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Preventing low birth weight: is prenatal care the answer?

Objectives: To review the evidence of effectiveness of prenatal care for preventing low birth weight (LBW). Methods: We reviewed original research, systematic reviews, meta-analyses and commentaries for evidence of effectiveness of the three core components of prenatal care - risk assessment, health promotion and medical and psychosocial interventions - for preventing the two constituents of LBW: preterm birth and intrauterine growth restriction (IUGR). Results: Clinical risk assessment will fail to identify the majority of pregnancies at risk for preterm delivery or IUGR. While biophysical and biochemical modalities appear promising, their cost-effectiveness has not been demonstrated, nor can their routine use be recommended in the absence of effective interventions. Smoking cessation programs appear to be modestly effective. There is insufficient evidence to conclude a benefit for nutrition interventions, work counseling or preterm birth education. Only antenatal corticosteroid therapy has demonstrated a clear benefit in the tertiary prevention of preterm delivery. Interventions for which there is insufficient evidence to conclude a benefit include bed rest, hydration, sedation, cerclage, progesterone supplementation, antibiotic treatment, tocolysis without concomitant use of corticosteroids, thyrotropin-releasing hormone, psychosocial support and home visitation. Additionally, there is a paucity of evidence supporting the effectiveness of prenatal interventions, such as low-dose aspirin, bed rest, maternal hyperoxygenation, plasma volume expansion and antenatal fetal assessment, in preventing IUGR or its associated morbidity and mortality. Conclusions: Neither preterm birth nor IUGR can be effectively prevented by prenatal care in its present form. Preventing LBW will require reconceptualization of prenatal care as part of a longitudinally and contextually integrated strategy to promote optimal development of womens reproductive health not only during pregnancy, but over the life course.

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.

Current practices in determining amnionicity and chorionicity in multiple gestations

To evaluate the accuracy of amnionicity and chorionicity (A/C) diagnosis of referral physicians and a tertiary care center as compared to histopathologic diagnosis.

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.

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.

Banking placental tissue: An optimized collection procedure for genome-wide analysis of nucleic acids

INTRODUCTION Banking of high-quality placental tissue specimens will enable biomarker discovery and molecular studies on diseases involving placental dysfunction. Systematic studies aimed at developing feasible standardized methodology for placental collection in a typical clinical setting are lacking. METHODS To determine the acceptable timeframe for placental collection, we collected multiple samples from first and third trimester placentas at serial timepoints in a 2-h window after delivery, simultaneously comparing the traditional snap-freeze technique to commercial solutions designed to preserve RNA (RNAlater™), and DNA (DNAgard(®)). The performance of RNAlater for preserving DNA was also tested. Nucleic acid quality was assessed by determining the RNA integrity number (RIN) and genome-wide microarray profiling for gene expression and DNA methylation. RESULTS We found that samples collected in RNAlater had higher and more consistent RINs compared to snap-frozen tissue. Similar RINs were obtained for tissue collected in RNAlater as large (1 cm(3)) and small (∼0.1 cm(3)) pieces. RNAlater appeared to better stabilize the time zero gene expression profile compared to snap-freezing for first trimester placenta. DNA methylation profiles remained quite stable over a 2 h time period after removal of the placenta from the uterus, with DNAgard being superior to other treatments. DISCUSSION AND CONCLUSION The collection of placental samples in RNAlater and DNAgard is simple, and eliminates the need for liquid nitrogen or a freezer on-site. Moreover, the quality of the nucleic acids and the resulting data from samples collected in these preservation solutions is higher than samples collected using the snap-freeze method and easier to implement in busy clinical environments.

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.

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.

Does Transparency Really Help?: Amniocentesis Teaching With Clear and Opaque Gelatin Models [85]

INTRODUCTION: To assess whether visualizing a fluid pocket during amniocentesis training helps improve skills required for the procedure, including needle placement and aspiration. METHODS: We performed an observational study using two models; one allowed trainees to visualize a fluid-filled area in a “uterus,” whereas the other required an ultrasonogram for localization. We randomly divided 16 obstetrics–gynecology residents into two groups. After a brief didactic, one group practiced their technique with the clear model (“clear” group), whereas the other group practiced with the opaque model (“opaque” group). Residents were compared with regard to time to aspiration, number of attempts (removal of entire needle), needle reorientations (movement of needle within space), and movement of the needle while aspirating. RESULTS: Pretest knowledge and skills were similar in both groups. Understanding of key amniocentesis concepts improved greatly after simulation (55% compared with 85%, P<.001) as did confidence in performing such procedures (P<.001). There was no significant difference in the aspiration time between the clear and opaque group (76.9 compared with 81.6 seconds, P=.8). The numbers of needle attempts and reorientations were not different between clear and opaque groups (P=.6 and P=1, respectively). Interestingly, the opaque group showed more needle tip movements during aspiration, although this was not significant (P=.2). CONCLUSION: In trying to teach a complex skill such as amniocentesis, “visualizing” a uterus does not appear to improve skills. Likely, “seeing” the uterus minimizes the need for ultrasound correlation, yet simulation didactics are effective at teaching rare skills to residents and help boost confidence in procedures.