Pregnancy outcomes following exposure to efavirenz based antiretroviral therapy in indian women.

OBJECTIVES: Mother-to-child transmission of HIV has witnessed a significant reduction due to effective antiretroviral therapy (ART). Efavirenz has been introduced as a part of ART since last few years in the national Prevention of Parent to Child Transmission (PPTCT) program for pregnant women living with HIV. However, data related to adverse pregnancy outcomes associated with efavirenz-based ART are limited in the Indian scenario. The present study evaluated pregnancy outcomes in HIV-infected pregnant women who were given efavirenz-based ART during pregnancy.
MATERIALS AND METHODS: It is a retrospective, observational, analytic study carried out at a referral hospital in Western India. Collection of data was done for a period of 5 years, and various adverse outcomes were studied which included preterm delivery, low birth weight (LBW), stillbirths, congenital anomaly, and neonatal death.
RESULTS: This study showed a preterm birth rate of 19% and LBW in 36% of cases. There was no significant association with congenital anomaly, stillbirth, or neonatal death.
CONCLUSION: There was an association of exposure to efavirenz with an increased incidence of adverse pregnancy outcomes, especially LBW infants. This study emphasizes the requirement of large prospective studies to investigate fetomaternal outcomes in pregnant women exposed to efavirenz.

Introduction

The prevalence of HIV in India is 0.22%, which is considerably low. The highest number of cases is reported in high-risk groups and the distribution shows significant geographic variation. However, India has the third highest load of HIV in the world in terms of absolute numbers amounting to 2.14 million people living with HIV. India reports nearly 87,000 new infections annually, and AIDS contributes to approximately 69,000 deaths per year. Nearly 22,000 out of 29 million pregnancies are reported in HIV-infected women annually.

Parent-to-child transmission of HIV still remains a major concern. This vertical transmission can occur either during antenatal period, during labor, or through breastfeeding. Without any intervention, mother-to-child transmission (MTCT) risk is reported to be as high as 40%. Antiretroviral therapy (ART) for pregnant women has been successful in reducing the risk of transmission considerably up to 2%, which has resulted in reducing maternal and infant mortality.[1] ART is being used in pregnant women living with HIV as per the treatment guidelines of the World Health Organization (WHO) published in 2013.[2]

These ARTs are given in various combinations in different treatment regimens to improve efficacy and prevent drug resistance. The preferred regimen in pregnancy constitutes of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and either a non-NRTI or protease inhibitor. Most of the pregnant patients are being treated with the recommended first-line drug regimen (tenofovir + lamivudine + efavirenz [TLE]) as per the recent guidelines. The National PPTCT Program had launched the new guidelines in August 2012 which was updated in October 2018. The national program recommends lifelong ART for all pregnant and breastfeeding women living with HIV. All pregnant women infected with HIV should be given a single pill of triple-drug fixed-dose combination (FDC, TLE), irrespective of clinical stage or CD4 count for preventing transmission to the child. Under these guidelines, the baby born to a HIV-positive mother is also given syrup nevirapine for a minimum of 6 weeks after birth.[3]

The safety of ART in pregnant women and its effects on the child has been established over the years. In spite of the proven benefits of ART in reducing vertical transmission of HIV, it has been associated with a potential risk of adverse effects due to placental transfer and altered metabolism of drugs.[4]

Many earlier studies have demonstrated adverse effects of ART on pregnancy outcome. These described adverse outcomes are mainly premature birth, low birth weight (LBW), congenital malformation, fetal growth restriction (FGR), and neonatal mortality.[56]

The exposure to efavirenz during conception and first trimester was previously linked with development of neural tube defects (NTDs) in fetus. However, multiple studies have shown that the risk of NTD associated with efavirenz is similar to the risk in general population, for which efavirenz has continued to be an integral part of ART in pregnant women living with HIV.[7] Review of the available data has dismissed the concerns of increased birth defects and significant toxicities associated with efavirenz exposure during conception or early pregnancy. However, the data available regarding the effect of efavirenz on pregnancy outcome in the Indian scenario are limited. Therefore, we carried out a study with an objective of evaluation of pregnancy outcomes in women who were continued on efavirenz-based ART during pregnancy.

Materials and Methods

Study design

A retrospective, observational study was carried out based on retrospective evaluation of singleton pregnant women infected with HIV who had conceived spontaneously and their infants at a referral hospital in Western India from January 2014 to December 2018.

Inclusion criteria

All pregnant women with HIV-positive status and in the WHO Clinical Stage I of the disease

Women who were started on ART (TLE regimen) either before pregnancy or in the first trimester of pregnancy (<12 weeks period of gestation). TLE regimen was defined as FDC of tablet tenofovir 300 mg, tablet lamivudine 300 mg, and tablet efavirenz 600 mg in a single pill once a day.

