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Antiretroviral combination use during pregnancy and the risk of major congenital malformations

Bérard, Anicka,b; Sheehy, Odilea; Zhao, Jin-Pinga; Abrahamowicz, Michalc; Loutfy, Monad; Boucoiran, Isabellee; Bernatsky, Sashaf

doi: 10.1097/QAD.0000000000001610
Epidemiology and Social
Free
SDC

Objective: To quantify the risk of major congenital malformations (MCMs) associated with gestational combination antiretroviral use.

Design: Population-based prospective cohort study.

Methods: Using the Quebec Pregnancy Cohort from 1998 to 2015, we included women who were covered by the Quebec Drug Plan and had a singleton livebirth. All antiretroviral use alone or in combination were considered. MCMs overall and organ-specific malformations in the first year of life were identified.

Results: In total, 214 240 pregnancies met inclusion criteria; 0.09% (n = 198) occurred while on antiretroviral combinations during the first trimester; 169 HIV-positive women without antiretroviral treatment were included. Compared with the general population in this cohort, the prevalence of MCMs was significantly higher in unexposed HIV-positive women (14.8 vs. 8.6%, P = 0.004) but not in antiretroviral-exposed HIV-positive women (10.3%, P = 0.41). Adjusting for potential confounders, including maternal HIV status, antiretroviral use during the first trimester was not associated with the risk of MCMs (adjusted odds ratio 0.59, 95% confidence interval 0.33–1.06). However, antiretroviral combination use during the first trimester was associated with an increased risk of defects of the small intestine (adjusted odds ratio 10.32, 95% confidence interval 2.85–37.38, P = 0.0004).

Conclusion: Antiretroviral therapy during the first trimester was not associated with the risk of overall MCMs but may be associated with an increased risk of defects of the small intestine. However, HIV-positive pregnant women who are not treated with antiretrovirals during pregnancy seem to have a higher risk of malformations; this is not seen among those who are treated, which could indicate that the underlying condition puts women at risk and not the treatment.

aResearch Center, CHU Sainte-Justine, Montreal

bFaculty of Pharmacy, University of Montreal

cFaculty of Medicine, Department of Clinical Epidemiology, McGill University, Montreal, Quebec

dWomen's College Hospital, University of Toronto, Toronto, Ontario

eDepartment of Obstetrics and Gynecology, CHU Sainte-Justine, Montreal

fFaculty of Medicine, McGill University, Montreal, Quebec, Canada.

Correspondence to Anick Bérard, Research Center, CHU Sainte-Justine, 3175 Chemin de la Côte-Ste-Catherine, Montréal, Québec H3T 1C5, Canada. Tel: +514 345 4931 ext. 4363; fax: +514 345 4801; e-mail: anick.berard@umontreal.ca

Received 2 May, 2017

Revised 7 July, 2017

Accepted 18 July, 2017

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).

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Introduction

The HIV prevalence rates in pregnant women in Canada ranged from 2 to 9/10 000 between 1998 and 2008 [1]. Since WHO first issued recommendations on the use of antiretrovirals during pregnancy to prevent vertical transmission in 2000 [2]; both the number and proportion of HIV-positive pregnant women receiving antiretrovirals have increased, which had a direct impact on the vertical transmission rate (25% to <1%) [3]. In Canada, the prevalence of HIV-positive pregnant women receiving antiretrovirals increased from 78 to 97% between 2000 and 2015 [1,4]. With this change, concerns have been raised over the possible teratogenic effects on the fetus and newborn [5]. Particularly, first-trimester efavirenz exposure has been associated with central nervous system defects in monkeys [6]. Therefore, pregnancy exposure registries such as the Antiretroviral Pregnancy Registry [7] were put in place to monitor pregnancy use of antiretrovirals for the purpose of providing early signals of teratogenicity associated with specific antiretroviral therapy [8]. In parallel, other prospective observational studies have been performed [9–21], but the evidence thus far is still inconclusive as the ascertainment of cases and selection of control groups often vary across studies [22,23]. Indeed, the majority of these studies were conducted in volunteered-based selective samples. To our knowledge, to date, only two studies have used healthcare utilization databases to explore the potential association between prenatal antiretroviral exposure and major congenital malformations (MCMs) [24,25]. However, given that these were performed in Medicaid populations, which are particularly vulnerable to the occurrence of birth defects, and that they have solely included HIV-infected women [24,25] using the general population as comparator [25], potential bias remain.

