Adverse Pregnancy Outcomes Among Women with 
Human Immunodeficiency Virus Taking Isoniazid 
Preventive Therapy During the First Trimester
Amita Gupta,1, Michael D. Hughes,2 Jorge Leon Cruz,2 Anchalee Avihingsanon,3 Noluthando Mwelase,4 Patrice Severe,5 Ayotunde Omoz-Oarhe,6

Gaerolwe Masheto,6 Laura Moran,7 Constance A. Benson,8 Richard E. Chaisson,1 and Susan Swindells9, ; for the ACTG 5279 BRIEF-TB study team
1Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; 2Center for Biostatistics in AIDS Research, Harvard TH Chan School of Public Health, 
Boston, Massachusetts, USA; 3HIV-NAT, Thai Red Cross AIDS Research Centre and Center of Excellence in Tuberculosis, Faculty of Medicine Chulalongkorn University, Bangkok, Thailand; 
4Department of Medicine, University of Witwatersrand, Johannesburg, South Africa; 5Clinical Trials Unit, Les Centres GHESKIO, Port-au-Prince, Haiti; 6Botswana Harvard AIDS Institute Partnership, 
Clinical Trials Unit, Gaborone, Botswana; 7Public Health and Scientific Research Unit, Social & Scientific Systems, a DLH Company, Silver Spring, Maryland, USA; 8Division of Infectious Diseases, 
University of California San Diego School of Medicine, La Jolla, California, USA; and 9Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA

Background. Isoniazid preventive therapy (IPT) is recommended for tuberculosis prevention yet data on the safety of first- 
trimester pregnancy exposure are limited.

Methods. Planned secondary analysis in a TB prevention trial of adverse pregnancy outcomes among participants assigned to 
9-month IPT who became pregnant during (IPT-exposed) or after (unexposed) IPT. Regression models compared binary outcomes 
of a composite adverse outcome (any non-live birth, excluding induced abortion); preterm delivery <37 weeks; and low birth weight 
<2500 g) among exposure groups. Models were adjusted for latent TB infection, maternal age, CD4 count, and antiretroviral 
therapy (ART).

Results. In total, 128 participants had a known pregnancy outcome; 39 IPT-exposed and 89 unexposed. At pregnancy outcome, 
ART use was lower in IPT-exposed (79%) than unexposed women (98%). Overall, 29 pregnancies ended in a composite adverse 
outcome (25 spontaneous abortions, 2 stillbirths and 2 ectopic pregnancies), 15 preterm deliveries, and 10 infants with low 
birth weight. IPT was associated with the composite adverse outcome adjusting for covariates at enrollment (adjusted relative 
risk [aRR] 1.98; 95% confidence interval [CI] 1.15, 3.41), but the effect was attenuated when adjusted for covariates at 
pregnancy outcome (aRR 1.47; 95% CI .84, 2.55); IPT was not associated with preterm delivery (relative risk [RR] 0.87; 95% CI 
.32–2.42) or low birth weight (RR 1.01; 95% CI .29, 3.56).

Conclusions. First-trimester IPT exposure was associated with nearly two-fold increased risk of fetal demise, mostly 
spontaneous abortion, though the association was attenuated when adjusted for covariates proximal to pregnancy outcome 
including ART use. Further study is needed to inform TB prevention guidelines.

Keywords. TB preventive therapy; isoniazid; HIV infection; pregnancy; adverse pregnancy outcome.

Provision of isoniazid prevention therapy (IPT) is a key global 
strategy for reducing tuberculosis (TB) and death in the context 
of human immunodeficiency virus (HIV) [1]. The World 
Health Organization (WHO) currently recommends IPT with 
antiretroviral therapy (ART) for all people with HIV, including 
during pregnancy [1, 2]. However, this guidance is primarily 
supported by safety and efficacy data from nonpregnant popu-
lations. A systematic review by Sobhy et al found that 

tuberculosis in pregnancy was associated with 4-fold increased 
maternal mortality, 9-fold increased risk of miscarriage, 2-fold 
risk of preterm birth. 2-fold risk of low term birth, and 4-fold 
increased risk of perinatal death [3], Pregnant women continue 
to be excluded from most IPT trials [4] and the limited studies 
of IPT during pregnancy report conflicting associations be-
tween antenatal exposure and adverse pregnancy outcomes 
[5, 6]. Pregnancy increases the risk of TB [7], and maternal 
TB is linked to poor maternal [8] and infant outcomes 
[9, 10], yet without high quality data, the safety of isoniazid 
exposure during pregnancy is uncertain. Data on IPT exposure 
during conception and early pregnancy are particularly limited.

