Matthew R. Grace

Chikungunya Fever: Obstetric Considerations on an Emerging Virus.

&NA; Chikungunya fever is an increasingly common viral infection transmitted to humans by species of the Aedes mosquitoes. Characterized by fevers, myalgias, arthralgias, headache, and rash, the infection is endemic to tropical areas. However, identification of disease vectors to Europe and the Americas has raised concern for possible spread of chikungunya to these areas. More recently, these concerns have become a reality; with more than 500,000 new cases in the Western hemisphere in the last 2 years, questions have arisen about the implications of infection during pregnancy and delivery. A literature review was performed using MEDLINE in order to gather information regarding the obstetric implications of this infection. It appears that although this virus can cross the placenta in the first and second trimester leading to fetal infection and miscarriage, this is a very rare occurrence. In contrast, active maternal infection within 4 days of delivery conveys a high risk of vertical transmission. Maternal infection during pregnancy does not appear to be more severe than infection on the nonpregnant female. Given the increasing incidence of chikungunya, obstetric providers should be aware of the disease and its implication for the gravid female. Target Audience Obstetricians and gynecologists, family physicians, emergency medicine physicians, nurse midwives Learning Objectives After completing this activity, the learner should be better able to: describe the presentation, symptoms, and diagnosis of chikungunya fever; describe the risks of chikungunya fever to fetus and to the mother in each trimester and at the time of delivery; and outline the management considerations for pregnant women with active chikungunya infection.

Sexual epigenetic dimorphism in the human placenta: implications for susceptibility during the prenatal period

AIM Sex-based differences in response to adverse prenatal environments and infant outcomes have been observed, yet the underlying mechanisms for this are unclear. The placental epigenome may be a driver of these differences. METHODS Placental DNA methylation was assessed at more than 480,000 CpG sites from male and female infants enrolled in the extremely low gestational age newborns cohort (ELGAN) and validated in a separate US-based cohort. The impact of gestational age on placental DNA methylation was further examined using the New Hampshire Birth Cohort Study for a total of n = 467 placentas. RESULTS A total of n = 2745 CpG sites, representing n = 587 genes, were identified as differentially methylated (p < 1 × 10-7). The majority (n = 582 or 99%) of these were conserved among the New Hampshire Birth Cohort. The identified genes encode proteins related to immune function, growth/transcription factor signaling and transport across cell membranes. CONCLUSION These data highlight sex-dependent epigenetic patterning in the placenta and provide insight into differences in infant outcomes and responses to the perinatal environment.

Management Considerations for Ongoing Pregnancies Complicated by Trisomy 13 and 18.

Pregnancies complicated by trisomy 13 (T13) or trisomy 18 (T18) present unique challenges for obstetric management. From the initial diagnosis, the task of counseling these women and families is difficult because fetal and neonatal outcomes vary depending on the phenotype and degree of intervention chosen by the family. A literature review was performed using PubMed to gather information regarding obstetric management and outcomes of pregnancies complicated by T13 and T18. Spontaneous abortion and in uterofetal demise occur at rates well above those seen in chromosomally normal pregnancies. In addition, infants with T13 or T18 frequently have structural anomalies, which lead to worse prognoses and long-term survival. In cases in which a woman and her family desire to continue the pregnancy, multidisciplinary consultation with obstetrics, social work, genetics, and pediatrics can optimize care of both the fetus and the mother. Most commonly, prenatal care does not differ from routine. A detailed delivery plan should be generated, specifically discussing interventions for the patient and her fetus. When managing pregnancies complicated by T13 and T18, active, open, and frequent communication between the patient, her family, and a multidisciplinary health care team throughout the pregnancy is crucial. Target Audience Obstetricians and gynecologists, family physicians Learning Objectives After completing this activity, the learner should be better able to describe the in utero findings and neonatal outcomes for pregnancies complicated by T13 and T18, recognize central aspects to caring for women and families with pregnancies complicated by T13 and T18, and outline the antepartum and intrapartum management considerations for pregnant women T13 and T18.