Therefore, the purpose of this study was to quantify the risk of MCMs overall and according to organ systems associated with first-trimester antiretroviral combination exposure within the population-based Quebec Pregnancy Cohort (QPC). The risk of MCM associated with specific antiretrovirals was also studied.

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Methods

Cohort and study design

We conducted a population-based prospective cohort study using data from the QPC. The QPC is described in Bérard and Sheehy [26]. Briefly, the QPC is an ongoing population-based cohort with prospective data collection on all pregnancies that occurred between January 1998 and December 2015 in the province of Quebec. Data on the mothers and children after the end of pregnancy are also collected. Individual-level information is obtained from province-wide databases and linked using unique personal identifiers. The QPC was first constructed by identifying all pregnancies in the Régie de l’assurance maladie du Québec (RAMQ) and the Quebec hospitalization archives [MedEcho; Le ministère de la Santé et des Services sociaux du Québec (MSSS), Quebec, Canada)] databases; subsequently, first day of the last menstrual period (first day of gestation) was defined using data on gestational age, which was validated against ultrasound measures in patients’ charts [27]. Prospective follow-up was available from 1 year before the first day of gestation, during pregnancy, and until December 2015.

The QPC data sources for this study included the medical service database [RAMQ: diagnoses, medical procedures, socioeconomic status (SES) of women and prescribers], the Quebec Public Prescription Drug Insurance database (drug name, start date, dosage, duration), the hospitalization archive database (MedEcho: in-hospital diagnoses, and procedures), and the Quebec Statistics database (Institut de la statistique du Québec: patient sociodemographic, birth weight).

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Study population

To be included in the present study, QPC study participants had to be between 15 and 45 years of age on the first day of gestation, continuously insured by the RAMQ drug plan for at least 6 months before the first day of gestation and during pregnancy, and have a singleton live birth. To increase the validity of findings, we excluded women: exposed to any known teratogens or feto-toxic drugs during the first trimester of pregnancy (0–14 completed weeks of gestation) according to Chaabane and Bérard [28] and Briggs et al.[29], newborns with a diagnosis of chromosomal abnormalities, or newborns with minor malformations only (Table S1, http://links.lww.com/QAD/B144). Given that multiple births are associated with congenital malformations [30], we only considered singleton birth. Table S2, http://links.lww.com/QAD/B144 lists the pregnancies excluded in each group.

The study was approved by the Quebec Data Access Agency and the CHU Sainte-Justine Institutional Review Board.

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First-trimester antiretroviral exposure

The following antiretroviral exposures were considered alone or in combinations if occurring during the first trimester (first day of gestation to 14 completed weeks of pregnancy): nucleoside/nucleotide reverse transcriptase inhibitors, protease inhibitors, nonnucleoside reverse transcriptase inhibitors, integrase inhibitors, and fusion inhibitors, including fixed-dose combinations. We identified antiretroviral prescriptions dispensed to women in the cohort from the Quebec Public Prescription Drug Insurance database, with the timing of exposure determined by the dispensed date and duration of prescription. Data on prescription fillings have been validated and compared to maternal reports; the positive predictive value was found to be at least 87% [95% confidence interval (CI): 70–100%] and the negative predictive value was at least 92% (95% CI: 86–98%) [31]. The relevant exposure time window was the first trimester confirmed by ultrasound.

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Major congenital malformations

MCM diagnosed in the first year of life were identified in the RAMQ and MedEcho databases and defined according to International classification of diseases (ICD)-9 and ICD-10 codes (Table S1, http://links.lww.com/QAD/B144). ICD-9 and ICD-10 codes of MCMs in the QPC have been validated against patient charts [32]. All organ systems were considered and malformations were defined according to the European Registration of Congenital Anomalies and Twins registry [33]. The specific organ systems included were nervous system, circulatory system, cleft lip and cleft palate, digestive system, genital organs, urinary system, and musculoskeletal system.

