Christina Scifres

Intrauterine growth restriction, human placental development and trophoblast cell death.

Intrauterine growth restriction (IUGR) is a failure to achieve the growth potential of a fetus that is promised by the genetic constitution and environmental influences endogenous to the pregnancy. Optimal placental development and the ability of the placenta to compensate for stimulus‐induced injury are central in promotion of normal fetal growth. In this review, we will overview placental development with a focus on how villous structure relates to function. We will also describe the differentiation and turnover of villous trophoblast while highlighting selected features of microscopic placental injury. Histopathological studies of the placenta in IUGR indicate that abnormalities of the maternal spiral arterioles, dysregulated villous vasculogenesis, and abundant fibrin deposition are characteristic of the injuries associated with this condition. We identify selected insults, including oxidative stress and complement activation, and key pathways that regulate apoptosis in villous trophoblast, including increased p53 activity, altered translation of AKT and mTOR proteins, and the stress response of the endoplasmic reticulum. We surmise that trophoblast dysregulation at a subcellular level and loss of functional mass of villous trophoblast via cell death pathways are key contributors to the suboptimal placental performance that yields IUGR. We predict that a better understanding of placental dysfunction in IUGR will lead to targeted therapeutic options for this important clinical condition.

Fatty Acid Binding Protein 4 Regulates Intracellular Lipid Accumulation in Human Trophoblasts

CONTEXT Maternal obesity, gestational diabetes (GDM), or type 2 diabetes (T2DM) is associated with altered lipid metabolism and fetal overgrowth. OBJECTIVE The objective of the study was to test the hypothesis that hyperlipidemia and hyperinsulinemia regulate lipid content and expression of lipid-trafficking proteins in human placental trophoblasts. STUDY DESIGN Pregnant women were prospectively enrolled for clinical specimens collection, and cultured human trophoblasts were used for experiments. SETTING This was a translational study conducted at an academic biomedical research center. PATIENTS OR OTHER PARTICIPANTS Normal weight, obese, or obese with gestational diabetes or type 2 diabetes pregnant women (n = 10 in each group) undergoing scheduled cesarean delivery at term were enrolled. INTERVENTIONS Cultured primary human trophoblasts, exposed to insulin (10 nM) and/or fatty acids mix (1200 μM) in the absence or presence of an fatty acid binding protein 4 (FABP4) inhibitor or after small interfering RNA-mediated knockdown of FABP4. MAIN OUTCOME MEASURES Serum lipid levels were analyzed in the maternal venous and fetal cord blood. Placental biopsies and cultured trophoblasts were analyzed for FABP expression and lipid accumulation. RESULTS Obese diabetic women and their fetuses had elevated serum triglyceride levels. Nonesterified fatty acids were elevated and triglycerides were reduced in placental villi from obese diabetic women, and this was accompanied by a 2.6-fold increase in FABP4 expression (P < 0.05). In primary human trophoblasts, fatty acids markedly increased the expression of FABP4 (20- to 40-fold, P < 0.05) and cellular triglyceride content (4-fold, P < 0.05), and this effect was attenuated by small interfering RNA-mediated knockdown of FABP4 or the selective FABP4 inhibitor BMS309403. CONCLUSIONS Hyperlipidemia alters lipid content and increases the expression of FABP4 in trophoblasts. The reduced triglyceride content after FABP4 inhibition suggests that FABP4 is essential for trophoblast lipid accumulation.

Extreme obesity and postcesarean maternal complications.

OBJECTIVE: To estimate the association of obesity and extreme obesity with maternal complications after cesarean delivery. METHODS: This was a secondary cohort analysis of a randomized controlled trial. The parent study was designed to estimate the effect of supplemental oxygen on postcesarean infectious morbidity. Because the study intervention had no effect, study groups were combined as a cohort. For this secondary analysis, the exposure was obesity, stratified as normal or overweight (body mass index [BMI] less than 30), obese (BMI 30–45), or extremely obese (BMI higher than 45). The primary outcome was a composite of wound infection and endometritis. Secondary outcomes included wound infection, endometritis, wound opening, hematoma or seroma, and emergency department visit. We performed unadjusted and multivariable logistic regression analyses. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) are reported. RESULTS: We included 585 women in the analysis. Eighty-five patients (14.5%) had BMIs higher than 45. Rates of black race, chronic hypertension, diabetes, and gestational diabetes increased and operative duration increased with increasing obesity severity. Obese patients were more likely to have a cesarean delivery after labor and have a vertical skin incision or classical uterine incision. After controlling for confounders, extremely obese patients had a twofold to fourfold increase in postoperative complications, including the primary infectious outcome (18.8%, adjusted OR 2.7, CI 1.2–6.1), wound infection (18.8%, adjusted OR 3.4, CI 1.4–8.0), and emergency department visit (23.1%, adjusted OR 2.2, CI 1.03–4.9). CONCLUSION: Maternal extreme obesity is associated with a considerable increase in postcesarean wound complications. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00602603. LEVEL OF EVIDENCE: II