Two recent systematic reviews identified inconsistent results 
among non-randomized and randomized studies comparing 
adverse pregnancy outcomes among women with HIV infection 
with and without antenatal IPT exposure [5, 6]. A recent large 
programmatic observational study included in these two re-
views found that women with HIV who received IPT during 
pregnancy were less likely to experience poor pregnancy 

Received 28 June 2023; editorial decision 15 September 2023; published online 28 
September 2023

Presented in part: CROI March 6–10, 2021, virtual. Abstract 178.

Correspondence: S. Swindells, University of Nebraska Medical Center, 804 S 52nd St, 
988106 Nebraska Medical Center, Omaha, NE 68198-8106 (sswindells@unmc.edu); 
A. Gupta, Division of Infectious Diseases, Johns Hopkins University School of Medicine, 
1830 East Monument Street, Baltimore, MD 21205 (Agupta25@jhmi.edu).

Clinical Infectious Diseases® 2024;78(3):667–73 
© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases 
Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@ 
oup.com
https://doi.org/10.1093/cid/ciad583

Isoniazid Adverse Pregnancy Outcomes • CID 2024:78 (15 March) • 667

Clinical Infectious Diseases                                          

M A J O R  A R T I C L E

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https://orcid.org/0000-0001-7036-2718
https://orcid.org/0000-0001-5826-6037
mailto:sswindells@unmc.edu
mailto:Agupta25@jhmi.edu
https://doi.org/10.1093/cid/ciad583


outcomes than those who did not receive IPT [10]. This protec-
tive effect was primarily identified among women starting IPT 
during the second and third trimesters; no effect was identified 
among women starting IPT in the first trimester. In contrast, the 
multi-country International Maternal Pediatric Adolescent 
AIDS Clinical Trials network TB APPRISE, a randomized 
double-blind placebo controlled trial (IMPAACT P1078), en-
rolled women during the second or third trimesters and docu-
mented an increased risk of composite adverse pregnancy 
outcomes with antenatal IPT exposure, including stillbirth, 
spontaneous abortion and low birth weight [11]. Theron et al 
subsequently confirmed this increased risk of second- and 
third-trimester IPT exposure on composite adverse outcomes 
and low birth weight in a follow-up analysis, which identified 
and adjusted for multiple confounders of adverse pregnancy 
outcomes [12]. IPT during pregnancy was also associated with 
adverse longer term growth outcomes in infants born to partic-
ipants receiving IPT during pregnancy compared to postpartum 
(especially among male infants) [13].

To address this knowledge gap, we conducted a pre-specified 
secondary analysis among women who became pregnant dur-
ing the AIDS Clinical Trials Group Brief Rifapentine- 
Isoniazid Evaluation for TB Prevention trial (ACTG A5279 
BRIEF-TB). This multi-country, randomized trial assessed 
standard nine-month IPT versus a 1-month isoniazid plus rifa-
pentine regimen (1HP) in adolescents and adults with HIV in 
TB endemic settings [14]. Here, we describe and compare a 
composite adverse pregnancy outcome (any non-live birth) 
and individual adverse outcomes (preterm delivery before 37 
weeks gestational age and low birth weight less than 2500 g) 
among trial participants with an index pregnancy during IPT 
(IPT-exposed) or after IPT completion (unexposed). No preg-
nancies occurred during receipt of 1HP. The results provide 
data to enhance our understanding of the potential risks of an-
tenatal isoniazid as we advance the agenda to inform global 
health policy for women of reproductive age with HIV.

