Pregnancy outcomes among HIV-infected women who conceived on antiretroviral therapy
Pregnancy outcomes among HIV-infected women who conceived on antiretroviral therapy
Elizabeth M. Stringer 0 1
Michelle A. Kendall 1
Shahin Lockman 1
Thomas B. Campbell 1
Karin Nielsen-Saines 1
Fred Sawe 1
Susan Cu-uvin 1
Xingye Wu 1
Judith S. Currier 1 2
0 Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of North Carolina , Chapel Hill, NC , United States of America, 2 Center for Biostatistics in AIDS Research, Harvard T. H. Chan School of Public Health , Boston, MA , United States of America, 3 Brigham and Women's Hospital and Harvard T.H. Chan School of Public Health , Boston, MA , United States of America, 4 Division of Infectious Diseases, Department of Medicine University of Colorado School of Medicine, Aurora, CO, United States of America, 5 Division of Infectious Diseases, Department of Pediatrics David Geffen School of Medicine at UCLA , Los Angeles, CA , United States of America, 6 Kenya Medical Research Institute (KEMRI), United States Army Medical Research Directorate-Kenya (USAMRD-K), Henry Jackson Foundation Medical Research International (HJFMRI) , Kericho, Kenya, 7 Director , Providence/Boston Center for AIDS Research, Director, Brown Global Health Initiative, Brown University , Providence, RI , United States of America
1 Editor: Matthew Law, University of New South Wales , AUSTRALIA
2 Division of Infectious Diseases, David Geffen School of Medicine at UCLA , Los Angeles, CA , United States of America
As antiretroviral therapy (ART) expands in resource-limited settings, understanding the impact of ART on pregnancy outcomes is critical. We analyzed women who became pregnant on ART while enrolled in a clinical trial (HPTN 052, ACTG A5208, and ACTG A5175); the majority of women were from Africa, with a median age of 29 years. Eligible women were on ART at conception and had a documented date of a last menstrual period and a pregnancy outcome. The primary outcome was non-live birth (stillbirth; spontaneous abortion; elective termination; or ectopic pregnancy) versus live birth. Preterm birth (<37 weeks completed gestation) was a secondary outcome. We used Cox proportional hazards regression models with time-varying covariates. 359 women became pregnant, of whom 253 (70%) met inclusion criteria: 127 (50%) were on NNRTI-based ART, 118 (47%) on PI-based ART, and 8 (3%) on 3-NRTIs at conception. There were 160 (63%) live births (76 term and 84 preterm), 11 (4%) stillbirths, 51 (20%) spontaneous abortions, 28 (11%) elective terminations, and 3 (1%) ectopic pregnancies. In multivariable analysis adjusted for region, parent study, and pre-pregnancy ART class, only older age was associated with increased hazard of preterm birth [HR: 2.49 for age 25±30 years; 95% CI: 1.18±5.26; p = 0.017]. Women conceiving on ART had high rates of preterm birth and other adverse pregnancy outcomes. Despite the benefits of ART, studies designed to investigate the effects of preconception
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: Research reported in this publication was
supported by the National Institutes of Health
grants to the HIV Prevention Trials Network as well
as grants to the AIDS Clinical Trials Group, and
Division of Intramural Research, National Institute
of Allergy and Infectious Diseases, U01-A1068619/
UMI-A1068619 and U01A1068636/A168634/
A138838. The content is solely the responsibility of
ART on pregnancy outcomes are needed.
the authors and does not necessarily represent the
official views of the National Institutes of Health.
The funders had no role in the study design, data
collection and analysis, decision to publish, or
preparation of the manuscript.
Women of reproductive age comprise more than half of all people living with HIV infection
worldwide and it is estimated that more than 1.5 million women with HIV will give birth
]. Antiretroviral clinical trials that are not specifically designed for pregnant
populations have generally excluded women who are pregnant or who express a desire to become
pregnant. Because of this, there are limited data on pregnancy rates and outcomes among
women who conceive while on antiretroviral therapy (ART), especially in resource-limited
Starting in 2013, the World Health Organization (WHO) and UNICEF recommended that
all pregnant HIV-infected women commence ART in pregnancy regardless of CD4+ cell
count and continue ART for life[
]. Given the subsequent additional WHO recommendation
of universal ART for all persons with HIV,[
] an increasing number of women are becoming
pregnant while taking ART. As vertical transmission rates continue to decline worldwide,
attention has more recently turned to the relationship between exposure to ART during
pregnancy and adverse pregnancy outcomes, including low birth weight and/or preterm birth[4±
9]. Until recently, few large prospective studies have examined the pregnancy outcomes of
women who either conceived while taking ART or commenced ART in pregnancy[
data are particularly sparse from RLS. Virtually no prospectively and carefully collected data
exist on pregnancy outcomes among women who conceive on ART.
A recent meta-analysis of 11 studies that included 19,189 mother-infant pairs found a
higher rate of preterm birth among women starting ART prior to conception when compared
to those starting ART in pregnancy[
]. Other studies have also suggested that certain
antiretroviral regimens may be associated with adverse infant outcomes[
]. As the availability of
ART expands in RLS, it is critical to understand the impact these drugs may have on maternal
and infant outcomes, especially for women whose fetuses are exposed to ART at conception or
early in gestation. We sought to describe pregnancy outcomes and factors associated with
successful pregnancy outcomes among women who conceived while on ART while prospectively
followed in the context of interventional ART trials conducted in RLS.