Supplemental oxygen for the prevention of postcesarean infectious morbidity: a randomized controlled trial

OBJECTIVE The purpose of this study was to investigate whether supplemental oxygen during and for 2 hours after cesarean delivery reduces the incidence of postcesarean infectious morbidity. STUDY DESIGN We conducted a randomized, controlled trial from 2008-2010. Women who underwent cesarean delivery were randomly assigned to receive either 2 L of oxygen by nasal cannula during cesarean delivery only (standard care) or 10 L of oxygen by nonrebreather mask (intervention group) during and for 2 hours after cesarean delivery. Women who underwent scheduled or intrapartum cesarean delivery were eligible and were observed for 1 month after the procedure. The primary composite outcome was maternal infectious morbidity, which included endometritis and wound infection. RESULTS Five hundred eighty-five women were included in the final analysis. Infectious morbidity occurred in 8.8% of patients in the standard care group and in 12.2% of patients in the supplemental oxygen group. There was no significant difference in the rate of infectious morbidity between the standard care and intervention groups (relative risk, 1.4; 95% confidence interval, 0.9-2.3). CONCLUSION Supplemental oxygen does not reduce the rate of postcesarean delivery infectious morbidity, including endometritis and wound infection.

The impact of maternal obesity and gestational weight gain on early and mid-pregnancy lipid profiles

The impact of maternal overweight/obesity and excessive weight gain on maternal serum lipids in the first and second trimester of pregnancy was evaluated.

Effect of excess gestational weight gain on pregnancy outcomes in women with type 1 diabetes.

OBJECTIVE: To evaluate the prevalence and clinical effects of excess gestational weight gain on birth weight and other pregnancy outcomes in women with type 1 diabetes. METHODS: We performed a retrospective cohort study of women with type 1 diabetes delivered between 2009 and 2012. Patients with excess weight gain were identified using the 2009 Institute of Medicine weight gain recommendations adjusted for gestational age at delivery and prepregnancy body mass index (BMI) category. Demographic and outcome data were abstracted from the medical record, and pregnancy outcomes were compared between women with and without excess gestational weight gain. RESULTS: Excess gestational weight gain occurred in 114 of 175 women (65.1%). Large-for-gestational-age (LGA) birth weight occurred in 48 of 114 (42.1%) of women with excess gestational weight gain and 5 of 61 (8.2%) of women with recommended weight gain (P<.001). The association between excess maternal weight gain and LGA birth weight remained significant after adjustment for prepregnancy BMI, gestational age at delivery, nulliparity, vascular complications, and hemoglobin A1c measurements (adjusted odds ratio 8.9, 95% confidence interval 3.1–26.2, P<.001). Stratified analyses demonstrated that excess maternal weight gain is associated with LGA neonates in both normal-weight and overweight or obese women. CONCLUSIONS: Excess maternal weight gain is common and leads to higher rates of LGA neonates in both normal-weight and overweight or obese women with type 1 diabetes. Interventions designed to limit excess gestational weight gain may reduce the risk for fetal overgrowth in women with type 1 diabetes. LEVEL OF EVIDENCE: II

Maternal Serum Fatty Acid Binding Protein 4 (FABP4) and the Development of Preeclampsia

CONTEXT Serum fatty acid binding protein 4 (FABP4) is associated with components of the metabolic syndrome in nonpregnant individuals, including dyslipidemia and insulin resistance. Preeclampsia shares many features with the metabolic syndrome, but the relationship between early pregnancy serum FABP4 levels and the development of preeclampsia is unknown. OBJECTIVE The aim of the study was to test the hypothesis that FABP4 is elevated in women who develop preeclampsia before the onset of disease. STUDY DESIGN This was a nested case-control study within a larger prospective cohort of healthy women with singleton gestations. Cases included 22 women who developed preeclampsia, and a random sample of 72 unmatched controls delivered without preeclampsia was identified. Maternal serum FABP4 was measured at less than 13 wk gestation and 24-28 wk gestation, which was before the onset of preeclampsia in all patients. MAIN OUTCOME MEASURES The main outcome measure was preeclampsia (new-onset gestational hypertension and proteinuria for the first time after 20 wk gestation). RESULTS Maternal serum FABP4 concentrations were higher in women who ultimately developed preeclampsia both at 8-13 wk (20.4±12.3 vs. 10.1±4.7 ng/ml; P<0.01) and at 24-28 wk (20.7±11.7 vs. 9.9±4.5 ng/ml; P<0.01). After controlling for first trimester body mass index, systolic blood pressure, and nulliparity, FABP4 was associated with the development of preeclampsia (adjusted odds ratio, 1.2; 95% confidence interval, 1.1-1.3; P<0.01). CONCLUSION Maternal serum FABP4 levels are elevated before the clinical onset of preeclampsia, and this increase occurs independently of maternal body mass index.

