Caroline Marrs

Zika in the Americas, year 2: What have we learned? What gaps remain? A report from the Global Virus Network

In response to the outbreak of Zika virus (ZIKV) infection in the Western Hemisphere and the recognition of a causal association with fetal malformations, the Global Virus Network (GVN) assembled an international taskforce of virologists to promote basic research, recommend public health measures and encourage the rapid development of vaccines, antiviral therapies and new diagnostic tests. In this article, taskforce members and other experts review what has been learned about ZIKV-induced disease in humans, its modes of transmission and the cause and nature of associated congenital manifestations. After describing the make-up of the taskforce, we summarize the emergence of ZIKV in the Americas, Africa and Asia, its spread by mosquitoes, and current control measures. We then review the spectrum of primary ZIKV-induced disease in adults and children, sites of persistent infection and sexual transmission, then examine what has been learned about maternal-fetal transmission and the congenital Zika syndrome, including knowledge obtained from studies in laboratory animals. Subsequent sections focus on vaccine development, antiviral therapeutics and new diagnostic tests. After reviewing current understanding of the mechanisms of emergence of Zika virus, we consider the likely future of the pandemic.

Zika Virus and Pregnancy: A Review of the Literature and Clinical Considerations.

The latest Zika virus (ZIKV) outbreak has reached epidemic proportions as it spreads throughout South and Central America. In November 2015, the Brazilian Ministry of Health reported a 20-fold increase in the number of cases of neonatal microcephaly, which corresponds geographically and temporally to the ZIKV outbreak. Case reports have provided some evidence of a causal link between maternal ZIKV infection, fetal microcephaly, and intracranial calcifications. The sparse data regarding ZIKV in pregnancy come solely from case reports and personal communications, and recommendations for management of ZIKV exposure during pregnancy are rapidly evolving. Our objective is to review and synthesize the current literature regarding ZIKV as it pertains to pregnancy and provide some assistance to clinicians who may have to manage a pregnant patient with potential exposure to ZIKV. We will also explore certain aspects of related viruses in pregnancy in hopes to shed light on this little-known topic.

Infant Outcomes after Periviable Birth: External Validation of the Neonatal Research Network Estimator with the BEAM Trial

Objective The objective of this study was to use data from the 20-center beneficial effect of antenatal magnesium sulfate (BEAM) trial to assess the external validity of the Neonatal Research Network (NRN) estimator, a widely employed web-based counseling tool to estimate the probability of an adverse outcome for periviable infants given intensive care. Study Design The probability of different adverse outcomes predicted from the NRN estimator was compared with observed rates at 18 to 22 months for ventilated, nonanomalous infants born at 23 to 25 weeks and assessed in BEAM as in the NRN. Results were assessed using rigorous validation methods for prediction models. Results Among 289 eligible infants, 26% died, 40% died or had profound neurodevelopmental impairment (PNDI), and 71% died or had NDI. The area under the receiver operating characteristic curve was 0.70 (95% confidence interval [CI], 0.63-0.78) for death, 0.64 (95% CI, 0.56-0.71) for death or NDI, and 0.71 (95% CI, 0.65-0.78) for death or PNDI. Observed and predicted rates were somewhat different for death or NDI but quite similar for death and for death or PNDI in different risk groups. Brier scores for accuracy were favorable (0.17-0.22) for all outcomes. Conclusion Our results provide external validation of the NRN estimator for assessing the probability of adverse outcomes at 18 to 22 months for periviable infants given intensive care.

Should We Add Pravastatin to Aspirin for Preeclampsia Prevention in High-risk Women?

Preeclampsia is a multisystem disorder that affects 3% to 5% of pregnant women and remains a significant source of short-term and long-term maternal and neonatal mortality and morbidity. Many professional societies recommend the use of low-dose aspirin to prevent preeclampsia in high-risk women. Owing to the similarities in pathophysiology between preeclampsia and atherosclerotic cardiovascular disease, and the encouraging data from preclinical and pilot clinical studies, pravastatin has been proposed for preventing preeclampsia. However, before statin administration becomes part of routine clinical practice, a large, well-designed, and adequately powered randomized-controlled trial is needed.

Differential Morbidity in Preterm Small versus Appropriate for Gestational Age: Perhaps Unverifiable

OBJECTIVE The objective of this study was to determine the morbidity of preterm small for gestational age (SGA) infants compared with appropriate for GA (AGA). STUDY DESIGN This is a secondary analysis of the randomized trial evaluating magnesium sulfate for the prevention of cerebral palsy (CP). We compared outcomes of preterm (< 37 weeks) nonanomalous infants who were SGA (birth weight < 10% for GA) versus AGA (birth weight 10-89% for GA). We compared (1) the parent trial primary outcome, a composite of stillbirth, infant death by 1 year of age, or moderate to severe CP at 2 years of age and (2) composite neonatal morbidity (CNM). RESULTS Of the 1,948 infants who met inclusion criteria, 95% were AGA and 5% were SGA. The primary outcome was similar (10 and 15%, p = 0.08), as was the CNM (24 and 25%, p = 0.89). Sample size calculations indicate that detection of a one-third higher rate of CNM among SGA compared with AGA infants requires more than 93,900 preterm births; for a one-third difference in moderate to severe CP, more than 1.4 million infants. CONCLUSION Owing to the prohibitive sample size required, ascertaining a difference in sequela between preterm SGA and AGA infants is possibly unverifiable.

