Population-based biomarker screening and the development of severe preeclampsia in California.

OBJECTIVE: The purpose of this study was to examine the relationship between second-trimester maternal serum biomarkers and the development of early- and late-onset severe preeclampsia in euploid pregnancies. STUDY DESIGN: Included were 136,139 pregnancies that obtained second-trimester prenatal screening through the California Prenatal Screening Program with live births in 2006-2008. We identified severe preeclampsia diagnoses from hospital discharge records. We used log binomial regression to examine the association between abnormal second-trimester maternal serum biomarkers and the development of severe preeclampsia. RESULTS: Approximately 0.9% of all women (n = 1208) in our sample experienced severe preeclampsia; 329 women at <34 weeks' gestation and 879 women ≥34 weeks' gestation. High levels of alpha fetoprotein (AFP), human chorionic gonadotropin, inhibin (multiple of the median, ≥95th percentile), and low unconjugated estriol (multiple of the median, ≤5th percentile), were associated with severe preeclampsia (relative risk, 2.5-11.7). Biomarkers were more predictive of early-onset severe preeclampsia (relative risk, 3.8-11.7). One in 9.5 pregnancies with combined high AFP, inhibin, and low unconjugated estriol levels experienced severe early-onset preeclampsia compared with 1 in 680.5 pregnancies without any abnormal biomarkers. CONCLUSION: The risk of the development of severe preeclampsia increases for women with high second-trimester AFP, human chorionic gonadotropin, inhibin, and/or low unconjugated estriol; this is especially true for early-onset severe preeclampsia. When abnormal biomarkers co-occur, risk dramatically increases. Although the screening value of second-trimester biomarkers is low, abnormal biomarkers, especially when occurring in combination, appear to indicate placental dysfunction that is associated with the development of severe preeclampsia.

Current practices in determining amnionicity and chorionicity in multiple gestations.

OBJECTIVE: To evaluate the accuracy of amnionicity and chorionicity (A/C) diagnosis of referral physicians and a tertiary care center as compared to histopathologic diagnosis. METHOD: A retrospective study of 289 multi-fetal gestations was performed comparing A/C diagnoses of referring physicians, a tertiary care center, and histopathology. RESULTS: Two hundred and eighty-nine multi-fetal pregnancies were referred for evaluation; only 43.6% (126/289) carried an accurate diagnosis of A/C before tertiary care center evaluation. The tertiary care center accurately identified A/C in 94.8% (274/289) overall and 100% in first trimester twins and triplets. Referrals with an unspecified A/C diagnosis included 46.1% (113/245) twins and 64.1% (25/39) triplets. CONCLUSION: Accurate diagnosis of A/C can be obtained by the early assessment of key sonographic findings. Referral providers are less accurate at determining A/C of multifetal gestation when compared to a tertiary center, suggesting that an emphasis should be placed on enhancing these diagnostic skills in the general community or encouraging referral when diagnosis is ambiguous.

Three-dimensional obstetric ultrasound.

Three-dimensional ultrasound has gained a significant popularity in obstetrical practice in recent years. The advantage of this modality in some cases is in question, however. This article provides a basic review of volume acquisition, mechanical positioning, and display modalities. Multiple uses of this technique in obstetrical care including first trimester applications and its utility in clarification of fetal anatomy such as brain, face, heart, and skeleton is discussed.

Delayed cord clamping during elective cesarean deliveries: results of a pilot safety trial.