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Statistical analyses

A priori we planned and conducted separate analyses for overall MCM, and for each organ system malformation. The unit of analysis was a pregnancy and the index date was the date of delivery. The following potential confounders were compared between antiretroviral-exposed and unexposed pregnancies: Sociodemographic variables, including maternal age on the first day of gestation, receipt of social assistance 1 year before pregnancy, and area of residence on the first day of gestation (urban/rural); Maternal chronic comorbidities during the 6 months prior to pregnancy, hypertension (chronic and pregnancy induced), diabetes (mellitus and gestational), and asthma (all the previous conditions were identified from either diagnoses or disease-specific medications); HIV status in the 6 months prior or during pregnancy using ICD-9 codes 042–044 and 795.8 or ICD-10 codes B20–B24, Z21, and R75; Health care use during the 6 months prior to the first day of gestation, including visits to an infectious disease specialist (yes/no), number of visits to a general practitioner, number of other specialist visits, hospitalizations or emergency department visits, the number of medication use other than antiretrovirals, and number of different prescribers; and follow-up of the current pregnancy by a gynecologist/obstetrician (yes/no). Crude and adjusted odds ratio (aOR) with 95% CI were calculated for overall MCM and for each organ-specific outcome separately using generalized estimating equation models with logit-link function for the binary response and exchangeable correlation structure. The generalized estimating equation model takes into account the multiple pregnancies per woman. For all analyses, the reference category was pregnancies without antiretroviral exposure during the first trimester. Further similar analyses were performed on specific organ system defects.

A sensitivity analysis was also performed within the subgroup of women with a diagnosis of HIV before pregnancy. Although our main analyses were adjusting for maternal HIV diagnosis, we performed the same analyses in this subgroup of women to further determine the impact of maternal HIV on our association between gestational antiretroviral use and the risk of MCM.

Statistical analyses were done using SAS (SAS Institute Inc., Version 9.2; Cary, North Carolina, USA).

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Results

Overall, 214 240 pregnancies met inclusion criteria and were considered (Fig. 1); 198 pregnancies (0.09%) were exposed to antiretrovirals alone or in combinations during the first trimester. The majority of exposure were started before pregnancy (n = 181, 91.4%), and an increasing rate of first-trimester antiretroviral use was seen between 1998 and 2014 (Fig. S1, http://links.lww.com/QAD/B144). The antiretrovirals most frequently used during the first trimester were lamivudine [151 (76.3%)], zidovudine [104 (52.5%)], ritonavir [83 (41.9%)], tenofovir [53 (26.8%)], emtricitabine [41 (20.7%)], abacavir [40 (20.2%)], and lopinavir [40 (20.2%)] (Table S3, http://links.lww.com/QAD/B144).

Fig. 1

Fig. 1

A total of 18 407 infants had at least one MCM; 19 (9.6%) in the antiretroviral-exposed group as compared with 18 388 (8.6%) among the 214 042 pregnancies unexposed to antiretrovirals during the first trimester (Fig. 1). Among the unexposed group, 169 pregnancies were HIV positive and 25 of them had at least one MCM diagnostic (14.8%). The specific MCMs are listed in Table S4, http://links.lww.com/QAD/B144. Table S5, http://links.lww.com/QAD/B144, lists the characteristic of the 343 HIV-positive pregnancies (174 exposed and 169 unexposed-antiretroviral during first trimester). Compared with the non-HIV-positive unexposed pregnancies, the prevalence of MCM was significantly higher in infants of unexposed HIV-positive women (14.8 vs. 8.6%, P = 0.004) but not in infants of exposed HIV-positive women (10.3%, P = 0.41; Fig. 2). First-trimester antiretroviral users were older, more likely to be living in urban areas and be on welfare, have more visits to infectious disease specialists, and more likely to have follow-ups by obstetricians (Table 1). They were more likely to be diabetic and used more medications (other than antiretrovirals) with multiple prescribers (P < 0.05: Table 1). Finally, antiretroviral users were delivering 1 week earlier, and had smaller newborns on average, and had higher prevalence of premanutiry (<37 weeks gestation) and low birth weight (LBW; <2500 g) (all P < 0.0001; Table 1). Further, both antiretroviral-positive antiretroviral-exposed and HIV-positive antiretroviral-unexposed pregnancies had higher prevalence of prematurity and LBW than the reference population (Fig.S2 and S3, http://links.lww.com/QAD/B144). There were no significant differences in gestational age, birth weight, and the prevalence of prematurity and LBW between the two HIV-positive groups regardless of antiretroviral treatment status (Table S5, http://links.lww.com/QAD/B144).