METHODS

Study Design and Procedures

The ACTG 5279 BRIEF-TB trial was an open-label, random-
ized noninferiority trial of a standard 9-month IPT regimen 
(IPT) and a weight-based 1-month isoniazid plus rifapentine 
regimen (1HP) for TB prevention among people with HIV 
(NCT 01404312). The trial was conducted from May 2012 to 
November 2017 at multiple study sites across 10 countries 
(Botswana, Brazil, Haiti, Kenya, Malawi, Peru, South Africa, 
Thailand, USA, and Zimbabwe) with TB prevalence more 
than 60 cases per 100 000 population. Details of the trial design 
and conduct have been previously described [14 ]. The protocol 
enrolled adolescents and adults aged 13 years or older with HIV 
and no evidence of active TB. Females of reproductive potential 

(had menses within the preceding 24 months or had not under-
gone surgical sterilization, such as hysterectomy, bilateral oo-
phorectomy, or bilateral tubal ligation) were required to have 
a negative serum or urine pregnancy test within 7 days before 
enrollment and were required to use 1 reliable non-hormonal 
form of contraceptive (ie, condoms, with a spermicidal agent; 
a diaphragm or cervical cap with spermicide; or an intrauterine 
device [IUD]) while receiving RPT and for 6 weeks after stop-
ping this drug. Evidence of latent TB infection (LTBI) was not 
required prior to study enrollment, as participants all had HIV 
and lived in high TB burden countries but was requested at en-
rollment by TB skin testing or interferon-gamma release assay 
(IGRA). Participants began IPT or 1HP immediately after ran-
domization; all participants received pyridoxine with isoniazid 
to minimize side effects. Antiretroviral therapy (ART) was lim-
ited to the use of efavirenz or nevirapine for the first month of 
trial participation because of concerns about drug-drug inter-
actions with rifapentine, with any other ART regimen permit-
ted after the first month. Follow-up visits were at weeks 2, 4, 8, 
12, 16, 20, 24, and 36, then every 12 weeks starting at week 48 
and continued until 3 years after the last participant enrolled.

This planned secondary analysis included all female partici-
pants who were randomized to standard IPT (300 mg of isoni-
azid daily for 36 weeks), became pregnant during the trial and 
had a known pregnancy outcome by the end of trial follow-up. 
We excluded participants assigned to 1HP because no pregnan-
cies occurred during 1HP, possibly due to the contraceptive re-
quirement surrounding rifapentine use. The A5279 protocol 
required pregnancy testing as indicated during IPT (ie, through 
week 36) but not after IPT completion. Women who experi-
enced pregnancy during the trial could continue IPT and 
were encouraged to continue study participation and complete 
evaluations per the schedule of events. All pregnancy outcomes, 
including adverse events among mothers and infants, were re-
corded using a dedicated Case Report Form. Pregnancies that 
occurred on study in female participants receiving ART were 
reported to the Antiretroviral Pregnancy Registry.

Ethical Approval

All participants provided written informed consent at enroll-
ment. The trial was approved by local and collaborating insti-
tutional review boards.

Isoniazid Exposure and Study Outcomes

The pregnancy outcome analysis was restricted to the first preg-
nancy experienced by each participant during the trial. 
Exposure was evaluated using a combination of computerized 
and manual review. A pregnancy was considered IPT-exposed 
if a positive pregnancy test, pregnancy outcome, or the estimat-
ed date of conception (based on gestational age at birth) oc-
curred on or before the date of the final isoniazid dose 
(definite exposure), or if the interval between the pregnancy 

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event and the final isoniazid dose was close but could not be de-
finitively determined (possible exposure). A pregnancy was 
considered unexposed if the pregnancy outcome occurred 
more than 45 weeks after the date of the final isoniazid dose 
or within 45 weeks of the final dose and manual review deter-
mined that the pregnancy event was outside of the isoniazid ex-
posure window.

We defined a composite adverse pregnancy outcome as any 
event resulting in a non-live birth other than induced abortion. 
This included spontaneous abortion (fetal demise before 20 
weeks gestational age), ectopic pregnancy, and stillbirth (fetal 
demise at or beyond 20 weeks gestational age). An extended 
composite adverse outcome that included induced abortion 
was also used in the analysis. Preterm delivery (delivery before 
37 weeks gestational age) and low birth weight (< 2500 g) were 
assessed among live births. Measured confounding variables 
were LTBI status at enrollment and maternal age, CD4 count 
(cells per microliter), and ART use at enrollment and proximal 
to pregnancy outcome.

