Katherine Bianco

Reversal of gene dysregulation in cultured cytotrophoblasts reveals possible causes of preeclampsia

During human pregnancy, a subset of placental cytotrophoblasts (CTBs) differentiates into cells that aggressively invade the uterus and its vasculature, anchoring the progeny and rerouting maternal blood to the placenta. In preeclampsia (PE), CTB invasion is limited, reducing placental perfusion and/or creating intermittent flow. This syndrome, affecting 4%-8% of pregnancies, entails maternal vascular alterations (e.g., high blood pressure, proteinuria, and edema) and, in some patients, fetal growth restriction. The only cure is removal of the faulty placenta, i.e., delivery. Previously, we showed that defective CTB differentiation contributes to the placental component of PE, but the causes were unknown. Here, we cultured CTBs isolated from PE and control placentas for 48 hours, enabling differentiation and invasion. In various severe forms of PE, transcriptomics revealed common aberrations in CTB gene expression immediately after isolation, including upregulation of SEMA3B, which resolved in culture. The addition of SEMA3B to normal CTBs inhibited invasion and recreated aspects of the PE phenotype. Additionally, SEMA3B downregulated VEGF signaling through the PI3K/AKT and GSK3 pathways, effects that were observed in PE CTBs. We propose that, in severe PE, the in vivo environment dysregulates CTB gene expression; the autocrine actions of the upregulated molecules (including SEMA3B) impair CTB differentiation, invasion and signaling; and patient-specific factors determine the signs.

History of miscarriage and increased incidence of fetal aneuploidy in subsequent pregnancy.

OBJECTIVE: The purpose of this study was to examine the association between history of spontaneous abortion and aneuploidy in a subsequent pregnancy. METHODS: This was a retrospective cohort study of women who underwent fetal karyotype analysis with amniocentesis or chorionic villus sampling at a single prenatal diagnosis center. Information on spontaneous abortions, parity, maternal age, ethnicity, type of prenatal diagnosis, and karyotype was assessed. Univariable and multivariable analyses were conducted. RESULTS: A total of 46,939 women were included in our analysis. Women with no prior spontaneous abortions had a 1.39% risk for any aneuploidy. In women with one prior spontaneous abortion, this risk increased to 1.67%; for women with 2 previous spontaneous abortions, the risk increased to 1.84%; and for those women who had had 3 or more prior spontaneous abortions, the risk increased further to 2.18% (P < .007). When controlling for maternal age, parity, ethnicity, and mode of prenatal diagnosis and compared with women with no prior spontaneous abortions, women with one prior spontaneous abortion (adjusted odds ratio [AOR] 1.21, 95% confidence interval [CI] 1.01–1.47) or 3 or more prior spontaneous abortions (AOR 1.51, 95% CI 1.02–2.25) had a statistically significant increase in aneuploidy in a subsequent pregnancy. Women with 2 prior spontaneous abortions had an AOR of 1.26 for aneuploidy, but the 95% CI contained unity. CONCLUSION: An increased risk of karyotypic abnormality identified at the time of prenatal diagnosis is demonstrated in patients with an increasing number of spontaneous abortions. This study provides information regarding this risk among women presenting for prenatal diagnosis. According to our data, for a woman with an a priori risk of 1 in 300 for Down syndrome, 3 prior spontaneous abortions would increase that risk by 47% to 1 in 204. These results should be confirmed in low-risk populations. LEVEL OF EVIDENCE: II-2