Predicting Perinatal Mortality in Preterm Intrauterine Growth Restriction

We evaluated if maternal demographic and ultrasound parameters predict perinatal mortality in preterm intrauterine growth restriction (IUGR). Retrospective cohort study of preterm IUGR (delivery gestational age <35 weeks and birth weight <10th percentile for gestation). We excluded twins and fetuses with aneuploidy, intrauterine infection, or major congenital malformations. Information collected included maternal demographic and medical information, estimated fetal weight, oligohydramnios (amniotic fluid index <5), abnormal umbilical artery Dopplers (absent or reverse end-diastolic flow), and abnormal biophysical score (score <6). Our outcome was perinatal mortality, which was defined as in utero death or neonatal death within the first 28 days of life. Statistical analysis included bivariate and multivariable techniques as well as receiver operator characteristic analysis. Two hundred thirty singleton pregnancies with preterm IUGR meeting the inclusion criteria were identified. Variables associated with perinatal mortality included oligohydramnios and abnormal umbilical artery Dopplers. These two variables had modest predictive value for perinatal mortality. In cases of preterm IUGR, only the presence of abnormal umbilical artery Dopplers or oligohydramnios predicts perinatal mortality.

Metaanalysis vs large clinical trials: which should guide our management?

Large, randomized clinical trials have long been considered the gold standard to guide clinical care. Metaanalysis is a type of analysis in which results of a number of randomized clinical trials are combined and a summary measure of effect for a given treatment is ascertained. The clinician in practice often is faced with a dilemma regarding the type of evidence that should be used to guide clinical practice; for many clinical problems, there are both randomized controlled trials and metaanalyses available. The cases of calcium and aspirin therapy for the prevention of preeclampsia afford an opportunity to explore the benefits and limitations of each type of study to guide clinical practice. We conclude that, when available, large randomized clinical trials should be used to guide clinical practice.

Neonatal outcomes following preterm birth classified according to placental features

BACKGROUND: Preterm birth has staggering health implications, and yet the causes of most cases are still unknown. Placental features have been understudied as an etiology for preterm birth, and the association between placental pathologic lesions and neonatal outcomes are incompletely understood. OBJECTIVE: We sought to characterize births according to placental pathology and relate these to adverse neonatal outcomes. STUDY DESIGN: We studied 20,091 births (15,710 term and 4381 preterm) with placental evaluations. Births were classified according to the presence or absence of placental lesions consistent with malperfusion (vasculopathy, infarct, advanced villous maturation, perivillous fibrin, fibrin deposition) and intrauterine inflammation/infection (chorioamnionitis, funisitis, vasculitis). Outcomes were gestational week of delivery, birthweight z‐score, neonatal respiratory distress syndrome, and intraventricular hemorrhage. RESULTS: Among all preterm births, evidence of placental malperfusion was identified more often than inflammation/infection (50.6% vs 27.3%, P < .0001). Placental malperfusion was associated with reduced fetal growth (adjusted birthweight z‐score, –0.83, P < .0001) and lesions of inflammation/infection were associated with earlier delivery (adjusted difference –2.08 weeks, P < .0001) than those with no lesions. When both placental lesions were present, earlier delivery (adjusted difference –2.28 weeks, P < .0001) and reduced fetal growth (adjusted birthweight z‐score difference, –0.24, P = .001) were observed more often than when neither lesion was present. Findings were similar when restricted to cases of spontaneous preterm birth. Intraventricular hemorrhage was higher in preterm births with malperfusion lesions than cases with no lesions (7.6% vs 3.4%; odds ratio, 1.98; confidence interval, 1.18–3.32), accounting for gestational age and other covariates. CONCLUSION: Placental pathology provides important insight into subtypes of preterm birth with adverse neonatal outcomes. Co‐occurrence of malperfusion and inflammation/infection, especially among spontaneous preterm births, may be a novel pattern of placental injury linked to severe adverse outcomes.