Statistical Analysis

Maternal covariates were summarized using descriptive statis-
tics and compared across exposure groups using Wilcoxon 
rank-sum and Fisher’s exact tests, as appropriate. The associa-
tion between isoniazid exposure and binary adverse pregnancy 
outcomes was evaluated using Poisson regression models with 
estimation of standard errors using robust methods [15]. 
Models were adjusted for potential confounders at study enroll-
ment and separately for the same variables measured proximal 
to pregnancy outcome.

RESULTS

The BRIEF-TB trial enrolled 1614 nonpregnant females with 
HIV, including 812 assigned to IPT. No women became preg-
nant while taking or within 6 weeks of completing rifapentine 
and isoniazid (1HP), so women in this arm of the trial were not 
analyzed further. Among the 812 women assigned IPT, 136 
(17%) became pregnant during the trial period, including 12 
who became pregnant twice. We excluded 5 participants who 
were lost to follow-up and 3 who were still pregnant at the 
end of the trial. The first pregnancies of the remaining 128 
participants were included in this analysis, yielding 39 
IPT-exposed and 89 unexposed pregnancies (Figure 1). All 
were singleton pregnancies, and except for ART use, maternal 
characteristics were similar among exposure groups at enroll-
ment and proximal to pregnancy outcome (Table 1). Overall, 
participants were predominantly recruited from sub-Saharan 
Africa (70% of 128); at enrollment, median age was 29 years, 
median CD4 count was 534 cells per microliter, and 35% 
were taking ART. 20% had positive test results for LTBI, but 
a shortage of reagents limited TB skin testing. At pregnancy 

outcome, median age was 31.5 years (interquartile range 
[IQR] 27.1, 36.2), and median CD4 count was 552 cells per mi-
croliter (IQR 415, 706). Compared to the unexposed group, 
fewer IPT-exposed participants were receiving ART at preg-
nancy outcome (79% vs 96%, P = .007), and the ART regimen 
was less likely to include efavirenz at enrollment (23% vs 33%, 
P = .010) and pregnancy outcome (64% vs 87%, P = .006).

Isoniazid Exposure

By definition, IPT exposure always occurred during the first tri-
mester (all IPT-exposed pregnancies were conceived while tak-
ing isoniazid); a smaller proportion of participants also had 
second-trimester exposure, and relatively few had third- 
trimester exposure. Based on the trial data collected, duration 
of IPT exposure could not be estimated for pregnancies that 
ended in a composite adverse outcome or induced abortion. 
Overall, 19 of 39 (49%) women completed IPT while pregnancy 
was ongoing, 9 (23%) discontinued IPT early (6 due to preg-
nancy, 2 due to non-compliance, and 1 withdrew consent), 8 
(21%) had a pregnancy outcome while taking IPT (6 spontane-
ous abortions and 2 induced abortions), and 3 (8%) had possi-
ble early exposure (Table 1). We were able to estimate IPT 
exposure duration during pregnancy for the 19 (of 23) live 
births for whom data on gestational age at delivery was avail-
able; exposure duration ranged from 5.7 to 34.3 weeks with a 
median duration of 14.7 weeks (IQR 7.3, 24.3).

Adverse Pregnancy Outcomes

A total of 35 pregnancies (27% of 128) ended in a non-live birth 
outcome, including 25 spontaneous abortions (fetal demise be-
fore 20 weeks gestational age), 6 induced abortions, 2 stillbirths 
(fetal demise at or beyond 20 weeks gestational age), and 2 ec-
topic pregnancies. Aside from ectopic pregnancy, the propor-
tion of each individual outcome was approximately 2-fold 
higher in IPT-exposed than unexposed pregnancies, and a 
greater proportion of IPT-exposed than unexposed pregnan-
cies experienced the composite adverse outcome which exclud-
ed induced abortions (33% vs 18%), primarily spontaneous 
abortions (Figure 2). In regression models, antenatal IPT was 
associated with the composite adverse outcome in unadjusted 
analysis (relative risk [RR] 1.85; 95% confidence interval [CI] 
.99, 3.47; P = .054) and analysis adjusted for maternal covari-
ates at enrollment (adjusted relative risk [aRR] 1.90; 95% CI 
1.01, 3.54; P = .04). The effect was attenuated in separate anal-
ysis adjusted for the same covariates measured proximal to 
pregnancy outcome, largely driven by ART use, which in-
creased substantially between study entry and pregnancy out-
come (aRR 1.45; 95% CI .75, 2.80; P = .27, Table 2). We 
obtained a similar pattern of results in 2 separate analyses: 1 
that excluded pregnancies ending in induced abortion from 
the risk set, and 1that included induced abortions in the ex-
tended composite adverse outcome (Table 2).