Perinatal outcomes in the setting of active phase arrest of labor

OBJECTIVE: To examine the association between active phase arrest and perinatal outcomes. METHODS: This was a retrospective cohort study of women with term, singleton, cephalic gestations diagnosed with active phase arrest of labor, defined as no cervical change for 2 hours despite adequate uterine contractions. Women with active phase arrest who underwent a cesarean delivery were compared with those who delivered vaginally, and women who delivered vaginally with active phase arrest were compared with those without active phase arrest. The association between active phase arrest, mode of delivery, and perinatal outcomes was evaluated using univariable and multivariable logistic regression models. RESULTS: We identified 1,014 women with active phase arrest: 33% (335) went on to deliver vaginally, and the rest had cesarean deliveries. Cesarean delivery was associated with an increased risk of chorioamnionitis (adjusted odds ratio [aOR] 3.37, 95% confidence interval [CI] 2.21–5.15), endomyometritis (aOR 48.41, 95% CI 6.61–354), postpartum hemorrhage (aOR 5.18, 95% CI 3.42–7.85), and severe postpartum hemorrhage (aOR 14.97, 95% CI 1.77–126). There were no differences in adverse neonatal outcomes. Among women who delivered vaginally, women with active phase arrest had significantly increased odds of chorioamnionitis (aOR 2.70, 95% CI 1.22–2.36) and shoulder dystocia (aOR 2.37, 95% CI 1.33–4.25). However, there were no differences in the serious sequelae associated with these outcomes, including neonatal sepsis or Erbs palsy. CONCLUSION: Efforts to achieve vaginal delivery in the setting of active phase arrest may reduce the maternal risks associated with cesarean delivery without additional risk to the neonate. LEVEL OF EVIDENCE: II

Fetal cerebellar hemorrhage in parvovirus-associated non-immune hydrops fetalis

We report two cases of fetal cerebellar hemorrhage in the setting of parvovirus-associated hydrops fetalis and fetal blood transfusion. In both cases, the cerebellar hemorrhage was diagnosed by fetal magnetic resonance imaging after intrauterine blood transfusion. To our knowledge, this is the first report of fetal cerebellar hemorrhage in the setting of parvovirus-associated hydrops fetalis, and may be the result of cerebrovascular changes both during and after the transfusion.

Comparative analysis of maternal-fetal interface in preeclampsia and preterm labor

The maternal-fetal interface, a chimeric structure, is formed when fetal cytotrophoblasts (CTBs) from the placenta invade the uterine wall and its resident vasculature. In preeclampsia (PE), interstitial and endovascular invasion are often shallow, and fewer spiral arterioles are breached in toto. Our previous work has shown that faulty CTB differentiation to an invasive phenotype is a contributing factor. Here, we have tested the hypothesis that the constellation of morphological and molecular defects that are associated with PE are unique to this condition. Specifically, we have compared the histology of the maternal-fetal interface and CTB expression of stage-specific antigens in PE and in preterm labor (PTL) with or without inflammation. In the absence of inflammation, biopsies obtained after PTL were near normal at histological and molecular levels. In accord with previously published data, PE had severe negative effects on the endpoints analyzed. Biopsies obtained after PTL with inflammation had an intermediate phenotype. Our results suggest that the maternal-fetal interface from cases of PTL without inflammation can be used for comparative purposes, e.g., as age-matched controls, in studies of the effects of PE on cells in this region.

Timing of operative vaginal delivery and associated perinatal outcomes in nulliparous women

Objective. To compare perinatal outcomes in nulliparous women who had operative vaginal delivery early during second stage (1–3 h) to those who delivered vaginally with a prolonged second stage (>3 h). Methods. This is a retrospective cohort study of nulliparas with term, singleton, vaginal deliveries beyond the first hour of second stage. Women who underwent operative vaginal deliveries (OVD) during 1–3 h of the second stage were compared to women who delivered vaginally but with a second stage duration of >3 h. Perinatal outcomes were examined using chi-square test, and potential confounders were controlled for using multivariable logistic regression analysis. Results. Nulliparas delivered vaginally beyond 3 h of second stage had lower odds of third or fourth degree perineal lacerations (aOR = 0.63, 95% CI 0.51–0.77), neonatal cephalohematoma (aOR = 0.48, 95% CI 0.28–0.83) and admissions to intensive care nursery (aOR = 0.70, 95% CI 0.49–0.99) compared to operative vaginal deliveries during 1–3 h of second stage. Conclusion. Compared to nulliparas who had operative vaginal deliveries performed early (1–3 h) in the second stage, women who delivered later (>3 h duration of second stage), either by spontaneous or operative vaginal delivery, had lower risk of third or fourth degree perineal lacerations without incurring risk of increased adverse neonatal outcomes.