BACKGROUND: Delayed cord clamping (DCC) results in decreased iron deficiency in infancy. The American College of Obstetrics and Gynecology has called for research on the optimal time to clamp the cord during cesarean deliveries (CD). Our objective was to conduct a pilot trial examining the safety of delayed cord clamping (DCC) for maternal-infant dyads during elective cesarean delivery (CD). METHODS: We enrolled 39 dyads [23 at 90 s, 16 at 120 s; (DCC Pilot)] between 10/2013 and 9/2014. We abstracted data from the electronic medical record (EMR) for historical controls (HC) birthing between 1/2012-6/2013 for whom DCC was not performed (n = 112). RESULTS: Available data for 37 mothers and 30 infants compared to HC revealed 174 (95% CI: 61-286) mL lower mean estimated maternal blood loss [(EBL) mean (SD) mL]: DCC Pilot 691(218) vs. HC 864(442), p = 0.003 and lower incidence of maternal transfusions, DCC Pilot 2.7% vs. HC 18.8%, p = 0.016. There was no significant between group difference between DCC Pilot and HC in other a priori definitions of excess maternal blood loss: a) EBL > 800 ml, 21.6% vs. 38.8%, p = 0.07 or b) post-op hgb/pre-op hgb < 80%, 16.7% vs. 20.6%, p = 0.81. There were also no statistically significant between group differences in rates of NICU admission DCC Pilot 8.1% vs. HC 7.1%, p = 1.0., but there was a higher rate of newborn cold stress or hypothermia ≤36.2 °C in study subjects, DCC Pilot 27.0% vs. HC 11.9%, p = 0.038.Prevalence of newborn anemia was decreased [DCC pilot 3.3% (1 of 30) vs. HC 40.0% (4 of 10 infants with data), p = 0.012. No infants were polycythemic. CONCLUSIONS: These pilot data suggest cord clamping can be delayed to 120 s during elective CD without increased risk of excessive maternal blood loss. More aggressive prevention of infant heat loss may be warranted. A randomized trial to evaluate long-term maternal and infant outcomes is indicated. TRIAL REGISTRATION: Clinical trials.gov, NCT02229162; registered: 1 September, 2014.

Sirtuin1 is required for proper trophoblast differentiation and placental development in mice.

INTRODUCTION: Placental insufficiency, arising from abnormal trophoblast differentiation and function, is a major cause of fetal growth restriction. Sirtuin-1 (Sirt1) is a ubiquitously-expressed NAD-dependent protein deacetylase which plays a key role in numerous cellular processes, including cellular differentiation and metabolism. Though Sirt1 has been widely studied, its role in placentation and trophoblast differentiation is unclear. METHOD: Sirt1-heterozygous mice were mated and evaluated at various points during embryogenesis. In situ hybridization and immunohistochemistry were used to further characterize the placental phenotype of Sirt1-null mice. Wild-type (WT) and Sirt1-null mouse trophoblast stem cell (TSC) lines were derived from e3.5 littermate blastocysts. These cells were then evaluated at various points following differentiation. Differentiation was evaluated by expression of lineage specific markers using qPCR and flow cytometry, as well as Matrigel invasion assays. Global gene expression changes were evaluated using microarray-based RNA profiling; changes in specific pathways were validated using qPCR and western blot. RESULTS: In the absence of Sirt1, both embryos and placentas were small, with placentas showing abnormalities in both the labyrinthine layer and junctional zone. Sirt1-null TSCs exhibited an altered phenotype in both undifferentiated and differentiated states, phenotypes which corresponded to changes in pathways relevant to both TSC maintenance and differentiation. Specifically, Sirt1-null TSC showed blunted differentiation, and appeared to be suspended in an Epcamhigh trophoblast progenitor state. DISCUSSION: Our results suggest that Sirt1 is required for proper TSC differentiation and placental development.

Lipoyltransferase 1 Gene Defect Resulting in Fatal Lactic Acidosis in Two Siblings.

A term male neonate developed severe intractable lactic acidosis on day of life 1 and died the same day at our institution. The family previously lost another term, female newborn on day of life 1 from suspected sepsis at an outside hospital. After performing an autopsy on the neonate who died at our institution, extensive and lengthy neonatal and parental genetic testing, as well as biochemical analyses, and whole exome sequencing analysis identified compound heterozygous mutations in the lipoyltransferase 1 (LIPT1) gene responsible for the lipoylation of the 2-keto dehydrogenase complexes in the proband. These mutations were also identified in the deceased sibling. The clinical manifestations of these two siblings are consistent with those recently described in two unrelated families with lactic acidosis due to LIPT1 mutations, an underrecognized and underreported cause of neonatal death. Conclusions. Our observations contribute to the delineation of a new autosomal recessive metabolic disorder, leading to neonatal death. Our case report also highlights the importance of an interdisciplinary team in solving challenging cases.

Hypoxia and trophoblast differentiation: a key role for PPARγ.