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With respect to individual adverse outcomes among live births 
(n = 93), 68 had data on gestational age at delivery (20 
IPT-exposed and 48 unexposed), and 74 had data on birth weight 
(22 IPT-exposed and 52 unexposed). IPT-exposed and unexposed 
participants had similar proportions of preterm delivery (20% vs 
23%) and low birth weight (14% vs 13%) (Figure 2). Antenatal IPT 
was not significantly associated with either outcome in unadjusted 
regression models (RR 0.87; 95% CI .32, 2.42 for preterm delivery 
and RR 1.01; 95% CI .29, 3.56 for low birth weight); adjusted anal-
ysis was not done given the small number of events (15 preterm 
deliveries and 10 infants with low birth weight; Table 2).

DISCUSSION

This secondary analysis of the BRIEF-TB trial shows a nearly 
2-fold increased risk of fetal demise with IPT exposure at concep-
tion and continuing into at least the first trimester of pregnancy, 
which was largely driven by spontaneous abortions. However, 
there was no significant association between exposure starting 
during the first trimester and preterm delivery or low birth 
weight. Overall, our results complement the TB-APPRISE trial 
[11, 12], which documented increased adverse pregnancy out-
comes with second- and third-trimester IPT exposure and pro-
vides possible evidence of a negative impact of isoniazid 
during conception and early pregnancy. The high incidence of 
spontaneous abortion suggests the need for contraception coun-
seling, as women with HIV of reproductive potential may choose 
to take measures to avoid pregnancy while taking extended reg-
imens isoniazid or isoniazid-containing regimens.

Our study is generally complementary to a sub-analysis of 
the TB-APPRISE trial, which confirms the negative impact of 
antenatal IPT exposure later in pregnancy among women 
with HIV [12]. After adjustment for multiple confounders (ma-
ternal age at delivery, CD4 quartile, plasma HIV RNA, hepatitis 
B surface antigen status, timing of ART initiation, mid-upper 
arm circumference, IGRA status, twin vs singleton pregnancy, 
current smoking status, noninfectious pregnancy complica-
tions, infectious pregnancy complications, and hospitaliza-
tion), Theron et al report 62%–74% increased odds of 3 
composite adverse outcomes, which include at least fetal de-
mise, preterm delivery, and low birth weight. Although this ef-
fect was independently driven by low birth weight (adjusted 
odds ratio [aOR] 1.58, 95% CI 1.02, 2.46), antenatal IPT had 
an increased odds of perinatal death (fetal demise or early neo-
natal mortality), but this did not reach statistical significance 
(aOR 1.84, 95% CI .87–3.85). Notably, the TB-APPRISE trial 
included women with second- and third-trimester isoniazid ex-
posure (the protocol excluded pregnant women at < 14 weeks 
of gestation) so the vast majority of fetal demise was due to still-
births, whereas our analysis primarily included women with 
first-trimester exposure (IPT-exposed pregnancies were con-
ceived during 36-week IPT), and the majority of fetal demise 
was due to spontaneous abortions (fetal demise < 20 weeks ges-
tation). The effects of IPT exposure on fetal demise appear to 
vary by trimester exposure with spontaneous abortions appear-
ing to be increased when exposure occurs during the first tri-
mester, whereas stillbirths appearing more likely with second 
and third trimester exposure. Animal studies also provide 

Figure 1. CONSORT diagram of female participants enrolled in BRIEF-TB. Abbreviations: HIV, human immunodeficiency virus; IPT, isoniazid.

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evidence for an embryocidal effect of isoniazid, documenting 
small litter sizes among mice exposed to high concentrations 
of isoniazid during pregnancy [16].

