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Neural-Tube Defects and Antiretroviral
Treatment Regimens in Botswana
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Dolutegravir Use at Conception — Additional Surveillance Data from Botswana
Download the PDF here
Download the PDF here
The final analyses included only the three confirmed or probable neural-tube defects (Table 1). One neural-tube defect was found among the 152 deliveries in which the mother had been taking dolutegravir at conception (prevalence, 0.66%; 95% confidence interval [CI], 0.02 to 3.69), and two neural-tube defects were found among the 2326 deliveries in which the mother was HIV-negative (prevalence, 0.09%; 95% CI, 0.01 to 0.31). The difference in the prevalence of neural-tube defects between deliveries in which the mothers had been taking non–dolutegravir-based ART at conception and those among mothers who had been taking dolutegravir-based ART at conception was 0.66 percentage points (95% CI, −0.48 to 3.63). We conducted a sensitivity analysis to assess how inclusion of the possible neural-tube defect, which occurred in an infant born to an HIV-negative woman, would affect the estimate of the difference in prevalence and found no meaningful change.
Our findings suggest a slightly higher prevalence of neural-tube defects among deliveries in which the mothers were HIV-positive and had been taking dolutegravir at the time of conception than among deliveries in which the mothers were HIV-negative. However, because of the short duration of our study and the infrequent occurrence of neural-tube defects in the general population, the number of cases identified was small, the prevalence estimates were unstable, and the resultant differences in prevalence had confidence intervals that included the null value. These data suggest that the magnitude of the risk of neural-tube defects associated with dolutegravir exposure at the time of conception remains less than 1%, which is consistent with findings from the Tsepamo study (now published in the Journal)4 and important in individual decision making regarding ART options. Although our findings are independent from those of the Tsepamo study, together they represent coverage of more than 90% of all births in Botswana. These findings should be considered in an assessment of global data to further examine ART exposure and adverse birth outcomes.
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Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana
We performed nationwide birth surveillance in Botswana and found evidence of a potential association between neural-tube defects and dolutegravir exposure at the time of conception. Since our initial 2018 report, the estimated prevalence has diminished in magnitude to approximately 3 per 1000 births but remains greater than for all other types of antiretroviral exposure at conception.
NEJM July 22 2019
Rebecca Zash, M.D., Lewis Holmes, M.D., Modiegi Diseko, B.P.H., Denise L. Jacobson, Ph.D., M.P.H., Sean Brummel, Ph.D., Gloria Mayondi, B.Sc., Arielle Isaacson, B.A., Sonya Davey, M.Phil., Judith Mabuta, Mompati Mmalane, M.D., Tendani Gaolathe, M.D., M. Essex, D.V.M., Ph.D., Shahin Lockman, M.D., Joseph Makhema, M.B., B.S., and Roger L. Shapiro, M.D., M.P.H.
Abstract
Background
A preliminary safety signal for neural-tube defects was previously reported in association with dolutegravir exposure from the time of conception, which has affected choices of antiretroviral treatment (ART) for human immunodeficiency virus (HIV)–infected women of reproductive potential. The signal can now be evaluated with data from follow-up of additional pregnancies.
Methods
We conducted birth-outcomes surveillance at hospitals throughout Botswana, expanding from 8 to 18 sites in 2018. Trained midwives performed surface examinations of all live-born and stillborn infants. Research assistants photographed abnormalities after maternal consent was obtained. The prevalence of neural-tube defects and major external structural defects according to maternal HIV infection and ART exposure status was determined. In the primary analyses, we used the Newcombe method to evaluate differences in prevalence with 95% confidence intervals.
Results
From August 2014 through March 2019, surveillance captured 119,477 deliveries; 119,033 (99.6%) had an infant surface examination that could be evaluated, and 98 neural-tube defects were identified (0.08% of deliveries). Among 1683 deliveries in which the mother was taking dolutegravir at conception, 5 neural-tube defects were found (0.30% of deliveries); the defects included two instances of myelomeningocele, one of anencephaly, one of encephalocele, and one of iniencephaly. In comparison, 15 neural-tube defects were found among 14,792 deliveries (0.10%) in which the mother was taking any non-dolutegravir ART at conception, 3 among 7959 (0.04%) in which the mother was taking efavirenz at conception, 1 among 3840 (0.03%) in which the mother started dolutegravir treatment during pregnancy, and 70 among 89,372 (0.08%) in HIV-uninfected mothers. The prevalence of neural-tube defects was higher in association with dolutegravir treatment at conception than with non-dolutegravir ART at conception (difference, 0.20 percentage points; 95% confidence interval [CI], 0.01 to 0.59) or with other types of ART exposure. Major external structural defects were found in 0.95% of deliveries among women exposed to dolutegravir at conception and 0.68% of those among women exposed to non-dolutegravir ART at conception (difference, 0.27 percentage points; 95% CI, −0.13 to 0.87).