Tissue oxygen tension regulates differentiation of multiple types of stem cells. In the placenta, hypoxia has been associated with abnormal trophoblast differentiation and placental insufficiency syndromes of preeclampsia (PE) and intrauterine growth restriction (IUGR). Peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated transcription factor involved in many cellular processes, including differentiation. We have previously shown that PPARγ-null trophoblast stem (TS) cells show a defect in differentiation to labyrinthine trophoblast, instead differentiating preferentially to trophoblast giant cells (TGC). Since PPARγ is known to be regulated by hypoxia in adipose tissue, we hypothesized that there may be a link between oxygen tension, PPARγ expression, and trophoblast differentiation. We found that hypoxia reduced PPARγ expression by a mechanism independent of both hypoxia-inducible factor (HIF) and histone deacetylases (HDACs). In addition, PPARγ partially rescued hypoxia-induced inhibition of labyrinthine differentiation in wild-type TS cells but was not required for hypoxia-induced inhibition of TGC differentiation. Finally, we show that induction of labyrinthine trophoblast differentiation by HDAC inhibitor treatment is independent of both PPARγ and Gcm1. We propose a model with two pathways for labyrinthine trophoblast differentiation of TS cells, one of which is dependent on PPARγ and inhibited by hypoxia. Since hypoxia is associated with PE and IUGR, we propose that PPARγ may at least partially mediate hypoxia-induced placental insufficiency and as such may be a promising therapeutic target for these disorders.

Pregnancy outcome in anti-N-methyl-D-aspartate receptor encephalitis.

BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune disorder resulting in neurologic and psychiatric symptoms. Treatment is challenging in pregnancy, because little data exist to guide management. CASE: A 24-year-old woman with a known diagnosis of anti-NMDA receptor encephalitis using intravenous immunoglobulin therapy became pregnant. Her pregnancy was uncomplicated with no relapses. She delivered at 35 4/7 weeks of gestation after having preterm premature rupture of membranes. She had a relapse of symptoms after delivery. CONCLUSION: This patient with anti-NMDA receptor encephalitis had an uneventful pregnancy with overall good outcome; however, she experienced relapse soon after delivery. This disease may mimic other autoimmune diseases, with improvement during pregnancy and risk for relapse postpartum.

Placental expression of vascular endothelial growth factor receptor-1/soluble vascular endothelial growth factor receptor-1 correlates with severity of clinical preeclampsia and villous hypermaturity.

Overexpression of soluble vascular endothelial growth factor receptor-1 has been linked to preeclampsia and is thought to be secondary to placental insufficiency caused by hypoxia. Villous hypermaturity, characterized by presence of increased syncytial knots, has been associated with syndromes of placental insufficiency, particularly when severe. This study was undertaken to determine whether there is a link between soluble vascular endothelial growth factor receptor-1 expression, villous hypermaturity, and clinical severity of preeclampsia. We conducted a retrospective cohort study in which 48 placentas were selected from pathology archives (hypertensive group). Of these, 6 had chronic hypertension, 15 had mild preeclampsia, 14 had severe preeclampsia, and 13 had hemolysis, elevated liver enzymes, and low platelets syndrome. These were compared with 55 placentas from normotensive patients (control group). One representative section of placental parenchyma from each case was stained with an antibody to vascular endothelial growth factor receptor-1/soluble vascular endothelial growth factor receptor-1 and given a score based on extent and intensity of staining, representing expression level. Assignment of staining score was done, blinded to clinical history and pathologic diagnosis. Vascular endothelial growth factor receptor-1/soluble vascular endothelial growth factor receptor-1 staining was seen in placental syncytiotrophoblasts and was particularly strong in syncytial knots. There was a positive association between vascular endothelial growth factor receptor-1/soluble vascular endothelial growth factor receptor-1 staining score and severity of clinical hypertensive state, small placental size, and villous hypermaturity. The association between vascular endothelial growth factor receptor-1/soluble vascular endothelial growth factor receptor-1 score and small placentas did not persist after controlling for hypermaturity. Vascular endothelial growth factor receptor-1/soluble vascular endothelial growth factor receptor-1 overexpression in the placenta strongly correlates with both severity of hypertensive disease and villous hypermaturity. The correlation with villous hypermaturity further links hypoxia to vascular endothelial growth factor receptor-1/soluble vascular endothelial growth factor receptor-1 production in the placenta.