In contrast to our findings and those from the TB-APPRISE tri-
al, a large retrospective study of programmatic data among preg-
nant women with HIV in South Africa [17] provided evidence for 
protective effect on adverse pregnancy outcomes of IPT during 
the second and third trimesters with no effect of exposure in the 
first trimester. Overall, combining across trimesters of initial 
IPT exposure, Kalk et al found antenatal IPT to be protective 
against adverse pregnancy outcomes (composite of spontaneous 

abortion, stillbirth, low birth weight or neonatal death). 
Consistent with our findings, this effect appeared to be driven 
by fetal demises. Further analysis according to trimester of start 
of IPT exposure showed significantly reduced risk in women 
who initiated IPT during the second or third trimester compared 
to unexposed women (aOR 0.71 95% CI .65, .79) but no difference 
in risk in women who initiated IPT during the first trimester com-
pared to unexposed women in both unadjusted and adjusted anal-
yses (aOR 1.04 95% CI .94, 1.16). It is unclear why findings related 
to first trimester exposure differ from this study. Possibilities in-
clude prospective versus retrospective study design which may in-
fluence ascertainment of outcomes particularly spontaneous 
abortions, and differences in populations studied. Perhaps of 
note, women in the study of Kalk et al had much more extensive 
antiretroviral exposure (77% were on ART prior to pregnancy for 
a median 175 months) than in our study (35% were on ART at en-
rollment, increasing to 91% at pregnancy outcome). In this re-
spect, our findings showed attenuation of effect when adjusted 
for variables assessed proximal to pregnancy outcome including 
antiretroviral status.

Two small secondary analyses have assessed outcomes 
among participants who were inadvertently exposed to IPT dur-
ing randomized clinical trials. In contrast to our study, Taylor 
et al reported reduced risk of a composite adverse outcome 
(spontaneous abortion, stillbirth, preterm delivery, low birth 
weight, neonatal death, or congenial abnormality) among 
HIV-infected women exposed to long-term IPT in Botswana 
(aOR 0.6; 95% CI, .3–1.1) [18]. Most IPT-exposed pregnancies 
(102 of 103) had first-trimester exposure, including a number of 
pregnancies conceived during IPT (median IPT initiation was 
341 days [48 weeks] before pregnancy outcome). Notably, 
only 37% of women were on ART; there were unmeasured po-
tential confounders and exposure groups (IPT-exposed and 
IPT-unexposed) were dissimilar, particularly with regard to 
ART use. Another sub-analysis of 2 multi-country TBTC trials 
reported 14% incidence of fetal loss (all spontaneous abortion) 
among 56 pregnancies exposed to IPT for a median 4 weeks 
[19]. By comparison, we observed 2-fold higher incidence of 
spontaneous abortion (31%, 12 of 39) in our IPT-exposed 
group. However, the study populations differ in important 
ways, as only participants without HIV from the United States 
and Canada became pregnant during the TBTC trials.

Limitations of our study include small sample size, and lim-
ited measurement and hence adjustment for potential con-
founders. Pregnancy testing in the study after entry was 
performed only if indicated, and some early pregnancy loss 
may have been missed. In addition, we could not accurately as-
sess duration of isoniazid exposure during pregnancy except 
for those carried to term. Although our analyses of low birth 
weight and preterm delivery are limited by missing data, our 
study highlights a potentially important association between 
antenatal IPT exposure and spontaneous abortion. Lastly, this 

Table 1. Characteristics of Adolescent and Adult Females With an 
Incident Pregnancy During ACTG 5279, According to Antenatal Isoniazid 
Exposure Classification (n = 128)

IPT-Exposed Unexposed
Characteristic N = 39 N = 89 P

Country, n (%) … … .47

Botswana 11 (28) 23 (26)

Brazil 1 (3) 5 (6)

Haiti 9 (23) 15 (17)

Kenya 5 (13) 8 (9)

Malawi 3 (8) 2 (2)

Peru 1 (3) 3 (3)

South Africa 7 (18) 29 (33)

Thailand 1 (3) 3 (3)

USA 1 (3) 0 (0)

Zimbabwe 0 (0) 1 (1)

Median age, y (IQR)

At enrollment 29.2 (25.7, 
35.5)

29.2 (25.0, 
33.7)

.44

At pregnancy outcome 30.0 (26.4, 
36.3)

31.8 (27.2, 
36.0)

.54

Median CD4 count, cells/μL (IQR)

