1502) | (n=911) | ||
| Maternal age (y) | |||
| Mean (SD) | 26.6 (6.0) | 27.0 (5.6) | .0664 |
| Category, n (%) | .0111 | ||
| 13–21 | 375 (25.0) | 191 (21.0) | |
| 22–35 | 1004 (66.9) | 662 (72.7) | |
| >35 | 122 (8.1) | 58 (6.4) | |
| Maternal race, n (%) | <.0001 | ||
| White non-Hispanic | 798 (53.2) | 583 (64.0) | |
| Black non-Hispanic | 302 (20.1) | 112 (12.3) | |
| Hispanic | 258 (17.2) | 146 (16.0) | |
| Asian | 53 (3.5) | 28 (3.1) | |
| Other | 90 (6.0) | 42 (4.6) | |
| Early pregnancy BMI (kg/m 2 ) | |||
| Mean (SD) | 27.6 (7.3) | 25.9 (5.9) | <.0001 |
| Category, n (%) | <.0001 | ||
| <25 | 673 (45.9) | 498 (55.6) | |
| 25 to <30 | 366 (24.9) | 229 (25.6) | |
| ≥30 | 428 (29.2) | 169 (18.9) | |
| Smoked during 3 mo before pregnancy, n (%) | 324 (21.6) | 135 (14.8) | <.0001 |
| Chronic hypertension, n (%) | 86 (5.7) | 12 (1.3) | <.0001 |
| Pregestational diabetes mellitus, n (%) | 68 (4.5) | 6 (0.7) | <.0001 |
| Education status attained, n (%) | <.0001 | ||
| Less than high school | 179 (11.9) | 69 (7.6) | |
| Completed high school or GED | 217 (14.5) | 107 (11.7) | |
| Some college | 327 (21.8) | 167 (18.3) | |
| Associate or technical degree | 169 (11.3) | 82 (9.0) | |
| Completed college | 339 (22.6) | 259 (28.4) | |
| Degree work beyond college | 269 (17.9) | 227 (24.9) | |
| Gestational age at visit 1 (wk) | |||
| Mean (SD) | 11.6 (1.5) | 11.6 (1.4) | .2382 |
| Gestational age at visit 2 (wk) | |||
| Mean (SD) | 18.6 (1.6) | 18.5 (1.5) | .2838 |
| Gestational age at birth (wk) b | |||
| Mean (SD) | 35.9 (3.9) | 39.3 (1.2) | — |
| Birthweight (g) b | |||
| Mean (SD) | 2571.9 (753.5) | 3421.5 (409.8) | — |
| SGA b (<5th percentile), n (%) | 406 (27.3) | 0 (0) | — |
| SGA b (<10th percentile), n (%) | 523 (35.2) | 47 (5.2) | — |
a P values are shown for chi-square tests and ANOVA F tests
b P values are not shown as preterm birth and SGA birth are defined as cases.
Levels of analytes in maternal serum at study visits 1 and 2 are presented in Table 2 . Test characteristics for each assay (sensitivity, intra-assay coefficient of variability [CV], and inter-assay CV) are provided in the Supplemental Table . The only analytes in maternal serum that were associated with PTB at both study visits ( P <.05) were AFP (elevated levels compared with controls) and PlGF (decreased levels compared with controls). At both study visits, elevated maternal serum levels of AFP were associated with SPTB and SGA births. At both study visits, decreased levels of maternal serum PlGF were associated with medically indicated PTB and common causes for medically indicated PTB, including preeclampsia and SGA growth. Similarly, decreased maternal serum levels of PAPP-A at both study visits were associated with medically indicated PTB, preeclampsia, and SGA births. In contrast, decreased maternal serum levels of PAPP-A were not associated with overall PTB (the primary outcome).
| Analyte | APO (n=1502) | |||||||
|---|---|---|---|---|---|---|---|---|
| No APO (n=911) | PTB (n=800) | SPTB (n=466) | Indicated PTB (n=330) | Preeclampsia (n=568) | Preeclampsia or gestational hypertension with PTB (n=630) | Small for gestational age (n=406) | Stillbirth (n=49) | |
| Visit 1 | (n=866) | (n=768) | (n=449) | (n=315) | (n=540) | (n=599) | (n=386) | (n=49) |
| sFlt-1 (pg/mL) | 931 (706–1203) | 830 (622–1133) a | 883 (646–1198) a | 805 (602–1092) a | 838 (626–1114) a | 833 (615–1129) a | 793 (615–1159) a | 900 (711–1163) |
