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Clinical Science

Is There a Safety Signal for Dolutegravir and Integrase Inhibitors During Pregnancy?

Chouchana, Laurent PharmD, PhDa,b; Beeker, Nathanael PhDb,c; Treluyer, Jean-Marc MD, PhDa,b,c

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: August 1, 2019 - Volume 81 - Issue 4 - p 481-486
doi: 10.1097/QAI.0000000000002065

Abstract

INTRODUCTION

Dolutegravir, an integrase strand transfer inhibitor (InSTI), is a major antiretroviral agent for HIV infection, allowing for a rapid decrease in viral load.1 Besides its high resistance barrier, dolutegravir has a better safety profile and fewer drug–drug interactions than boosted protease inhibitors.2,3 The World Health Organization (WHO) supports the expansion of dolutegravir-based first-line regimens in low and middle-income countries, particularly in certain regions such as in southern and eastern Africa where pretreatment drug resistance to nonnucleoside reverse transcriptase inhibitors is concerning.4,5 Furthermore, antiretroviral therapy in pregnant women infected with HIV is essential to reduce vertical transmission. Dolutegravir is thus promising in adults and children with HIV, and its safety is challenging, especially in pregnant women in whom knowledge is scarce.

So far, no evidence was found for increased birth defects with dolutegravir, in human or animal data.6 However, very recently, a preliminary safety concern has been raised regarding its use in pregnant women. Dolutegravir exposure during pregnancy has been associated with an unexpected high rate of neural tube defects among a cohort of women with HIV from the ongoing Tsepamo surveillance study in Botswana.7,8 This safety signal prompted the WHO, the European Medicines Agency (EMA), and the US Food and Drug Administration (FDA) to issue warnings about the use of dolutegravir in pregnant women.9–11 Thus, the EMA stated that “Dolutegravir HIV medicines should not be prescribed to women seeking to become pregnant; women who can become pregnant should use effective contraception while taking dolutegravir medicines […] women who have been prescribed dolutegravir should not stop taking their medicine without first consulting their doctor.”10

Other InSTI agents such as raltegravir and elvitegravir could also be prescribed in pregnant women with HIV. No safety issue has been raised for raltegravir in pregnancy within a literature review, but data were limited to 278 pregnancies.12 A recent report including 256 first-trimester raltegravir-exposed pregnancies from a nation-based surveillance study did not found an increase in the prevalence of birth defects.13 Regarding elvitegravir, the latest marketed InSTI agent, data are very limited concerning its use in pregnancy.13,14

The objective of this study was to analyze pregnancy outcomes exposed to InSTI agents, and to evaluate the potential risk of neural tube defects, within a nation-wide database.

METHODS

Data Sources and Study Population

This study has been conducted using the French National health data system système national des données de santé (SNDS)—formerly Système national d'information inter-régimes de l'assurance maladie (SNIIRAM), which is the national administrative database in France. The SNDS is a fully anonymized database based on the national health care reimbursement database linked to the national hospital discharge database.15 It comprises exhaustive data on all reimbursements for patient health care expenditure, including medicinal products as well as outpatient medical care and costly long-term disease codes. Moreover, it also displays the French hospital discharge database, which comprises inpatients' individual records of all hospital admissions in France. These records include physicians' diagnoses, classified according to the International Classification of Diseases, 10th Revision (ICD-10; www.who.int/classifications/icd/en/), including birth defects for live births, induced abortions or stillbirths, and medical procedures performed during the hospital stay.

Data from mother and pregnancy outcomes, regarding national health care reimbursement database and hospital discharge database, are linked together, so that pregnancy outcomes are related to a mother. Date of conception was estimated using the date of delivery and the gestational age at birth according to physician assessment. In the rare cases of missing gestational age at birth, date of conception was estimated from the date of the last period mentioned in the reimbursement database.

HIV infection was defined, within the 12 months before conception, as filling at least 3 reimbursements of one antiretroviral drug or as having a HIV-related ICD-10 code within the hospital discharge database (see Supplementary Data, Supplemental Digital Content, https://links.lww.com/QAI/B318).

Pregnancy Outcome

Our SNDS data query, during the study period from 2012 to 2016, retrieves about 4.1 millions of women who had about 5.1 million pregnancies that we integrated a data set with various outcomes. The following pregnancy outcomes were included: live birth, stillbirth (which is here defined as pregnancy loss after 20 weeks of gestation or a fetal weight under 500 g), and induced abortion after 20 weeks of gestation. We excluded induced abortion before 20 weeks of gestation, spontaneous abortion, ectopic pregnancy, and other abnormal products of conception (such as a mole hydatidiform), because of the lack of sensitivity regarding these situations in the SNDS. Indeed, early miscarriages, not always requiring hospitalization, are not widely identified in the SNDS inpatient data. We also excluded pregnancies in which the maternal age at birth was not included between 15 and 49 years.