Fig. 2

Fig. 2

Table 1

Table 1

Among cases exposed to antiretrovirals during the first trimester; the most prevalent MCMs were cardiac/circulatory defects (8/19, 42%), and musculoskeletal defects (6/19, 32%; Table 2). After adjustment for potential confounders including maternal age and HIV status, antiretroviral use during the first trimester was not associated with the risk of overall MCM (aOR 0.59, 95% CI 0.33, 1.06; 19 exposed cases; Table 2). However, antiretroviral use during the first trimester was associated with an increased risk of defects of the small intestine (aOR 10.32, 95% CI 2.85, 37.38, P = 0.0004; one exposed case) and other defects of the digestive system (aOR 6.83, 95% CI 2.18, 21.35, P = 0.001; one exposed case; Table 3). There was a trend between the use of antiretrovirals during the first trimester and the risk of defects of the great arteries (aOR 2.92, 95% CI 0.89, 9.54; one exposed case); the risk of other malformations of the heart (aOR 2.42, 95% CI 0.73, 7.99; one exposed case); and the risk of defects of the feet (aOR 3.68, 95% CI 0.35, 38.31; three exposed cases) although none of these comparisons reached statistical significance, which was most likely because of lack of statistical power (Table 3). The median time at diagnosis of MCM was similar between those with in-utero exposure to antiretrovirals and those without (53 days after birth – 25th percentile, 25 days; 75th percentile, 102 days). Table S6, http://links.lww.com/QAD/B144, lists the specific antiretroviral combination exposures for all 198 exposed pregnancies as well as the 19 specific MCM identified among them. The most frequent MCMs were seen with the combination ritonavir/tenofovir/emtricitabine/atazanavir (4/19 newborns with MCMs) and lamivudine/zidovudine/nevirapine (4/14 newborns MCMs); lamivudine alone or in combination were responsible for 11 (11/19) newborns with MCMs. One case of atrial septal defect was found in users of efavirenz in combination with tenofovir and emtricitabine; one case of pyloric stenosis was found with exposure to lamivudine/ritonavir/abacavir/atazanavir.

Table 2

Table 2

Table 3

Table 3

Table 3

Table 3

Twenty-four non-HIV-positive pregnancies used antiretrovirals during the first trimester (Table S7, http://links.lww.com/QAD/B144). Among them, 12 pregnancies had a diagnoses of hepatitis, 10 pregnancies had indications for using antiretroviral for preexposure prophylaxis (PrEP), and two pregnancies had both.

In sensitivity analyses, in the subgroup of women with prepregnancy diagnosis of HIV [169 with no antiretroviral use and 174 with antiretroviral use (Table S4, http://links.lww.com/QAD/B144)], the adjusted risk of MCM associated with antiretroviral use was aOR 0.48 [95% CI 0.22, 1.07; 18 exposed cases (P = 0.07)], which was similar to what was found in the overall study cohort analysis.

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Discussion

The study, performed in a large population-based pregnancy cohort, showed that the use of antiretrovirals, alone or in combinations, during the first trimester was not associated with the risk of overall MCM, which is reassuring. Furthermore, HIV-positive pregnant women that are not treated with antiretrovirals during pregnancy seem to have a higher risk of malformations; this is not seen among those who are treated, which could indicate that the underlying condition puts women at risk and not the treatment. Nevertheless, a signal for an increased risk of the small intestine in newborns exposed to antiretroviral in utero during organogenesis was detected. Given that we only had two exposed cases of small intestine defects, more research and replication are needed. Our study did not find any case of hypospadias, which is consistent with the Centers for Disease Control and Prevention (CDC) and Texas Registry studies [34,35].

Our findings on the risk of overall MCM are consistent with the published literature [13,18,19,25,33–36]. Specifically, studies performed by the European Collaborative Study and the United Kingdom and Ireland surveillance project have not detected an increased risk of MCM after gestational antiretroviral exposure [19,36].