At enrollment 527 (432, 735) 538 (432, 678) .54

Closest to pregnancy outcome 522 (398, 707) 555 (420, 704) .61

ART use, n (%)

At enrollment 15 (38) 30 (34) .69

EFV-based regimen 9 (23) 29 (33) .01

Non-EFV-based regimen 6 (15) 1 (1)

At pregnancy outcome 31 (79) 85 (96) .007

Efavirenz-based regimen 25 (64) 77 (87) .006

Non-efavirenz-based regimen 6 (15) 8 (9)

LTBI-positive at enrollment 10 (26) 16 (18) .35

Isoniazid exposure

Completed IPT during pregnancy 19 (49) …

Discontinued IPT earlya 9 (23) …

Pregnancy outcome occurred 
during IPT

8 (21) …

Possible exposure 3 (8) …

Median duration of exposure  
(n = 19b), wks (IQR)

14.7 (7.3, 24.3) …

Data presented as no. (%) unless otherwise indicated.  

Abbreviations: ACTG, AIDS Clinical Trials Group; ART, antiretroviral therapy; EFV, efavirenz; 
IPT, isoniazid prevention therapy; IQR, interquartile range; LTBI, latent tuberculosis infection.  
aBefore study week 36 due to pregnancy (n = 6), non-compliance (n = 2) or withdrawn 
consent (n = 1).  
bNumber of live births for which gestational age at delivery was available; exposure duration 
estimated as study week off isoniazid minus (study week of birth minus gestational age at 
delivery).

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Figure 2. Final pregnancy outcomes according to antenatal isoniazid exposure classification (n = 128). Composite and individual adverse pregnancy outcomes by antenatal 
isoniazid therapy exposure. Adverse pregnancy outcome was a composite of any event resulting in a non-live birth, excluding induced abortion; the expanded adverse preg-
nancy outcome included induced abortion. Preterm delivery (<37 wks) and low birth weight (<2500 g) were assessed among live births for which data were available. 
Abbreviation: IPT, isoniazid prevention therapy.

Table 2. Results From Regression Models Describing Relative Risk of Adverse Outcomes Among IPT-exposed Versus Unexposed Pregnancies

No./Total N (%) Unadjusted
Adjusted for Covariates 
Measured at Enrollment

Adjusted for Covariates 
Measured at Pregnancy 

Outcome

Outcome IPT-exposed Unexposed
RR 

(95% CI) P
aRR 

(95% CI) P
aRR 

(95% CI) P

Composite adverse outcomea  

(excludes induced abortion as adverse outcome)

Primary analysis (n = 128) 13/39 
(33)

16/89 (18) 1.85 
(.99, 3.47)

.05 1.90 
(1.01, 3.54)

.04 1.45 
(.75, 2.80)

.27

Restricted risk set analysis (n = 122b) 13/36 
(36)

16/86 (19) 1.94 
(1.04, 3.61)

.04 1.98 
(1.08, 3.65)

.03 1.52 
(.83, 2.81)

.18

Extended composite adverse outcome  
(includes induced abortion as adverse outcome)

16/39 
(41)

19/89 (21) 1.92 
(1.11, 3.33)

.02 1.98 
(1.15, 3.41)

.01 1.47 
(.84, 2.55)

.18

Preterm delivery <37 wks gestational age (n = 68c) 4/20 
(20)

11/48 (23) 0.87 
(.32, 2.42)

.80 … … … …

Low birth weight <2500 g (n = 74c) 3/22 
(14)

7/52 (13) 1.01 
(.29, 3.56)

.98 … … … …

Models adjusted for maternal age, CD4 count, antiretroviral use and latent tuberculosis status.  

Abbreviations: aRR, adjusted relative risk; CI, confidence interval; IPT, isoniazid prevention therapy; RR, relative risk.  
aAny event resulting in a non-live birth, other than induced abortion; individual component outcomes were spontaneous abortion (<20 wks), stillbirth (≥20 wks), and ectopic pregnancy.  
bExcluded six pregnancies that ended in induced abortion (3 in each exposure group).  
cAssessed among live births for which data were available; adjusted analyses not undertaken because of small number of events.

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study was conducted prior to the guidance that all people with 
HIV should receive ART, and the study did not include partic-
ipants receiving integrase inhibitor therapy.

