Andrea G. Edlow

Rethinking IUGR in preeclampsia: dependent or independent of maternal hypertension?

Objective:Chronic hypertension (CHTN) is a risk factor for both intrauterine growth restriction (IUGR) as well as preeclampsia. This study was performed to: (1) describe the prevalence of IUGR in women with preeclampsia (with and without CHTN) compared with controls, (2) investigate the relationship between preeclampsia and maternal CHTN with IUGR, and (3) investigate the relationship between IUGR and severity of preeclampsia.Study Design:A case–control study was performed. Cases were patients identified with preeclampsia. Controls were patients presenting for delivery at term (⩾37 weeks). IUGR prevalence by case–control status, or severity of disease was evaluated using Pearson χ2 tests. Multivariable logistic regression was used to control for confounders.Result:In all, 430 cases and 568 controls were studied. Preeclamptic women have a 2.7 (CI (1.94 to 3.86)) and 4.3 (CI (2.58 to 7.17)) times increased odds of having a fetus with IUGR at <10 and <5% compared with controls in adjusted analyses. There was a significant interaction between CHTN and IUGR. Therefore, in women without CHTN, women with PEC had increased odds of IUGR, whereas in women with CHTN, there was no difference in odds of IUGR in women with or without preeclampsia. Within the cases, severe preeclampsia was associated with IUGR<10% (AOR=1.82 (1.11 to 2.97)) but not IUGR<5% (AOR=1.6 (0.85 to 2.86)).Conclusion:Preeclampsia is independently associated with the development of IUGR. As suggested earlier, women with CHTN do not have the highest prevalence of IUGR, suggesting disparate pathways by which IUGR develops in women with superimposed preeclampsia compared with preeclampsia alone.

Estimated fetal weight by ultrasound: a modifiable risk factor for cesarean delivery?

OBJECTIVE The purpose of this study was to investigate whether knowledge of ultrasound-obtained estimated fetal weight (US-EFW) is a risk factor for cesarean delivery (CD). STUDY DESIGN Retrospective cohort from a single center in 2009-2010 of singleton, term live births. CD rates were compared for women with and without US-EFW within 1 month of delivery and adjusted for potential confounders. RESULTS Of the 2329 women in our cohort, 50.2% had US-EFW within 1 month of delivery. CD was significantly more common for women with US-EFW (15.7% vs 10.2%; P < .001); after we controlled for confounders, US-EFW remained an independent risk factor for CD (odds ratio, 1.44; 95% confidence interval, 1.1-1.9). The risk increased when US-EFW was >3500 g (odds ratio, 1.8; 95% confidence interval, 1.3-2.7). CONCLUSION Knowledge of US-EFW, above and beyond the impact of fetal size itself, increases the risk of CD. Acquisition of US-EFW near term appears to be an independent and potentially modifiable risk factor for CD.

Maternal obesity and neurodevelopmental and psychiatric disorders in offspring

There is a growing body of evidence from both human epidemiologic and animal studies that prenatal and lactational exposure to maternal obesity and high‐fat diet are associated with neurodevelopmental and psychiatric disorders in offspring. These disorders include cognitive impairment, autism spectrum disorders, attention deficit hyperactivity disorder, cerebral palsy, anxiety and depression, schizophrenia, and eating disorders. This review synthesizes human and animal data linking maternal obesity and high‐fat diet consumption to abnormal fetal brain development and neurodevelopmental and psychiatric morbidity in offspring. In addition, it highlights key mechanisms by which maternal obesity and maternal diet might impact fetal and offspring neurodevelopment, including neuroinflammation; increased oxidative stress, dysregulated insulin, glucose, and leptin signaling; dysregulated serotonergic and dopaminergic signaling; and perturbations in synaptic plasticity. Finally, the review summarizes available evidence regarding investigational therapeutic approaches to mitigate the harmful effects of maternal obesity on fetal and offspring neurodevelopment.

Maternal Obesity Affects Fetal Neurodevelopmental and Metabolic Gene Expression: A Pilot Study

