Showing papers by "Cynthia A. Moore published in 2019"

Dolutegravir Use at Conception — Additional Surveillance Data from Botswana

Abstract: Dolutegravir Use and Birth Defects in Botswana Identifying birth defects associated with medication use is complex, given the infrequency of events. In this study conducted in Botswana, a slightly ...

Optimizing responses to drug safety signals in pregnancy: the example of dolutegravir and neural tube defects

Abstract: INTRODUCTION The unexpected identification of a neural tube defect (NTD) safety signal with preconception dolutegravir (DTG) exposure in the Botswana Tsepamo birth outcomes study brought into sharp focus the need for reliable data on use of new antiretrovirals in pregnancy, improved pharmacovigilance systems to evaluate safety of new drugs being introduced into populations including women of reproductive potential, and balanced risk-benefit messaging when a safety signal is identified. DISCUSSION The Tsepamo study NTD safety signal and accompanying regulatory responses led to uncertainty about the most appropriate approach to DTG use among women of reproductive potential, affecting global DTG roll-out plans, and limiting DTG use in adolescent girls and women. It also revealed a tension between a public health approach to antiretroviral treatment (ART) and individual choice, and highlighted difficulties interpreting and messaging an unexpected safety signal with uncertainty about risk. This difficulty was compounded by the lack of high-quality data on pregnancy outcomes from women receiving ART outside the Tsepamo surveillance sites and countries other than Botswana, resulting in a prolonged period of uncertainty while data on additional exposures are evaluated to refute or confirm the initial safety signal. We discuss principles for evaluating and introducing new drugs in the general population that would ensure collection of appropriate data to inform drug safety in adolescent girls and women of reproductive potential and minimize confusion about drug use in this population when a safety signal is identified. CONCLUSIONS The response to a signal suggesting a possible safety risk for a drug used in pregnancy or among women who may become pregnant needs to be rapid and comprehensive. It requires the existence of appropriately designed surveillance systems with broad population coverage; data analyses that examine risk-benefit trade-offs in a variety of contexts; guidance to transform this risk-benefit balance into effective and agreed-upon policy; involvement of the affected community and other key stakeholders; and a communication plan for all levels of knowledge and complexity. Implementation of this proposed framework for responding to safety signals is needed to ensure that any drug used in pregnancy can be rapidly and appropriately evaluated should a serious safety alert arise.

Updated baseline prevalence of birth defects potentially related to Zika virus infection.

Abstract: Dear Editor, Zika virus (ZIKV) was first recognized as a human teratogen in 2016 (Rasmussen, Jamieson, Honein, & Petersen, 2016). During the ZIKV outbreak in the Americas, we launched rapid surveillance of pregnancies with laboratory evidence of ZIKV infection and targeted surveillance of birth defects. Because little was known about the birth defects associated with congenital ZIKV infection, a broad case definition was used for surveillance of birth defects potentially related to ZIKV based on early reports of congenital ZIKV infection in the literature and expert opinion. The initial case definition included microcephaly and/or brain abnormalities, neural tube defects (NTDs) and other early brain malformations (e.g., holoprosencephaly), eye abnormalities, and consequences of central nervous system (CNS) dysfunction such as arthrogryposis and hearing loss (Honein et al., 2017). The baseline prevalence of these defects in the United States prior to the ZIKV outbreak was estimated as 2.86 per 1,000 live births (95% CI: 2.65–3.07) using data from statewide birth defects surveillance programs in Massachusetts and North Carolina in 2013 and from three counties in metropolitan Atlanta, Georgia, during 2013–2014 (Cragan et al., 2017). For newly identified teratogens, case definitions often evolve over time. Based on new data, we now propose changes to the current case definition involving NTDs and other early brain malformations and consequences of CNS dysfunction. Accumulating evidence from surveillance of infants and fetuses born to mothers with laboratory evidence of ZIKV infection suggests that NTDs and other early brain malformations are not associated with ZIKV infection during pregnancy. For example, the prevalence of NTDs did not increase significantly during the ZIKV outbreak compared to before the outbreak (Delaney et al., 2018; Hurtado-Villa et al., 2017). In addition, in infants born to mothers with laboratory evidence of ZIKV infection during pregnancy, arthrogryposis was only noted in infants with structural brain abnormalities when imaging was available. This abnormality is therefore more appropriately classified with other neurodevelopmental sequelae, such as seizures and developmental delay. Moreover, many birth defects surveillance programs do not ascertain hearing loss not associated with an ear malformation making under-ascertainment likely. For these reasons, we have updated the baseline estimates of birth defects potentially related to congenital ZIKV infection prior to the outbreak to include only microcephaly and/or brain abnormalities and eye abnormalities. Cases included in the original baseline prevalence estimates of birth defects potentially related to congenital ZIKV infection were re-reviewed and categorized by expert clinicians to remove those with NTDs and other early brain malformations or CNS dysfunction with no other qualifying defects. Methods for calculating prevalence estimates have been previously reported (Cragan et al., 2017). The report on the follow-up of infants at least one-year-old with laboratory evidence of possible ZIKV infection during pregnancy in the U.S. territories and freely associated states followed this updated case definition with microcephaly, brain abnormalities, and eye abnormalities classified as Zika-associated birth defects, and other specific outcomes (hearing abnormalities, congenital contractures, seizures, body tone abnormalities, movement abnormalities, swallowing abnormalities, possible developmental delay, possible visual impairment, and postnatal onset microcephaly) classified as neurodevelopmental abnormalities potentially linked to Zika (Rice et al., 2018). From the original baseline population in 2013–2014, 747 infants/fetuses met the initial broad surveillance case definition; 229 with NTDs or other early brain malformations and 45 with CNS dysfunction have been excluded. The revised baseline prevalence of 1.81 infants/fetuses per 1,000 live births (95% CI: 1.65–1.98) comprised 473 infants/fetuses with microcephaly and/or brain abnormalities or with eye abnormalities (Table 1). In comparison, among infants at least 1 year of age in the U.S. territories and freely associated states born to mothers with laboratory evidence of ZIKV infection during pregnancy, an estimated 6% (or 60 infants per 1,000 live births) had a Zika-associated brain or eye defect (Rice et al., 2018). This suggests over a 30-fold increase in Zika-associated brain or eye defects compared to our updated baseline prevalence estimate prior to the ZIKV outbreak. Prospective surveillance systems continue to follow-up live born infants born to mothers with laboratory evidence of ZIKV infection to enable the evaluation of neurodevelopmental abnormalities. Our analysis provides an updated baseline prevalence estimate of birth defects potentially related to ZIKV infection Received: 6 June 2019 Accepted: 21 June 2019