To our knowledge, our study is the only one that used large register-based administrative in combination with clinical databases providing population-based coverage of all Quebec pregnant women meeting eligibility criteria with up to a maximum of 17 years of follow-up, with linkage of data on the individual level, limiting selection bias. We found that infants of untreated HIV-positive pregnant women had significantly higher prevalence of MCM when compared with non-HIV non-antiretroviral-exposed reference (14.8 vs. 8.6%, P = 0.004); infants of antiretroviral-treated HIV-positive women had a similar prevalence of MCM with the reference group (10.3%, P = 0.41), suggesting that the underlying HIV status was potentially responsible for the risk of MCM and not the antiretrovirals per se. To further study the impact of the underlying HIV status on the risk of MCM, we adjusted all our analyses on maternal HIV, and we performed a sensitivity analyses within the subgroup of women with prepregnancy HIV. These analyses gave similar results, which was reassuring. This potential protective effect may further strengthen the overwhelming benefits of antiretroviral therapy in maintaining maternal health as well as the prevention of perinatal HIV transmission [37].

Using the population-based QPC, we were able to obtain accurate information on dispensed medications, without reliance on maternal recall, on a large number of births and mothers, detailed information regarding outcome and potential confounders. Gestational age has been validated [27], decreasing exposure misclassification bias for the studied time window of interest. Physician reports were also prospectively collected, reducing the potential for detection bias. Antiretroviral exposure data and MCM have both been validated against maternal report (medication data) and medical charts (MCM) [31,32]. Even if the use of prescription dispensation data may not reflect actual use, De Jong van den Berg et al.[38] reported that 94% of all drugs dispensed to pregnant women are actually taken. Furthermore, our data on antiretroviral dispensations have been validated against maternal reports and were found to have good positive and negative predictive values [31]. HIV testing is an opt-out program in Quebec; hence, we feel confident that all pregnant women in our study have been tested for HIV, which limits detection bias.

Our study also showed that lower birth weights and shorter gestations as well as higher prevalence of prematurity and LBW were present in the first-trimester antiretroviral-exposed pregnancies compared with the reference population (all P < 0.0001). In this study, the mean gestational age (38.2 week) and the prevalence of prematurity in HIV-positive antiretroviral-exposed group (15.7%) were comparable with other similar studies [15,21,39].

Results of studies on pregnancy outcome and antiretroviral use are inconsistent [39–46], and some data suggest elevated risk of prematurity [39,41,42] and LBW [46]. Discrepant results have been ascribed to the large number of confounding factors, which are not uniformly measured across studies [47], especially the indication for antiretroviral use during pregnancy [48].

To further explore if this difference was related to HIV status itself or antiretroviral medications, we compared the pregnancy outcomes between HIV-positive antiretroviral-exposed and HIV-positive antiretroviral-unexposed groups.

To our knowledge, our study is the only one that compared head-to-head the prevalence of prematurity and LBW among HIV-positive untreated, HIV-positive antiretroviral-treated, and non-HIV-positive non-antiretroviral-exposed general population in a cohort, limiting the confounding by indication bias. Our study suggested that the underlying HIV status, not the antiretroviral medication, was potentially responsible for the risk of higher prevalence of prematurity and LBW. This is consistent with a previous study that showed that HIV status itself was associated with increased risk of prematurity [49].

In this study, 24 non-HIV-positive pregnancies used antiretrovirals during the first trimester. Among them, 12 pregnancies had a diagnoses of hepatitis; 10 pregnancies had indications for using antiretroviral for PrEP and two pregnancies had both. Antiretrovirals have been used to prevent HIV acquisition in women with HIV-infected partners [50–52]. Notably, in the randomized partners PrEP study, 1785 HIV-negative women with HIV-positive male partners had 431 pregnancies over the 3-year follow-up period [53]. There were no significant differences in birth outcome among women using antiretroviral or placebo [53]. However, in this study, there was no antiretroviral used later than 6 weeks into the pregnancy. To extend prevention benefit to the fetus and child, many women extend PrEP use during the periconception period into the pregnancy period. However, currently, there are no data on HIV-negative women throughout pregnancy using the PrEPagent study [54].