This work contributes to the existing fund of knowledge but 
also highlights the difficulties of generating solid evidence to in-
form guidelines. Overall, non-randomized studies provide some 
reassurance, documenting a protective effect of isoniazid during 
pregnancy [17, 18, 20], but pregnant women are systematically 
excluded from almost all randomized controlled trials of TB pre-
ventive therapy [4, 21]. As outlined above, results from prior 
studies are conflicting and exhibit substantial heterogeneity 
among study design, IPT exposure timing, ART exposure and 
outcomes assessed. Observational studies may also have inherent 
limitations such as small sample size [18, 20], confounding by in-
dication [17, 20], and unmeasured confounding factors [17, 18]. 
It is also difficult to ascertain early pregnancy loss and TB trials 
do not routinely collect this information. In addition, programs 
also rarely collect data on pregnancy status or outcomes.

In summary, we apriori included a study of pregnancy out-
comes in the BRIEF TB trial and observed that isoniazid expo-
sure during conception and first trimester was associated with 
spontaneous abortion but not preterm birth or low birth 
weight. It is notable that there were no incident pregnancies 
during the ultrashort course therapy of 1 month of isoniazid 
and rifapentine. Efforts to scale up short course TB preventive 
therapy, where incident pregnancies are unlikely to occur, 
should be prioritized. Our data also highlight the critical 
need to ensure pregnant women have full access and inclusion 
in relevant TB trials, so that robust data can be generated to in-
form guidelines, and pregnant women and providers can have 
the necessary information to weigh the benefits and the risks as-
sociated with tuberculosis therapies.

Notes
Acknowledgments. The authors thank the participants and other team 

members, including Katherine Shin, pharmacist; Anthony T. Podany, phar-
macologist; Ian Sanne, Network Leadership representative; Janet Nicotera, 
field representative; David L. Shugarts, laboratory technologist; Amina 
M. Shali, community representative; and the members of the Division of 
AIDS African data and safety monitoring board for their oversight of the trial; 
Timothy Sterling and Prudence Ive for performing the independent endpoint 
reviews; and Katie McIntyre for assisting with manuscript preparation.

Financial support. This work was supported by grants (grant numbers 
UM1AI069465, UM1 AI068634, UM1 AI068636, and UM1 AI106701) 
from the National Institute of Allergy and Infectious Diseases (NIAID) 
of the National Institutes of Health (NIH). The views expressed in this ar-
ticle are those of the authors and do not necessarily represent the official 
views of the NIH.

Potential conflicts of interest. A. G. reports Advisory Board roles from 
NIAID and Indo-US Science and Technology Forum (IUSSTF). 
M. H. reports institutional research and training grants related to infectious 
diseases from US NIH; board membership of Botswana-Harvard 
Partnership through employer; spouse’s research grants from NIH related 
to infectious diseases research. C. A. B. reports institutional grant support 
for clinical trials from Gilead and DNAe; consulting fees (paid to author) 
from National Data and Analytics Platform (NDAP), Inc.; honoraria for 
medical education lectures and travel support (paid to author) from 

International Antiviral Society–United States (IAS-USA), a non-profit 
medical education entity; and unpaid positions as Present of the non-profit 
Conference on Retroviruses and Opportunistic Infections (CROI) 
Foundation Board, and Secretary/Treasurer of the IAS-USA Board of 
Directors. R. E. C. reports spouse’s stock in Merck. S. S. reports institutional 
research support from ViiV Healthcare and participation on a Data Safety 
Monitoring or Advisory board for now completed NIH coronavirus disease 
(COVID)-related trials. All other authors report no potential conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential 
Conflicts of Interest. Conflicts that the editors consider relevant to the con-
tent of the manuscript have been disclosed.

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https://doi.org/icrobiolspec.TNMI7-0016-2016
https://doi.org/icrobiolspec.TNMI7-0016-2016

	Adverse Pregnancy Outcomes Among Women with Human Immunodeficiency Virus Taking Isoniazid Preventive Therapy During the First Trimester
	METHODS
	Study Design and Procedures
	Ethical Approval
	Isoniazid Exposure and Study Outcomes
	Statistical Analysis

	RESULTS
	Isoniazid Exposure
	Adverse Pregnancy Outcomes

	DISCUSSION
	Notes
	References