Birth defects were defined according to the European Surveillance of Congenital Anomalies (EUROCAT) classification system.16 We included all cases of major birth defects and did not considered minor defects. We also excluded all pregnancy outcomes associated with birth defects of known causes, ie, related to genetic syndromes, chromosomal aberrations, or congenital viral infections associated with malformation (see Supplementary Data, Supplemental Digital Content, https://links.lww.com/QAI/B318).

Drug Exposure

The SNDS comprises drug reimbursement data but does not display information on drug consumption. Drug exposure during the first trimester of pregnancy was analyzed for the pharmacological group of InSTI, that is, dolutegravir, raltegravir, or elvitegravir (see Supplementary data, Supplemental Digital Content, https://links.lww.com/QAI/B318). As in France, drugs dispensed by community pharmacies are on a monthly basis, drug exposure over the first trimester of pregnancy was defined as filling at least one reimbursement of one of these drugs from 30 days before the date of conception until the 91th day of gestation. Drug exposure during the second trimester (ie, filling at least one reimbursement inducing to a potential drug intake between the 92nd day and the 182nd day of gestation) and during the third trimester (ie, filling at least one reimbursement inducing to a potential drug intake between the 183rd day of gestation and until the pregnancy outcome) has also been reported but not taken into account in the analysis for birth defects. Treatment dose was not taken into account in this study.

Ethics

In agreements with French regulations, observational studies conducted on anonymous medicoadministrative data do not require an ethics committee approval.

Data Analysis

Characteristics of pregnant women (age at childbirth, infection with HIV, and InSTI exposure) and related to the pregnancy, such as type of pregnancy outcome, gestational age at birth, weight at birth, and birth defect cases, are presented in this study. For InSTI-exposed pregnancy outcomes, the type of birth defect, if applicable, is presented according to the EUROCAT classification system. Data are presented as mean ± SD. Comparisons between 2 groups were made using a Student t test with a significance threshold level of 0.05. All analyses were performed using R software.

RESULTS

Between 2012 and 2016, among the pregnancy outcomes registered in the SNDS, we considered 3,907,678 pregnancy outcomes who led to 12,397 induced abortions, 18,482 stillbirths, and 3,876,799 live births (Table 1). Among them, there were 3263 pregnancy outcomes related to mothers with known medical history of HIV infection, leading to 3204 live births. Age of the mother at childbirth was higher in women with HIV infection compared with general population (33.43 ± 5.29 vs. 29.95 ± 5.34 years; P < 0.001). Gestational age at birth was slightly lower for children of women infected with HIV (35.99 ± 2.84 vs. 36.95 ± 2.14 weeks; P < 0.001), consistent with a slightly lower weight at birth for live birth outcomes (3054 ± 601 vs. 3280 ± 523 g; P < 0.001).

T1
TABLE 1.:
Pregnancy Outcomes Among Pregnant Women in the Nation-Wide Database

Among all births from this nation-wide population, 74,203 total birth defects were ascertained (1.9% of the general population): 70,438 (94.9%) among live births, 3394 (4.6%) among induced abortions, and 371 (0.5%) among stillbirths. Among HIV-infected women, they were 67 (2.1%) pregnancy outcomes associated with a birth defect, including 64 live births and 3 induced abortions (Table 1).

During the study period, InSTI exposure increased over time, especially for dolutegravir: no exposure between 2012 and 2014, 5 pregnancy outcomes in 2015, and the remainder in 2016 (Fig. 1). Regarding the timing of exposure to InSTI during pregnancy, the majority of the pregnant women started the treatment before pregnancy (Table 2). We found, among all pregnancies, 49, 240, and 70 pregnancy outcomes from women exposed to dolutegravir, raltegravir, and elvitegravir, respectively, during the first trimester (Table 2). Among them, there were 2, 3, and 1 live births, exposed to dolutegravir, raltegravir, or elvitegravir, respectively, and associated with at least one major birth defect. These birth defects were of various types, and no special pattern was found (Table 3). Among induced abortions or stillbirths, we did not detect any birth defect. No case of neural tube defect, including spina bifida, was found among these InSTI-exposed pregnancies. More precisely, among these 6 live births with birth defects found to be associated with InSTI exposure, 3 newborns had injuries related to the central nervous system: one case of macrogyria, associated with a heart defect, in a child exposed to dolutegravir; one case of corpus callosum malformation and one case of hydrocephalus associated with deformity of spine and multiple malformations, in 2 children exposed to raltegravir (Table 3).