Risk of gastroschisis with maternal genitourinary infections: the US National birth defects prevention study 1997–2011

Abstract: Objective To assess the association between occurrence and timing of maternal self-reported genitourinary tract infection (urinary tract infections [UTIs] and/or sexually transmitted infection [STI]) and risk for gastroschisis in the offspring. Design Population-based case–control study. Setting National Birth Defects Prevention Study, a multisite study in the USA. Participants Mothers of 1366 gastroschisis cases and 11 238 healthy controls. Main outcome measures Crude and adjusted ORs (aORs) with 95% CIs. Results Genitourinary infections were frequent in case (19.3%) and control women (9.9%) during the periconceptional period (defined as 3 months prior to 3 months after conception). UTI and/or STI in the periconceptional period were associated with similarly increased risks for gastroschisis (aOR 1.5, 95% CI 1.3 to 1.8; aOR 1.6, 95% CI 1.2 to 2.3, respectively). The risk was increased with a UTI before (aOR 2.5; 95% CI 1.4 to 4.5) or after (aOR 1.7; 95% CI 1.1 to 2.6) conception only among women ≥25 years of age. The risk was highest among women Conclusions UTI and/or STI were associated with an increased risk for gastroschisis, with the strength of the association varying by maternal age and timing of infection.

Diaphragmatic paralysis: Evaluation in infants with congenital Zika syndrome.

Abstract: Background Paralysis of the diaphragm in newborn infants can lead to recurrent infections and life-threatening respiratory insufficiency. The clinical diagnosis of unilateral diaphragmatic paralysis has been reported in infants with laboratory evidence of congenital Zika virus infection and/or the congenital Zika syndrome (CZS) phenotype but no evaluation of phrenic nerve function has been described. All reported infants have had accompanying arthrogryposis. High infant mortality is reported. Methods The causal mechanism of congenital diaphragmatic paralysis was evaluated in three infants with arthrogryposis as a manifestation of CZS (two of the three infants had laboratory evidence of ZIKV infection shortly after birth; the remaining infant had negative serology for ZIKV when first tested at 7 months of age). Electromyography and phrenic nerve compound muscle action potential (CMAP) were performed in all infants with diaphragmatic paralysis demonstrated on imaging studies. Results All infants had evidence of moderate chronic involvement of peripheral motor neurons. Phrenic nerve CMAP was reduced on the side of the diaphragmatic paralysis in two infants and reduced bilaterally in the remaining infant who had primarily anterior involvement of the diaphragm. All three infants had multiple medical complications and one infant died at 18 months of age. Conclusion Evaluation of three infants with CZS and diaphragmatic paralysis demonstrated phrenic nerve dysfunction. In these and other affected infants, arthrogryposis appears to be a constant co-occurring condition and health problems are significant; both conditions are likely due to involvement of the peripheral nervous system in some infants with CZS.

Health Care Autonomy of Women Living with HIV

Abstract: Health Care Autonomy of Women Living with HIV HIV policy discussions have focused on a potential link between dolutegravir-based HIV treatment in pregnant women and neural-tube defects in infants, ...