Exclusion criteria

All those pregnant women started on any Highly Active Antiretroviral Therapy (HAART) other than TLE regimen

Women with HIV-positive status and belonging to clinical stages other than stage I of the disease

Women with any other preexisting comorbidities

Women who developed pregnancy-related complications such as hypertensive disorders, gestational diabetes mellitus, or anemia (Hb <9 g%) were also excluded to minimize the effect of confounding factors on birth weight of the neonate.

Data were collected about the pregnant women and newborn babies from their clinical files. Sociodemographic, clinical, and laboratory characteristics and obstetric history which included previous stillbirth and preterm birth were also collected. Strict confidentiality was maintained about any data collected during the study.

Outcomes

The following parameters were analyzed: epidemiological and clinical characters of pregnant women, route of delivery, vertical transmission of HIV, and neonatal parameters (Apgar score, birth defects, and neonatal disease). The following pregnancy outcomes were studied: preterm birth (delivery before 37 completed weeks and very preterm as before 34 weeks), stillbirth, and LBW (defined as birth weight <2500 g). Period of gestation of the fetus was calculated using the date of the last menstrual period and dating ultrasound scan. If calculated period of gestation by the last menstrual period and ultrasound had a difference of more than 2 weeks, the ultrasound dating was used.

Statistical analysis

Prevalence of adverse pregnancy outcomes in our study population was calculated with 95% confidence intervals (CIs) using suitable statistical tests.

Ethical clearance

This study was carried out after clearance from the institutional ethics committee (Ref. No.: IEC/Oct/2019 dated October 18, 2019).

Results

During the study period, a total of 58 women conceived on efavirenz-based ART (TLE regimen). However, 54 women fulfilled the inclusion criteria and were included in the study.

Baseline characteristics

The baseline demographic characteristics before conception are tabulated in Table 1. The median age of the pregnant patients infected with HIV was 26 years. Only two patients were illiterate and most of the patients had completed secondary schooling (43 out of 54). Most of the women were homemakers (50 out of 54) and only 7% (4 out of 54) were employed. 18 out of 54 patients were primigravida women (33%) of whom 16 were detected to have HIV during routine screening in the first trimester of pregnancy. 31 patients were carrying their second pregnancy out of which 28 were on ART before conception. Two patients were detected with HIV during their second pregnancy and one woman was not on ART before pregnancy though detected to have HIV earlier. A total of 34 patients (63%) were on ART before conception and 20 patients were started during the first trimester. Only five patients had CD4+ count ≤200 cells/μL.

Table 1

Characteristics of study population

Characteristic	Frequency
Median age	26
Educational status
Illiterate	2
Primary school	9
Secondary school	36
College	7
Occupation
Employed	4
Unemployed	50
Parity
0	18
1	31
>1	5
Initiation of ART
During pregnancy	20
Before pregnancy	34
CD4+ count ≤200 cells/µL
Yes	5
No	49

ART=Antiretroviral therapy

Pregnancy outcome

The details of pregnancy outcome and mode of delivery are summarized in Table 2. Out of the 54 women, eight women underwent medical termination of pregnancy in the first trimester due to various reasons but none for fetal anomaly. Four women had spontaneous abortion out of which two were in the second trimester. No abortus showed any congenital anomaly. Only one intrauterine death was recorded in our study which occurred at 32 weeks period of gestation. The cause of intrauterine death could not be established. Postmortem examination of the fetus had ruled out any congenital anomaly. Out of the 41 live births (76%), 22 women had vaginal delivery (54%) and the rest 19 women underwent cesarean delivery.

Table 2

Details of pregnancy and delivery

	n=54
Pregnancy outcome
MTP	8
Abortion	4
Stillbirth	1
Live birth	41
Type of delivery
Normal	22
Cesarean	19

MTP=Medical Termination of Pregnancy

Among 41 participants who had live births, 10 (19%) pregnancies were preterm deliveries (95% CI: 18.92–19.08) and 2 (3.7%) were very preterm deliveries [Table 3]. Among 42 babies for whom birth weight was available, 15 (36%) live births were LBW infants (95% CI: 35.91–36.09). Only one case of MTCT was reported. No neonatal death was recorded in our study population. No congenital anomaly was detected in our study. No correlation of baseline CD4 count with adverse pregnancy could be found in our study.