miRNAs as common regulators of the transforming growth factor (TGF)-β pathway in the preeclamptic placenta and cadmium-treated trophoblasts: Links between the environment, the epigenome and preeclampsia

Preeclampsia (PE) is a pregnancy disorder characterized by high blood pressure and proteinuria that can cause adverse health effects in both mother and fetus. There is no current cure for PE other than delivery of the fetus/placenta. While the etiology is unknown, poor placentation due to aberrant signaling of growth and angiogenic factors has been postulated as a causal factor of PE. In addition, environmental contaminants, such as the metal cadmium (Cd), have been linked to placental toxicity and increased risk of developing PE. Here, we use a translational study design to investigate genomic and epigenomic alterations in both placentas and placental trophoblasts, focused on the angiogenesis-associated transforming growth factor-beta (TGF-β) pathway. Genes within the TGF-β pathway displayed increased expression in both the preeclamptic placenta and Cd-treated trophoblasts. In addition, miRNAs that target the TGF-β pathway were also significantly altered within the preeclamptic placenta and Cd-treated trophoblasts. Integrative analysis resulted in the identification of a subset of Cd-responsive miRNAs, including miR-26a and miR-155, common to preeclamptic placentas and Cd-treated trophoblasts. These miRNAs have previously been linked to PE and are predicted to regulate members of the TGF-β pathway. Results from this study provide future targets for PE treatment.

Prophylactic negative pressure wound therapy for obese women after cesarean delivery: A systematic review and meta-analysis

OBJECTIVE To summarize available studies on wound complication outcomes after prophylactic negative pressure wound therapy for obese women (body mass index 30 or greater). DATA SOURCES We conducted a systematic review and meta-analysis using electronic database search (PubMed, Cumulative Index to Nursing and Allied Health Literature, EMBASE, Google scholar, and Web of Science), Cochrane, and trial registries including ClinicalTrials.gov. METHODS OF STUDY SELECTION We conducted an electronic search of research articles from 1966 to January 2017 for randomized controlled trials (RCTs), prospective cohort, and retrospective cohort studies of negative pressure wound therapy compared with standard dressing after cesarean delivery among obese women. Our primary outcome was defined as a composite of wound complication, including wound or surgical site infection, cellulitis, seroma, hematoma, wound disruption, or dehiscence. For cohort studies and RCTs, we performed a descriptive systematic review. For available RCTs, we performed a meta-analysis and pooled risk ratios using a random-effects model. We assessed for heterogeneity using χ test for heterogeneity and I test. We assessed for publication bias using a funnel plot. TABULATION, INTEGRATION, AND RESULTS Of 10 studies meeting eligibility criteria, five were RCTs and five were cohort studies. Results of cohort studies were varied; however, all had a high potential for selection bias. In the meta-analysis, there was no difference in primary composite outcome among those women with negative pressure wound therapy (16.8%) compared with those who had standard dressing (17.8%) (risk ratio 0.97, 95% CI 0.63-1.49). There was no statistically significant heterogeneity (χ test 4.80, P=.31, I=17%). CONCLUSION Currently available evidence does not support negative pressure wound therapy use among obese women for cesarean wound complication prevention. SYSTEMATIC REVIEW REGISTRATION PROSPERO: International prospective register of systematic reviews, 42016033948.

Cell-Free DNA Screening: Complexities and Challenges of Clinical Implementation.