F1
FIGURE 1.:
Evolution of dolutegravir, raltegravir, and elvitegravir exposure in pregnant women over time in France: Drug exposure related to the first trimester of pregnancy. Date corresponding to outcome of pregnancy.
T2
TABLE 2.:
Timing of Exposure to Dolutegravir, Raltegravir, and Elvitegravir During Pregnancy
T3
TABLE 3.:
Birth Defects by the Organ/System Associated With Exposure to InSTI Antiretroviral Agents During the First Trimester of Pregnancy

DISCUSSION

The experience of InSTI in pregnant women with HIV is based on case reports or small cohorts. To date, this is the first nation-wide database study that analyzes birth defect cases associated with dolutegravir, raltegravir, or elvitegravir use during pregnancy. We did not found any increase or specific pattern of birth defect among the children exposed in utero to InSTI drugs, during the first trimester of pregnancy. Especially, there was no case of neural tube defect.

Dolutegravir has a superior efficacy, tolerability, and a high barrier to resistance compared with other first-line antiretroviral agents.5 Its use is promising, especially in low and middle-income countries where pretreatment drug resistance is concerning. The ability to induce rapid decrease in viral load is particularly interesting in pregnant women to prevent vertical transmission, but only limited data are available on dolutegravir safety during pregnancy. Thus, a large observational cohort to assess the efficacy and safety of dolutegravir-based, compared with efavirenz-based, regimens including also tenofovir and emtricitabine, has been settled in Botswana.5 The authors found no significant difference between dolutegravir and efavirenz-based regimens in the individual outcomes of stillbirth, neonatal death, preterm birth, or small gestational age. However, very recently, an unplanned preliminary analysis of this ongoing Botswana cohort led to a safety pharmacovigilance signal regarding birth defects associated with dolutegravir in utero exposure.7 Thus, among 426 women who initiated dolutegravir before conception and who were exposed during the first trimester of pregnancy, 4 (0.94%) gave birth to a children with a neural tube defect, compared with 14 (0.13%) among 11,173 women who received another antiretroviral-based regimen.8 As a consequence, the WHO, EMA, and FDA recommended dolutegravir not to be prescribed to women seeking to become pregnant and to use effective contraception, pending the final analysis.9 No mechanism was proposed to explain the occurrence of a neural tube defect in these children. One could hypothesis that there was a folic acid deficiency in these pregnant women.

The development of the neural tube is early during organogenesis and it closes by 28 days after conception. Exposure window of interest for neural tube defects is thus narrow and theoretically before the end of the fourth week of gestation. Failure of closure of the neural tube results in a birth defect such as anencephaly or open spina bifida.17 These congenital anomalies could be detected in western countries by regular ultrasound monitoring during pregnancy. They may be related to folate deficiency, other medications, or family history. So far, folic acid supplementation or fortification is recommended in Europe and in the United States in women who plan to child bear and in pregnant women.17 In the Botswana cohort, according to the authors, the 4 mothers delivered in 3 geographically separated hospitals, none had epilepsy or diabetes, and none received folate supplementation at conception.8

Dolutegravir has been shown to cross the blood–placental barrier in an ex vivo human cotyledon perfusion model.18 Its placental transfer is however probably limited because of a high plasma protein binding of about 99%. Placental transfer has also been shown in rodents. Preclinical safety assessment of dolutegravir is based on animal reproduction studies conducted in rats and rabbits. In pregnant rats, a daily dose that was about 27 times the 50 mg twice-daily human clinical exposure, based on area under the curve (AUC), did not cause maternal toxicity or any form of developmental toxicity, except a slight increase in preimplantation losses.19 A similar dose in pregnant rabbits corresponding to about 0.4 times the human clinical exposure, based on AUC, did not lead to any form of developmental toxicity but was associated with general maternal toxicity (decreased food consumption, scant/no feces or urine, and decreased weight gain).19 Thus, no direct evidence for teratogenicity or developmental delay has been shown in preclinical studies. To date, drugs that are teratogen in humans have been shown to be teratogen at least in one animal species. These data do not suggest that dolutegravir is expected to be teratogen in humans. However, because limited human data are available, it is recommended that dolutegravir should be used during pregnancy only if clearly needed. Furthermore, the dolutegravir marketing authorization holder has mentioned the use in pregnancy in the risk management plan of this drug.19