Table 3

Adverse pregnancy outcome

Outcome	Total (%)
Stillbirth	1 (2)
Preterm delivery	10 (19)
Low birth weight	15 (36)
Neonatal death	Nil
Congenital anomalies	Nil

Discussion

This study demonstrates the fact that only 66% of the mothers were aware of their HIV status before pregnancy which mandates the need for better health education and preconceptional counseling in the Indian population to reduce the burden of HIV. Most of the women are married and homemakers. The study also demonstrates low prevalence of unmarried women, elderly gravida, alcohol, illegal drug, and tobacco users in the Indian scenario in contrast to western countries.

In this study, 89% of pregnancies had resulted in live birth (41 out of 46) when medical termination of pregnancy was excluded. This is similar to the live birth rate reported in a study conducted in Congo by Bisio et al. (31 out of 35 cases –88.5%).[8] The cesarean delivery rate in our study was 46% which was similar to 50% as reported in an American study conducted by Haeri et al.[9]

Preterm birth rate of 19% was observed in this study. It was at par with the prevalence rate reported in many studies evaluating effect of ART on pregnancy from Europe (14.7%–16.0%),[1011] Africa (13.3%–21.8%),[1213] Brazil (11.5%–21.7%),[141516] and the United States (17.0%–19.9%).[91718] However, the preterm birth rate was slightly higher when compared to that of HIV-infected pregnancies on efavirenz-based ART (19% vs. 12.9%).[8]

Our study showed a 36% prevalence of LBW which was higher in comparison to the 10%–18% prevalence reported from developed countries,[18] 9.0% from Brazil,[19] and 14.2% of a study from Latin America.[20] However, it was corresponding to the reported prevalence in studies from Europe and Africa.[1013] The prevalence of LBW was similar when compared to another study in Congo which evaluated HIV-infected pregnancies on efavirenz-based ART (36% vs. 33%).[8] The prevalence of LBW in the study group was compared with that of the women with HIV-negative status who delivered in the same hospital during the study period. There was a higher prevalence of LBW in the study group (36% vs. 27%). LBW is often related to FGR in developing countries which report a higher prevalence in contrast to lower prevalence in developed countries, where it is mainly due to preterm birth. Poor socioeconomic status, high-risk behaviors such as smoking and alcohol consumption, and medical diseases associated with pregnancy such as anemia, hypertension, and pregestational diabetes are well-known risk factors of preterm delivery as well as LBW babies, irrespective of HIV status. Such factors can confound the risk of preterm birth and FGR. Hence, it becomes difficult to differentiate the contribution of HIV independently on growth of fetus from that of many other risk factors which may have geographical variations. To study these factors independently, we would require a larger study population as these risk factors lead to creation of many subgroups.[21]

Our study demonstrated increased percentage of LBW infants and higher cumulative negative pregnancy outcomes. This finding does not match with the earlier studies which had suggested no increased risk of adverse outcomes after efavirenz exposure in pregnancy. In our study, no birth defects were observed among women exposed to TLE at conception. In a systematic review, the occurrence of NTDs was found to be low (0.05%) which included 2026 cases of efavirenz exposure in the first trimester and the incidence was similar to that in the general population.[7] Given the small size of our cohort and low overall incidence of birth defects (2%–3%), our results do not exclude a possibility of teratogenicity associated with the exposure to efavirenz. However, continued prospective surveillance is recommended due to low incidence of central nervous system anomalies in general populace and relatively limited exposure to efavirenz during pregnancy at present.

In our study, the analysis of pregnant women on TLE supports the hypothesis that efavirenz has a detrimental effect on pregnancy outcome with a significant effect on birth weight.

Limitations

The most significant limitation of our study was the limited sample size. Due to this, a multivariate analysis for important risk factors in the preterm birth and FGR determination could not be done. A second major limitation of our study is that all data were obtained through a retrospective analysis and the newborn data were restricted to the neonate's postdelivery hospitalization period and who were followed up at the same hospital. For this reason, minor and internal birth defects that take time to manifest may be underreported. Therefore, we have abstained from reporting on long-term data.

Furthermore, larger and multicenter studies on pregnant women with HIV infection are required to answer the interaction between HIV, use of ART, and pregnancy outcomes such as preterm birth and FGR. In spite of these limitations, authors are of the opinion that the results of the present study are significant in the background of limited Indian data regarding preterm birth and FGR prevalence in HIV-infected women on TLE-based ART.

Conclusion

Our results are not fully reassuring in contrast to earlier studies, as they suggest an association of exposure to efavirenz-based ART with an increased incidence of LBW infants. These observations need to be validated by large prospective cohort studies. We recommend that antenatal examination in HIV-positive pregnant women should include careful assessment of fetal growth by clinical examination and ultrasonography. However, the advantage of ART on maternal well-being and perinatal transmission outweighs these concerns and the present regimen of ART should not be changed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.