Conclusions
The prevalence of neural-tube defects was slightly higher in association with dolutegravir exposure at conception than with other types of ART exposure at conception (3 per 1000 deliveries vs. 1 per 1000 deliveries). (Funded by the National Institutes of Health.)
Discussion
We performed nationwide birth surveillance in Botswana and found evidence of a potential association between neural-tube defects and dolutegravir exposure at the time of conception. Since our initial 2018 report, the estimated prevalence has diminished in magnitude to approximately 3 per 1000 births but remains greater than for all other types of antiretroviral exposure at conception.
The potential association between dolutegravir and neural-tube defects was unexpected. Preclinical studies in animals did not identify a risk for birth defects associated with this compound.21 As of January 31, 2019, the Antiretroviral Pregnancy Registry (APR) has reported 1 instance of neural-tube defect (anencephaly) among 247 periconception exposures to dolutegravir that were identified prospectively22; outside the APR, no other neural-tube defects have been reported in association with dolutegravir treatment from conception in eight observational studies with a total of 245 exposures.23-31 However, a lack of such reports is not surprising, given the small number of preconception exposures outside Botswana to date. Because neural-tube defects could be affected by low folate levels (Botswana does not mandate folate-fortified grains) or by a genetic predisposition specific to Botswana, systematically collected data from other regions in which dolutegravir is being used are needed.
Folate deficiency is a well-known risk factor for neural-tube defects,32 and folate antagonism by dolutegravir has been investigated as a potential mechanism to explain our clinical data. Findings in in vitro studies performed by Cabrera et al. included partial antagonism between dolutegravir and folate at high concentrations and a link between dolutegravir and developmental toxic effects in a folate-reversible zebra fish model.33 An industry study showed high-dose folate antagonism in cell-culture experiments, which the authors of that study did not consider to be clinically relevant, although the cutoff values used in cell-culture experiments to determine clinical relevance to humans are of uncertain accuracy.34 At this time, no firm conclusions can be drawn as to whether a folate pathway should be implicated, but folic acid fortification of grains can decrease the population prevalence of neural-tube defects by half,32 and preconception folate supplementation is an existing WHO recommendation.35 Further research is critical to determine whether dietary or vitamin supplementation of folate in women of childbearing age who are receiving dolutegravir might mitigate the excess risk that was estimated in our study.
Our data show no signal concerning the use of efavirenz at conception and the risk of neural-tube defects. Several additional findings deserve further study. We identified more major external structural abnormalities associated with dolutegravir treatment at conception (9 per 1000 births) than after dolutegravir treatment that was started during pregnancy (4 per 1000 births), with two cases of gastroschisis and two cases of omphalocele associated with dolutegravir exposure from conception that are notable. More surveillance is required to interpret these findings. In our study, we also observed that dolutegravir treatment from conception was associated with fewer adverse birth outcomes than efavirenz treatment from conception, with the exception of stillbirths, although the differences were not substantial. Continued surveillance to further evaluate birth outcomes is important, because small increases in the risk of common adverse birth outcomes have a proportionally large effect on overall infant morbidity and mortality.36-38
Our study was observational by necessity, and therefore it could have been susceptible to confounding. Because of the very low prevalence of neural-tube defects, we could not reliably adjust for potential measured confounders. However, no measured confounders (obesity, diabetes, or exposure to antiepileptic agents or to trimethoprim–sulfamethoxazole at conception) were present in the five cases of neural-tube defects associated with dolutegravir treatment at conception, so bias from measured confounding cannot explain our results. Maternal age was lower among women who were taking dolutegravir at conception than among those who were taking other types of ART at conception, and this could have biased our estimated effect toward zero. Differences in preconception folate levels or genetic predisposition could have led to unmeasured confounding, but the distribution of these differences would not be expected to differ between exposure groups. Misclassification of exposure among cases of neural-tube defects associated with dolutegravir exposure at conception could also lead to bias for this rare outcome. However, in all five cases, the start date of ART occurred when dolutegravir was being used as the first-line drug nationally, the ART regimen and start date reported by the mother at delivery matched what was recorded in the obstetrical record, and all these women started dolutegravir more than 3 months before the estimated date of conception. We did not have a direct assessment of ART adherence; however, the incidence of in utero mother-to-child transmission among women taking ART in Botswana is 0.4%, which includes women who started ART late in pregnancy.39 Therefore, we infer that the level of ART adherence was high among the women in our study. Although increased numbers of pregnancy terminations among women taking dolutegravir after the signal report could have biased results toward the null, the number of deliveries among women who were taking dolutegravir at conception continued to rise after May 2018 (Table S3 in the Supplementary Appendix), which suggests that terminations were not increasing.