Safety of the use of dolutegravir during pregnancy is based on few case reports or small cohorts, corresponding to about 200 exposures to date.20 In a Swedish retrospective cohort study, none of the 30 live born infants whose mothers were treated with dolutegravir during pregnancy were found to have major malformations.21 Data from a prospective registry, including 161 live birth outcomes exposed to dolutegravir in the first trimester, showed 5 cases of birth defects and none regarding the central nervous system; unfortunately, details of the defects were not provided.22 Furthermore, a retrospective analysis from 2 urban clinics including 66 pregnant women exposed to dolutegravir found 2 children with congenital anomalies: one infant from a twin pregnancy developed a nonimmune hydrops fetalis and a second infant had a heart defect.23 Finally, one of the largest published studies is the Tsepamo cohort in Botswana that includes 1729 women with HIV who initiated dolutegravir before pregnancy, of whom 280 were exposed during the first trimester. As mentioned, among these dolutegravir-exposed pregnancies, the authors did not found an increase in birth defects, or an increase in other adverse pregnancy outcomes compared to women treated with efavirenz.5 More specifically, no case of major birth defect was observed among women exposed to dolutegravir; however, there was no regular ultrasound monitoring available in this observational study in Botswana. In addition, there were 2 cases of postaxial polydactyly type B among women exposed to dolutegravir, compared with 4 in the efavirenz group.5

We also analyzed pregnancy outcomes in pregnant women exposed to other InSTI such as raltegravir and elvitegravir. Regarding raltegravir, we found in our study 3 (1.3%) cases over 240 pregnancy outcomes having at least one major malformation (all live births), but no neural tube defect (Table 3). Raltegravir is known to have a highly variable placental transfer.24 A review of the literature that included 278 maternal–infant pairs who received raltegravir during pregnancy showed that there were no consistently reported adverse effects in infants.12 However, the prospective, as well as retrospective, studies included in this review had a large heterogeneity. In the same way, the analysis of a prospective registry found 9 major birth defects among 291 women (3.1%) exposed to raltegravir during the first trimester and concluded to a nonincreased risk of teratogenicity.22 These results are consistent with the recently published nation-wide cohort analysis that included 256 first-trimester raltegravir-exposed pregnancies.13

Elvitegravir, the most recently marketed InSTI, was associated in our study with one (1.4%) major birth defect (live birth) among 70 pregnancy outcomes, which did not concern the central nervous system (Table 3). Data from a prospective registry are limited, but not of concern.22 One case report in the literature described a safe use during pregnancy.14 Thus, data regarding its safety in pregnancy are very limited and caution is required.

Our study has strengths and limitations. The SNDS allows describing and analyzing a nation-wide cohort, which includes all the community drug prescriptions. The use of filled prescriptions as a measure of drug exposure eliminates recall bias and increases the accuracy of information on specific types of drugs, as compared with survey studies or self-reported use. However, this type of study could not assess noncompliance to treatment after filling of prescriptions. Furthermore, the SNDS structure associated with the French practices allows us to capture major birth defects that could lead to induced abortion. However, our system does not have a good sensitivity to capture an induced abortion before 20 weeks of gestation, especially if it is performed in outpatient settings or too early to diagnose a congenital anomalies with accuracy. These limitations could explain the low prevalence of major birth defects found in our analysis. Nevertheless, congenital anomalies of major concern such as anencephaly are usually referred to specialized hospital settings in accordance with French prenatal diagnosis practices. Besides, the number of InSTI-exposed women during the first trimester of pregnancy is relatively low in our cohort. Indeed, InSTI drugs are not used as a first-line treatment in women who plan a pregnancy in France. Their prescription is limited to the cases of intolerance to other drugs, therapeutic failure, or late discovery of an HIV infection requiring a rapid decline in viral load. However, it tends to increase over time.

Finally, we consider that the pharmacovigilance signal regarding dolutegravir safety could not be validated in our study. Although our results are not of concern regarding InSTI use during pregnancy, owing to the small number of exposed pregnancies, further studies are needed to analyze the safety signal found in the Botswana cohort.

In conclusion, this nation-wide database study provides comprehensive safety information on dolutegravir, raltegravir, or elvitegravir use during pregnancy. Based on these data, we did not found an increased rate of major birth defects, including neural tube defects, in women exposed to InSTI drugs in the first trimester of pregnancy. These results need to be confirmed on further analyses.

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Keywords:

HIV; dolutegravir; raltegravir; elvitegravir; integrase inhibitors; pregnancy; birth defect; neural tube defect

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