Objective One in three pregnant women in the United States is obese. Their offspring are at increased risk for neurodevelopmental and metabolic morbidity. Underlying molecular mechanisms are poorly understood. We performed a global gene expression analysis of mid-trimester amniotic fluid cell-free fetal RNA in obese versus lean pregnant women. Methods This prospective pilot study included eight obese (BMI≥30) and eight lean (BMI<25) women undergoing clinically indicated mid-trimester genetic amniocentesis. Subjects were matched for gestational age and fetal sex. Fetuses with abnormal karyotype or structural anomalies were excluded. Cell-free fetal RNA was extracted from amniotic fluid and hybridized to whole genome expression arrays. Genes significantly differentially regulated in 8/8 obese-lean pairs were identified using paired t-tests with the Benjamini-Hochberg correction (false discovery rate of <0.05). Biological interpretation was performed with Ingenuity Pathway Analysis and the BioGPS gene expression atlas. Results In fetuses of obese pregnant women, 205 genes were significantly differentially regulated. Apolipoprotein D, a gene highly expressed in the central nervous system and integral to lipid regulation, was the most up-regulated gene (9-fold). Apoptotic cell death was significantly down-regulated, particularly within nervous system pathways involving the cerebral cortex. Activation of the transcriptional regulators estrogen receptor, FOS, and STAT3 was predicted in fetuses of obese women, suggesting a pro-estrogenic, pro-inflammatory milieu. Conclusion Maternal obesity affects fetal neurodevelopmental and metabolic gene expression as early as the second trimester. These findings may have implications for postnatal neurodevelopmental and metabolic abnormalities described in the offspring of obese women.

Investigating the risk of hypertension shortly after pregnancies complicated by preeclampsia.

OBJECTIVE Women with a history of preeclampsia are at increased risk for long-term cardiovascular morbidity and mortality. This study assessed whether a pregnancy complicated by preeclampsia is associated with an increased prevalence of maternal hypertension and other cardiovascular risk factors shortly after delivery. STUDY DESIGN Seventy-nine cases and 140 controls that had been enrolled in a prospective case-control study were evaluated in this planned follow-up analysis. The presence of hypertension, diabetes and dyslipidemia were assessed by standardized questionnaire 6-13 months after delivery. RESULTS Women with preeclampsia were significantly more likely than controls to have hypertension (adjusted odds ratio, 13.92; 95% CI, 5.17-37.4; P < .001) after adjusting for confounders. Women with preterm preeclampsia also had an increased odds of hypertension (adjusted odds ratio, 18.31; 95% CI, 5.04-66.46; P < .001) compared with controls. CONCLUSION Pregnancy complications, such as preeclampsia, may provide opportunities to identify women at risk for cardiovascular morbidity years before the onset of disease, allowing a window for prevention and intervention.

Determination of bisphenol-A levels in human amniotic fluid samples by liquid chromatography coupled with mass spectrometry

Bisphenol A (BPA) is one of the environmental endocrine-disrupting chemicals used widely in common consumer products. There is an increasing concern about human exposure to BPA, particularly in fetuses, due to the potential adverse effects related to the estrogenic activity of BPA. In assessing environmental exposure to BPA, it is essential to have a sensitive, accurate, and specific analytical method, particularly for low BPA levels in complex sample matrices. In this study, we developed and validated an accurate, sensitive, and robust liquid chromatography-mass spectrometry (LC-MS) method for determining the BPA concentrations in human amniotic fluid (AF). In this method, BPA and the internal standards (13)C(12) -BPA were extracted from 500 μL of human AF using solid-phase extraction. Calibration curves were linear over a concentration range of 0.3-100 ng/mL for BPA. The analytes were quantitatively determined using LC-MS operated in a negative electrospray ionization selected ion monitoring mode. This validated method has been used successfully in the clinical sample analysis of BPA in second-trimester AF specimens.

Can placental pathology explain second-trimester pregnancy loss and subsequent pregnancy outcomes?

OBJECTIVE This study sought to determine whether specific placental pathology may provide further insight into the mechanisms of second-trimester pregnancy loss, particularly in cases without inflammation. STUDY DESIGN A blinded pathologist examined placentas from 90 patients with spontaneous second-trimester pregnancy loss and 17 controls who presented for induction of labor for fetal indications. Inflammation was staged and evidence of other vascular pathology recorded. Significant associations were determined by chi(2) analysis and Fishers exact test. A secondary analysis examined losses without inflammation. Twelve patients with a subsequent pregnancy were also evaluated. RESULTS Acute inflammation was more prevalent in cases than controls (P < .001). Sixty-seven percent of all cases and none of the controls showed a stage 2-3 inflammatory response. Histologic abruption was also more prevalent in cases than controls (P = .05). CONCLUSION Second-trimester pregnancy loss is strongly associated with placental inflammation. Histologic abruption is likely another etiology. Future research should focus on subsequent pregnancy outcomes in these women based on initial placental pathology to help determine etiology and recurrence risk.

Global gene expression analysis of term amniotic fluid cell-free fetal RNA.