Additional limitations of our study include the inability to evaluate defects that require more than a routine surface examination to detect, including heart defects, which are the most common type of major birth defect worldwide and can be associated with folate deficiency.1 We also could not evaluate pregnancy loss before 24 weeks, which could have resulted in bias.40-42 The strengths available with our study design included a large sample size that made it possible to ascertain the outcomes of most pregnancies (>95% of deliveries occur in hospitals, and termination of pregnancy is not legal in Botswana except in extreme circumstances), nearly complete reporting of a surface examination for all live births and stillbirths, photographic confirmation of trained midwife examinations for a majority of neural-tube defects, and nearly complete information on HIV infection status and ART regimen. Although our sample was large, neural-tube defects are a rare outcome, and additional surveillance is warranted. Future surveillance trends are particularly important given the decline in overall neural-tube defects that has been observed since May 2018.
The data from nationwide birth surveillance in Botswana examined in our study suggest a potential association between dolutegravir exposure at conception and the development of neural-tube defects. Although the prevalence of neural-tube defects was 3 times as high with dolutegravir as with non-dolutegravir antiretrovirals, this represented only approximately 2 excess defects per 1000 exposures. Clinical and policy recommendations based on these findings should consider the lack of similar data for most other modern antiretrovirals (with the exception of efavirenz), the lack of data on malformations that could not be evaluated in our study, unstudied long-term childhood effects of in utero ART exposure, the magnitude of the risk of other adverse birth outcomes, and the benefits of dolutegravir for maternal health.43-45 Our findings highlight the need to address global disparities in access to effective contraception and preconception folate repletion, which would benefit the health of all women. Finally, given that women of reproductive age make up close to half the global population living with HIV infection, the inclusion of pregnant women in clinical safety trials and strengthened requirements mandating postmarketing surveillance for rare outcomes are needed for new agents that treat or prevent HIV infection.46-49
Introduction
Neural-tube defects occur by the end of the sixth week of pregnancy (i.e., the fourth week after fertilization) and have been associated with exposure to specific drugs early in pregnancy.1 Concerns about neural-tube defects among children exposed to efavirenz at the time of conception were raised by an early study in nonhuman primates2 and from case reports in patients,3-5 but no subsequent clinical association was detected.6 Dolutegravir is a newer antiretroviral agent with a higher barrier to resistance, fewer side effects, and more effective viral suppression than efavirenz,7 but data on congenital abnormalities and other potential adverse birth outcomes associated with exposure at the time of conception have been lacking. In 2016, Botswana became the first African country to shift from efavirenz-based antiretroviral treatment (ART) to dolutegravir-based ART as first-line therapy for all adults with human immunodeficiency virus (HIV) infection.8
In 2014, to confirm the safety of efavirenz exposure at conception, surface examination surveillance to detect neural-tube defects was initiated at eight large government maternity wards in Botswana as part of the Tsepamo Study. This surveillance system captures all antiretroviral exposure, including dolutegravir exposure since the introduction of the drug in 2016. In May 2018, a review of data to inform the development of World Health Organization (WHO) HIV guidelines revealed a potential early signal for neural-tube defects associated with dolutegravir exposure at conception, with 4 such defects found among 426 exposures.9 Since that time, advisory statements from regulatory agencies have recommended more-limited use of dolutegravir among women planning pregnancy.10,11 In the present study, we evaluated the signal for neural-tube defects with follow-up of additional births.
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