On the other hand, to prevent vertical transmission of hepatitis B virus, antiretroviral has been used in late pregnancy [55–57]. Additionally, antiretroviral therapy has been used in childbearing women with chronic hepatitis B and these women may become pregnant. At present, there are no data regarding the safety of antiretroviral therapy in early pregnancy in women with chronic hepatitis B. Thus, future studies could focus on HIV-negative women using PrEP throughout pregnancy or antiretroviral therapy in early pregnancy in women with chronic hepatitis B.

Limitations include missing information on potentially important confounders such as smoking, folic acid, and alcohol intake. Although we were not able to adjust our models for these variables, any exposure misclassification should be nondifferential, resulting in conservative estimates. Although we adjusted for HIV status, we cannot fully rule out residual confounding by indication, such is the case specifically for our analysis on overall MCM. Nevertheless, our sensitivity analysis on the subgroup of women with prepregnancy HIV provided reassurance that confounding was not the most likely explanation for our results; it also adjusted for potential confounders associated with HIV or antiretroviral use such as smoking, alcohol intake, providing further reassurance in our results. Only singletons were considered because of the fact that singleton pregnancies have different adverse pregnancy outcome rates than multiple births [30]. Only livebirths were considered, as is the case in all studies like ours. No adjustment was made for multiple comparisons because analyses were based on hypotheses emanating from previous studies as was done in Sibiude et al.[58]. Although we cannot completely rule out chance finding given the number of comparisons made, exact P values are given for the interpretation of findings using different significance levels. Given the small number of exposed cases in our organ-specific analyses, our estimates might be unstable, which is the case when studying rare outcomes. This is reflected with the wide CIs and the exact P values. In addition, although our cohort included a large sample of pregnancies and newborns, sample size decreased in analyses on specific organ system malformations, resulting in low statistical power for organ-specific analyses. In this study, 19 hypotheses were tested. Using the Bonferroni correction the new critical P value would be 0.05/19 (P ≤ 0.00026) suggesting that most associations calculated lacked statistical power. Our MCM population prevalence may seem somewhat higher than the routinely reported 3–5%, but in fact our rate is consistent with what is expected in the province of Quebec, because of high concentration of genetic risk factors stemming from the ‘founding’ French ancestors [59]. Nevertheless, given that the baseline rate of MCM is similarly higher in the antiretroviral group, it has no impact on the internal validity of our study because it cancels out when comparing the exposed and unexposed groups. Finally, as we considered pregnant women insured by the Prescription Drug Insurance program, whether the results may be generalizability to those insured by private drug insurance is unclear. However, validation studies have shown that pregnant women receiving medication insurance from Quebec's public system have similar characteristics and comorbidities than those who have private medication insurance. Although SES might differ between the two groups, it does not affect internal validity given that all have similar SES status [60].

In conclusion, antiretroviral use during the first trimester of pregnancy was not associated with the risk of overall MCM but may be associated with an increased risk of defects of the small intestine. In addition, first-trimester antiretroviral therapy may be protective against MCMs in HIV-positive women. Although our results are reassuring, our findings warrant further investigations. Future studies could focus on HIV-negative women using PrEP throughout pregnancy or antiretroviral therapy in early pregnancy in women with chronic hepatitis B.

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Acknowledgements

All authors conceived and designed this study. Data were acquired by A.B. A.B. and O.S. carried out the statistical analysis and all authors interpreted the data. The manuscript was drafted by A.B. and J-P.Z.; all authors were involved in the critical revision of this and approval of the final manuscript.

The study was funded by the Canadian Institutes of Health Research (CIHR) – CAN-AIM grant; Fonds de la recherche du Québec – Santé (FRQ-S) – Réseau de recherche sur les médicaments. A.B. is the holder of a FRQ-S research chair on Medications and Pregnancy. J-P.Z. is the recipient of a Quebec–China postdoctoral fellowship from the CIHR. S.B. holds a FRQS senior career award.

The (CIHR) – CAN-AIM had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

antiretroviral; HIV; major congenital malformations; pregnancy; Quebec Pregnancy Cohort

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