Screening for fetal aneuploidy in pregnant women using cell-free DNA has increased dramatically since the technology became commercially available in 2011. Since that time, numerous trials have demonstrated high sensitivity and specificity to screen for common aneuploidies in high-risk populations. Studies assessing the performance of these tests in low-risk populations have also demonstrated improved detection rates compared with traditional, serum-based screening strategies. Concurrent with the increased use of this technology has been a decrease in invasive procedures (amniocentesis and chorionic villus sampling). As the technology becomes more widely understood, available, and utilized, challenges regarding its clinical implementation have become apparent. Some of these challenges include test failures, false-positive and false-negative results, limitations in positive predictive value in low-prevalence populations, and potential maternal health implications of abnormal results. In addition, commercial laboratories are expanding screening beyond common aneuploidies to include microdeletion screening and whole genome screening. This review article is intended to provide the practicing obstetrician with a summary of the complexities of cell-free DNA screening and the challenges of implementing it in the clinical setting. Target Audience Obstetricians and gynecologists, family physicians. Learning Objectives After completing this activity, the learner should be better able to understand the complexities of cell-free DNA screening and describe considerations involved in its clinical implementation.

Management of Pregnancy and Survival of Infants with Trisomy 13 or Trisomy 18

Objective The objective of this study was to describe antenatal/intrapartum management and survival of liveborn infants with known trisomy 13 (T13) or trisomy 18 (T18) based on planned neonatal care. Study Design This is a retrospective cohort study of singleton pregnancies complicated by T13/T18 at a tertiary center from 2004 to 2015. We included pregnancies with antenatal or neonatal cytogenetic T13/T18 diagnosis and excluded those which were terminated or had a fetal demise < 20 weeks. We compared antenatal/intrapartum management and neonatal survival by planned neonatal care, defined as either neonatal intervention (INT), including neonatal cardiopulmonary resuscitative measures or comfort care (CC) without resuscitative measures. Results In this study, 32 women (10 with T13 and 22 with T18) met study criteria; 12 (38%) elected INT and 20 (62%) CC. Compared with those who elected INT, women who elected CC were more likely to undergo elective induction (40 vs. 0%, p = 0.01), have an intrapartum stillbirth (0 vs. 32%, p = 0.14), and deliver vaginally (25 vs. 63%, p < 0.01). In neonatal survival analysis (n = 26), median survival was longer in the INT group compared with CC group (64 days [interquartile range, IQR: 2, 155) vs. 3 days [IQR]: 0.3, 42), p = 0.28), but survival to hospital discharge was similar (53 vs. 57%, p = 0.95). Conclusion Regardless of desired level of neonatal INT, many women who continue pregnancies complicated by T13/18 have infants who survive beyond hospital discharge.

Maternal Morbidity After Previable Prelabor Rupture of Membranes.

OBJECTIVE To identify risk factors for maternal morbidity after previable prelabor rupture of membranes (PROM). METHODS We conducted a case-control study of singleton and twin pregnancies complicated by previable PROM (14.0-22.9 weeks of gestation) at a single tertiary care referral institution, 2000-2015. Pregnancies complicated by fetal anomalies, previable PROM within 2 weeks of chorionic villus sampling or amniocentesis, and those with contraindications to expectant management (eg, chorioamnionitis) were excluded. Cases were women with the primary outcome of composite maternal morbidity (defined as having at one or more of the following: sepsis, intensive care unit admission, acute renal insufficiency, uterine curettage, hysterectomy, deep vein thrombosis, pulmonary embolus, blood transfusion, readmission, or maternal death). Controls were women without the primary composite morbidity. Bivariate analysis compared demographic, clinical, and management characteristics of women in the case group and those in the control group. Multivariable logistic regression models were developed to quantify the association between maternal characteristics and composite severe maternal morbidity. RESULTS During the study period, 174 women presented with by previable PROM and were candidates for expectant management. Sixty-five (37%) women opted for immediate delivery; 109 (63%) elected expectant management. Twenty-five of 174 (14%) experienced one or more components of the composite maternal morbidity (cases) and were compared with 149 (86%) women in the control group. Women in the case group were more not more likely to elect expectant management (68% compared with 59%, P=.40), but were more likely to be aged 35 years or older (40% compared with 14%, P=.002) or to be carrying twins (52% compared with 16%, P<.01). In the regression model, twin gestation and age 35 years or older were both significantly associated with increased odds of composite maternal morbidity (odds ratio [OR] 5.62, 95% confidence interval [CI] 2.21-14.3 and OR 4.00, 95% CI 1.48-10.8, respectively). CONCLUSION Antenatal counseling of women with previable PROM should include that one in seven women experience significant morbidity. Although expectant management was not associated with increased risk in this cohort, women with twins or those aged 35 years or older were at substantially increased risk.