Maternal human telomerase reverse transcriptase variants are associated with preterm labor and preterm premature rupture of membranes

Objective Premature aging and short telomere lengths of fetal tissues are associated with spontaneous preterm labor (PTL) and preterm premature rupture of membranes (pPROM). Maintenance of telomere length is performed by the enzyme telomerase. Human telomerase reverse transcriptase (hTERT) is a subunit of telomerase, and its dysfunction affects telomere shortening. This study assessed whether maternal or fetal genetic variations in the hTERT gene are associated with PTL or pPROM. Methods A case (PTL or pPROM) control (term birth) genetic association study was conducted in 654 non-Hispanic white mothers (438 term, 162 PTL, 54 pPROM) and 502 non-Hispanic white newborns (346 term, 116 PTB, 40 pPROM). Maternal and fetal DNA samples were genotyped for 23 single nucleotide polymorphisms (SNPs) within the hTERT gene. Allele frequencies were compared between cases and controls, stratified by PTL and pPROM. Maternal and fetal data were analyzed separately. Results Allelic differences in one SNP of hTERT (rs2853690) were significantly associated with both PTL (adjusted OR 2.24, 95%CI 1.64–3.06, p = 2.32e-05) and with pPROM (adjusted OR 7.54, 95%CI 3.96–14.33, p = 2.39e-07) in maternal DNA. There was no significant association between the hTERT SNPs analyzed and PTL or pPROM in the fetal samples. Conclusion hTERT polymorphisms in fetal DNA do not associate with PTL or pPROM risk; however, maternal genetic variations in hTERT may play a contributory role in risk of PTL and PPROM.

The association of hyperuricemia and immediate postpartum hypertension in women without a diagnosis of chronic hypertension

ABSTRACT Our objective was to determine if elevated uric acid (UA) is associated with postpartum hypertension (PP HTN) in women without chronic hypertension. This is a secondary analysis of a randomized trial. We compared those with elevated UA to those with normal UA. Logistic regression was conducted to determine the association of elevated UA with PP HTN. Five hundred and fifty-six women met criteria. An UA level ≥ 5.2 mg/dL was associated with immediate PP HTN (adjusted odds ratio 2.44, 95% CI 1.63–3.64). The association was stronger among overweight and obese women. We conclude that hyperuricemia is associated with PP HTN, especially among obese women.

Pfannenstiel versus Vertical Skin Incision for Cesarean Delivery in Women with Class III Obesity: A Randomized Trial

Objective To compare Pfannenstiel versus vertical skin incision for the prevention of cesarean wound complications in morbidly obese women. Study Design Women with body mass index ≥ 40 kg/m2 undergoing cesarean delivery (CD) were randomly allocated to Pfannenstiel or vertical skin incision. The primary outcome was a wound complication within 6 weeks. Due to a low consent rate, we limited enrollment to a defined time period for feasibility. We conducted a traditional frequentist analysis with log‐binomial regression to obtain relative risks (RRs), and a Bayesian analysis to estimate the probability of treatment benefit. A priori, we decided that a ≥60% probability of treatment benefit for either incision type would be convincing evidence to pursue a larger trial. Results A total of 648 women were approached, 228 were consented, and 91 were randomized. The primary outcome rate was 19% in the Pfannenstiel group and 21% in the vertical group (RR: 1.18; 95% confidence interval: 0.49‐2.85). Bayesian analysis revealed a 59% probability that Pfannenstiel had a lower primary outcome rate. Conclusion In the first published randomized trial to compare skin incision types for obese women undergoing CD, we were unable to demonstrate differences in clinical outcomes. Our trial suggests that a larger study would have a low probability for different findings. Trial Registration NCT 01897376 (www.clinicaltrials.gov).

Effect of Low-Dose Aspirin on the Time of Onset of Preeclampsia and Time of Delivery

Objective To determine whether low‐dose aspirin (LDA) affects the time of onset of preeclampsia and the time of delivery in high‐risk women. Study Design Secondary analysis of a multicenter randomized controlled trial of LDA (60 mg) in high‐risk women. Quantile regression was used to identify the median gestational age at preeclampsia diagnosis and median gestational age at delivery, whereas logistic regression was used to determine the likelihood of preeclampsia‐indicated delivery within 7 days. Results Total of 2,479 women were randomized and 461 developed preeclampsia. The mean gestational age at enrollment was 20 ± 4 weeks. On multivariate analysis, LDA did not affect the time of preeclampsia diagnosis (coefficient −0.4 weeks, 95% CI: −1.1 to 0.2; p = 0.2), time of delivery (coefficient 0 weeks, 95% CI: −0.3 to 0.3; p = 1), or likelihood of preeclampsia‐indicated delivery within 7 days (OR = 0.8; 95% CI: 0.5‐1.2; p = 0.2). In multifetal gestations, preeclampsia was diagnosed at least 1 week earlier than women with diabetes or previous preeclampsia (p < 0.05), and delivery occurred at least 2 weeks prior (p < 0.001). Conclusion LDA prophylaxis did not significantly affect time of diagnosis of preeclampsia, time of delivery, or likelihood of preeclampsia‐indicated delivery within 7 days. LDA prophylaxis did not significantly affect time of diagnosis of preeclampsia, time of delivery, or likelihood of preeclampsia‐indicated delivery within 7 days.