OBJECTIVE: To identify the tissue expression patterns and biological pathways enriched in term amniotic fluid cell-free fetal RNA by comparing functional genomic analyses of term and second-trimester amniotic fluid supernatants. METHODS: This was a prospective whole genome microarray study comparing eight amniotic fluid samples collected from women at term who underwent prelabor cesarean delivery and eight second-trimester amniotic fluid samples from routine amniocenteses. A functional annotation tool was used to compare tissue expression patterns in term and second-trimester samples. Pathways analysis software identified physiologic systems, molecular and cellular functions, and upstream regulators that were significantly overrepresented in term amniotic fluid. RESULTS: There were 2,871 significantly differentially regulated genes. In term amniotic fluid, tissue expression analysis showed enrichment of salivary gland, tracheal, and renal transcripts as compared with brain and embryonic neural cells in the second trimester. Functional analysis of genes upregulated at term revealed pathways that were highly specific for postnatal adaptation such as immune function, digestion, respiration, carbohydrate metabolism, and adipogenesis. Inflammation and prostaglandin synthesis, two key processes involved in normal labor, were also activated in term amniotic fluid. CONCLUSIONS: Transcriptomic analysis of amniotic fluid cell-free fetal RNA detects fetal maturation processes activated in term pregnancy. These findings further develop the concept of amniotic fluid supernatant as a real-time gene expression “summary fluid” and support its potential for future studies of fetal development. LEVEL OF EVIDENCE: II

Postpartum internal carotid and vertebral arterial dissections.

OBJECTIVE: Headache and neck pain are common postpartum symptoms. However, these symptoms can rarely be associated with internal carotid artery and vertebral artery dissections. We aimed to review five cases of postpartum cervical artery dissection and to review the clinical course of previously reported cases. METHODS: Patients with postpartum dissections diagnosed at our institution since 2005 were identified through a database maintained by the senior author, and their clinical data were reviewed. Additionally, a literature search for previously reported cases was performed, and the clinical data in those reports were reviewed. RESULTS: Five patients presented with cervical artery dissections within 6 weeks postpartum. Four patients had delivered vaginally and one delivered by emergent cesarean. Headache and neck pain were the primary presenting symptoms of all five patients. Four patients demonstrated neurologic symptoms, and one had development of stroke. Two patients had single internal carotid artery dissections, one patient had bilateral dissections of the vertebral artery, and two patients had dissections in the internal carotid artery and vertebral artery. All patients were treated with either anticoagulation therapy or antiplatelet therapy. Two patients required endovascular stenting. Four of five patients returned to neurologic baseline after treatment. A literature search yielded 27 previously reported cases, with similar clinical characteristics of older reproductive age, presentation days to weeks from delivery, and recovery to neurologic baseline in the majority of patients. CONCLUSION: Postpartum cervical dissections are rare occurrences that require prompt diagnosis to prevent long-term neurologic deficits. Individualized management strategies include medical treatment (anticoagulation therapy, antiplatelet therapy, or anticoagulation and antiplatelet therapy) and endovascular recanalization. LEVEL OF EVIDENCE: III

Uterine Evacuation for Second-trimester Fetal Death and Maternal Morbidity

OBJECTIVE: To estimate maternal morbidity associated with uterine evacuation for second-trimester fetal demise compared with that associated with induced second-trimester abortion. METHODS: This retrospective cohort study compared the maternal outcomes of two cohorts: 1) women diagnosed with fetal demise between 14 and 24 weeks who subsequently underwent dilation and evacuation or induction of labor; and 2) women undergoing induced abortion between 14 and 24 weeks by either dilation and evacuation or induction of labor. The primary outcome was major maternal morbidity. Assuming morbidity rates of 11% for fetal demise and 1% for induced second-trimester abortion, 94 patients were needed per group to detect significant difference in maternal morbidity (80% power, 5% alpha). RESULTS: We identified 121 women with fetal demise and 121 women who underwent induced abortion for inclusion. There were no maternal deaths. In crude and adjusted analyses, treatment for fetal demise was not associated with increased maternal morbidity (25 of 121) compared with induced abortion (27 of 121) (adjusted odds ratio [OR], 1.15; 95% confidence interval [CI], 0.57–2.32). There were more blood transfusions in the fetal demise group (N=7) compared with the induced-abortion group (N=1) (P=.07). Induction of labor was more morbid than dilation and evacuation after adjusting for confounders (OR 5.36; 95% CI 2.46–11.69), primarily as a result of increased odds of infection requiring intravenous antibiotics. Gestational age of 20 weeks or greater was significantly associated with maternal morbidity (OR 2.59; 95% CI 1.39–4.84). CONCLUSION: In the second trimester, uterine evacuation for fetal demise was not significantly associated with maternal morbidity compared with induced abortion. Induction of labor was more morbid than dilation and evacuation as a result of an increased risk of presumed infection. LEVEL OF EVIDENCE: II