Risk Factors for Postpartum Septic Pelvic Thrombophlebitis: A Multicenter Cohort

Objective The objective of this study was to identify risk factors associated with the development of septic pelvic thrombophlebitis (SPT). Study Design This is a secondary case‐control study of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal‐Fetal Medicine Unit Network Cesarean Registry. SPT was defined as suspected infectious thrombosis of the pelvic veins, often persistent febrile illness in the setting of antibiotic therapy for endometritis. Women with SPT were compared with those without SPT using descriptive statistics. Logistic regression models estimated the association between selected risk factors and SPT. Results Of 73,087 women in the cohort, 89 (0.1%) developed SPT. Women with SPT were more likely to be < 20 years old (33.7 vs. 10.6%, p < 0.001), black race (58.4 vs. 29.1%, p < 0.001), and nulliparous (51.1 vs. 23.3%, p < 0.001). Hypertensive disorders of pregnancy (32.6 vs. 11.8%, p < 0.001) and multiple gestation (12.5 vs. 7.4%, p = 0.03) were also more common in women with SPT. In the multivariable regression model, maternal age < 20, black race, multiple gestation, and preeclampsia were all significantly associated with increased odds of SPT (adjusted odds ratio [aOR]: 1.96, 95% confidence interval [CI]: 1.22, 3.14; aOR: 2.6, 95% CI: 1.68, 4.02; aOR: 2.10, 95% CI: 1.13, 3.88; aOR: 2.91, 95% CI: 1.86, 4.57). Conclusion SPT is a rare pregnancy complication. Our analysis confirmed known risk factors (e.g., infections, cesarean delivery), and identified novel ones, including black race, young age, preeclampsia, and multiple gestation.

Targeted Multiplex Gene Expression Profiling to Measure High-Fat Diet and Metformin Effects on Fetal Gene Expression in a Mouse Model

Background: Maternal obesity and excessive gestational weight gain (GWG) are associated with delivery of a large-for-gestational-age infant. We used a high-fat diet (HFD) mouse model to separate the effect of maternal obesity from excessive GWG on fetal growth. Our objective was to identify fetal gene expression changes in an HFD and control diet (CD) mouse model with and without metformin exposure. Study Design: Normal weight timed-pregnant (Female Friend virus B) strain mice were allocated on day e0.5 to receive HFD or CD and either plain water or metformin (2.5 mg/mL in drinking water). Dams were euthanized on day e17.5 and fetal livers harvested and frozen at −80°C. RNA was extracted and hybridized to a customized 96-gene Nanostring panel focused on angiogenesis, inflammation, and growth gene expression. Fetal liver gene expression was compared between metformin and plain water groups using analysis of variance. Significant differences in gene expression, defined by a false discovery controlled q value <0.01, were then analyzed using Ingenuity pathway analysis (IPA). Results: In HFD-fed dams, compared to controls, the metformin-treated group had significantly lower fetal weight and 39 differentially expressed liver genes; 15 (38%) were in the growth/angiogenesis gene expression network. IPA predicted that fetal liver gene upregulation associated with metformin exposure is a result of metformin inhibition of the common upstream regulator, phosphatase and tensin homolog (PTEN). Conclusions: Metformin-exposed fetuses from dams fed HFD and CD have significant gene expression differences in genes specific to growth and angiogenesis pathways in the fetal liver. Diet alone did not alter fetal liver gene expression.