Second-Trimester Ductus Venosus Measurement and Adverse Perinatal Outcome in Fetuses With Congenital Heart Disease

Objective. The purpose of this study was to determine whether Doppler velocimetry of the ductus venosus (DV) predicts adverse perinatal outcome in congenital heart disease (CHD). Methods. We conducted a retrospective cohort study of all pregnant women undergoing fetal echocardiography for CHD in a single perinatal center during a 2‐year period. We compared outcomes for fetuses having a diagnosis of CHD in the second trimester and abnormal DV Doppler velocimetric findings with those having CHD and normal DV Doppler findings. Karyotype, gestational age at delivery, fetal loss rate, and rate of termination were assessed. The referral value for an abnormal DV pulsatility index was above the 95th percentile for gestational age. Statistical analysis included the t test, Fisher exact test, and χ2 test. Results. The incidence of CHD in our population was 7%. There were 98 patients with CHD; of those, 31 had DV measurement. A total of 9 patients had an abnormal DV. Three of this group (33%) had intrauterine fetal death or perinatal death. In patients with CHD and normal DV measurements, 83% had living children versus 33% in the group with an abnormal DV (P < .05). There was no statistically significant difference in the rate of aneuploidy between the normal DV (15%) and abnormal DV (20%) groups (P = .65). The mean gestational age at delivery was similar between the normal (37.63 weeks) and abnormal (38.33 weeks) DV groups (P = .71). There was no difference in the rate of pregnancy termination. Conclusions. Abnormal second‐trimester DV measurements are predictive of adverse perinatal outcome in patients with CHD, independent of karyotype or gestational age at delivery. This information may have a role in the counseling of parents with CHD.

Effect of estradiol on oocyte development

To determine whether elevated serum estradiol (E2) concentrations in oocyte donors affect assisted reproduction outcome.

OP04.08: The prognostic significance of a single umbilical artery (SUA) in fetuses with prenatally detected congenital diaphragmatic hernia (CDH)

extrophy and one case of multiple anomaly with holoprosencephaly, cleft lip and palate and hypotelorism. There were 6 cases with minor abnormal US findings including increased nuchal fold thickness (NFT), choroid plexus cyst (CPC), single umbilical artery, wide iliac angle, brachycephaly, intrauterine growth restriction, pericardial effusion, sandal gap deformity, and flattened nose. In 9 cases, there were no fetal anomalies found on the US. Among 15 cases of de novo balanced chromosomal translocations, there were 2 cases of major anomalies; one was cardiomyopathy and the other was ventricular septal defect with unusual mitral regurgitation and reversed aortic arch flow. There were 4 cases of minor congenital anomalies; CPC and increased NFT. In 9 cases, there were no fetal anomalies found on the US. Conclusions: Correlations between fetal US and de novo chromosomal aberrations were higher in unbalanced chromosomal aberration cases. We found several cases with abnormal US findings in de novo balanced translocation, although normal US findings were expected. Consequently, detailed fetal US evaluation is very important in prediction of the prognosis of de novo balanced translocation cases.

Placental transcriptomes in the common aneuploidies reveal critical regions on the trisomic chromosomes and genome‐wide effects

Chromosomal aberrations are frequently associated with birth defects and pregnancy losses. Trisomy 13, Trisomy 18 and Trisomy 21 are the most common, clinically relevant fetal aneusomies. This study used a transcriptomics approach to identify the molecular signatures at the maternal–fetal interface in each aneuploidy.