| ADAM12 (ng/mL) | 4.9 (3.7–6.2) | 4.5 (3.3–5.8) a | 4.6 (3.5–6.0) | 4.2 (2.9–5.5) a | 4.5 (3.3–5.7) a | 4.5 (3.2–5.7) a | 4.4 (3.4–5.7) a | 4.5 (2.9–5.5) a |
| Endoglin (ng/mL) | 6.3 (5.4–7.4) | 6.3 (5.4–7.6) | 6.4 (5.5–7.5) | 6.2 (5.2–7.7) | 6.3 (5.3–7.7) | 6.3 (5.2–7.7) | 6.5 (5.4–7.6) | 5.9 (4.8–7.8) |
| VEGF (pg/mL) | 0.72 (0.51–1.09) | 0.80 (0.54–1.33) a | 0.77 (0.53–1.22) | 0.87 (0.54–1.66) a | 0.88 (0.57–1.57) a | 0.88 (0.57–1.64) a | 0.84 (0.57–1.50) a | 0.81 (0.54–1.38) |
| β-hCG (ng/mL) | 20.9 (13.8–31.9) | 19.9 (13.0–31.0) | 20.2 (13.4–31.4) | 19.6 (12.4–30.7) | 19.5 (12.1–29.9) a | 19.3 (11.9–29.7) a | 20.9 (13.3–30.4) | 22.1 (14.7–40.2) |
| AFP (IU/mL) | 12.9 (8.1–18.9) | 14.3 (8.2–20.8) a | 15.0 (8.6–21.9) a | 13.4 (7.4–19.8) | 13.5 (8.4–19.3) | 13.7 (8.4–19.4) | 15.4 (9.4–22.5) a | 13.0 (8.4–21.3) |
| PlGF (pg/mL) | 41.9 (29.6–58.0) | 38.1 (27.3–55.1) a | 40.4 (29.5–57.2) | 34.3 (25.1–50.9) a | 37.4 (26.9–52.6) a | 37.2 (27.0–51.9) a | 36.9 (24.1–55.2) a | 39.7 (27.2–61.7) |
| Inhibin A (pg/mL) | 306 (224–424) | 314 (227–432) | 313 (231–430) | 320 (223–440) | 313 (225–453) | 311 (221–446) | 317 (219–450) | 307 (206–441) |
| PAPP-A (mU/mL) | 1012 (485–1973) | 819 (328–1661) a | 926 (406–1846) | 692 (249–1430) a | 776 (335–1604) a | 774 (322–1629) a | 801 (327–1418) a | 781 (287–1430) a |
| sFlt-1–to–PlGF ratio | 22.4 (14.4–32.1) | 22.0 (14.0–32.7) | 21.2 (13.6–31.6) | 22.6 (14.9–33.9) | 22.0 (15.3–33.1) | 21.9 (15.2–33.2) | 21.6 (13.8–34.1) | 20.9 (15.9–33.4) |
| Visit 2 | (n=839) | (n=713) | (n=418) | (n=291) | (n=514) | (n=571) | (n=370) | (n=42) |
| sFlt-1 (pg/mL) | 895 (648–1213) | 868 (614–1224) | 866 (605–1239) | 887 (625–1217) | 848 (594–1178) a | 845 (589–1178) a | 829 (611–1191) | 947 (776–1364) |
| ADAM12 (ng/mL) | 9.9 (7.9–12.1) | 9.9 (7.6–12.5) | 10.1 (7.6–12.6) | 9.7 (7.3–12.3) | 9.9 (7.7–12.4) | 9.8 (7.7–12.4) | 9.8 (7.8–12.3) | 8.9 (6.4–12.8) |
| Endoglin (ng/mL) | 5.3 (4.6–6.1) | 5.6 (4.8–6.8) a | 5.4 (4.7–6.4) a | 6.0 (4.9–7.4) a | 5.6 (4.7–6.8) a | 5.6 (4.7–6.8) a | 5.7 (4.9–7.0) a | 5.5 (4.9–6.4) |
| VEGF (pg/mL) | 0.91 (0.64–1.46) | 0.96 (0.66–1.70) | 0.97 (0.70–1.61) a | 0.94 (0.60–1.79) | 1.09 (0.67–1.92) a | 1.07 (0.68–1.94) a | 0.95 (0.61–1.67) | 0.92 (0.58–1.34) |
| β-hCG (ng/mL) | 4.1 (2.7–6.4) | 4.2 (2.6–6.5) | 4.0 (2.4–6.3) | 4.3 (2.9–7.0) | 3.9 (2.4–6.2) | 3.8 (2.4–6.4) | 4.1 (2.4–6.9) | 4.7 (2.5–7.2) |
| AFP (IU/mL) | 44.2 (34.1–57.7) | 47.3 (35.9–62.7) a | 49.1 (37.2–63.8) a | 45.2 (34.7–61.3) | 45.3 (34.7–61.4) | 45.3 (34.9–60.9) | 49.6 (37.2–65.9) a | 42.4 (30.7–58.4) |
| PlGF (pg/mL) | 195.2 (133.8–282.7) | 179.9 (115.4–284.3) a | 209.2 (137.2–320.9) a | 145.2 (80.6–223.5) a | 161.1 (104.1–240.7) a | 162.6 (103.7–240.7) a | 152.3 (95.5–241.5) a | 166.2 (90.9–313.6) |
| Inhibin A (pg/mL) | 196 (155–254) | 214 (166–293) a | 204 (154–273) | 236 (178–330) a | 215 (163–294) a | 215 (161–293) a | 212 (158–294) a | 235 (173–299) |
| PAPP-A (mU/mL) | 9418 (5530–14,615) | 9165 (4986–16,029) | 9463 (5578–16,703) | 7660 (4077–15,443) a | 8232 (4350–14,907) a | 8292 (4417–14,918) a | 8459 (4833–14,099) a | 7516 (4035–15,416) |
| sFlt-1–to–PlGF ratio | 4.5 (2.9–7.1) | 4.7 (2.9–7.8) | 4.1 (2.6–6.4) a | 5.8 (3.7–10.1) a | 5.1 (3.1–8.9) a | 5.1 (3.1–8.8) a | 5.2 (3.3–9.0) a | 5.1 (3.5–8.9) |
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