Material and methods
In this exploratory analysis, we combined data across three randomized clinical trials of HIV
prevention or treatment conducted by the US National Institutes of Health, Division of AIDS
Clinical Trials Networks, and the National Institute of AIlergy and Infectious Diseases in
resource-limited settings. The deidentified dataset has been provided. (S2 Table) These are
AIDS Clinical Trials Group (ACTG) A5208, ACTG A5175, and HIV Prevention Trials
Network (HPTN) 052. Briefly, ACTG A5208 was a trial of a protease inhibitor (PI,
lopinavir/ritonavir (LPV/r))-based regimen versus a non-nucleoside reverse transcriptase inhibitor
(NNRTI, nevirapine (NPV))-based regimen among women with and without prior exposure
to single dose nevirapine[
]. ACTG A5175 was a trial of a once-daily PI (atazanavir (ATV),
didanosine-EC (DDI-EC) and emtricitabine (FTC))-based regimen versus a once-daily
NNRTI (efavirenz (EFV), FTC, and tenofovir disoproxil fumarate (TDF))-based regimen
versus a twice-daily regimen (EFV, lamivudine (3TC), zidovudine (ZDV)) for initial treatment of
]. HPTN 052 was a trial of immediate versus delayed ART (EFV, NVP, ATV,
LPV/r, and other select ARVs) to prevent sexual transmission of HIV-1 among serodiscordant
]. Pregnancy (or desire for pregnancy during the study period) was an exclusion
criterion for entry into each of the studies; however, a number of women became pregnant while
on study. Women in A5208 who became pregnant were continued on study drug, but switched
from a TDF-containing regimen to a ZDV-containing regimen, and from EFV to NVP or
2 / 12
another antiretroviral. Women who become pregnant while on A5175 were allowed to
continue on study-provided ART, except women who were taking EFV were required to substitute
a different antiretroviral drug such as NVP. All three protocols asked women to recall the date
of their last menstrual period at each study visit, and documented their method of
contraception. In A5208, women underwent urine pregnancy tests every 4 weeks while on EFV;
otherwise, testing was as indicated. Women in A5175 and HPTN 052 underwent urine pregnancy
tests every 8 and 4 weeks, respectively. The estimated due date (EDD) and pregnancy data
were obtained from patient self report as well as available prenatal records and was recorded
onto standardized data collection forms.
We aggregated data from all women enrolled in the three clinical trials who became
pregnant during the study period. Women were included in the analysis if a last menstrual period
and a pregnancy outcome (included a date of delivery/surgery and birth outcome) were
documented and if they were on ART prior to conception. We examined demographic
information, maternal HIV viral load prior to pregnancy and during gestation, CD4+/CD8
+ measurements prior to pregnancy and during gestation, ART regimen prior to pregnancy
and during gestation, pre-pregnancy alcohol/illicit drug use, pre-pregnancy body mass index
(BMI), pre-pregnancy graded creatinine and hemoglobin values, pre-pregnancy hepatitis B
infection status, and pregnancy history.
Our primary outcome measure was time to non-live birth versus live birth, where non-live
births included stillbirths (intrauterine fetal death >20 weeks), spontaneous abortions (<20
weeks), elective terminations, and ectopic pregnancies; these were determined in an a priori
manner. Among live births, preterm birth was defined as a live birth prior to 37 weeks.
Pregnancy outcomes were limited to women with at least one pregnancy while enrolled in the
parent study, but we only included the outcome of the first pregnancy; twins were counted as a
single outcome because the outcomes were concordant. Date of conception was approximated
as two weeks after the date of last menstrual period. Because many variables of interest were
related in some way to length of follow-up (i.e., longer pregnancies yielded longer exposure),
the variables were confounded with pregnancy outcome. This time bias was remedied by using
time-updated covariates in Cox proportional hazards regression models to identify predictors
of time from date of conception to date of stillbirth, spontaneous abortion, or elective
termination, or date of surgery for ectopic pregnancy; live births were censored at date of delivery. The
Cox regression models were adjusted for region and parent study. Multivariable models were
built using variables with p<0.20 from the univariable regression analysis and reduced using
backward elimination. Post hoc (unplanned) Cox regression models were adjusted for region,
parent study, and pre-pregnancy ART class and examined associations with maternal age. We
summarized demographic variables by parent study and by live birth versus other. Pregnancy
outcomes were summarized by pre-pregnancy ART class. We compared groups using
Wilcoxon tests for continuous variables and Chi-square or Fisher's exact tests for categorical data.
A two-sided p-value <0.05 was considered statistically significant. The study was approved by
institutional review boards or ethics committees at each study site as well as by other local
regularly bodies as deemed appropriate (S1 Table). Written informed consent was obtained
before enrollment for all participants.
In our pooled analysis, 359 women became pregnant while enrolled in one of the three studies.
Of these, 253 women (70%) met inclusion criteria for our study and were included in the
analysis. The most common reasons women were excluded from the analysis were undocumented
last menstrual period or pregnancy outcome (n = 53), or no date of pregnancy outcome and
3 / 12
no follow-up date (n = 39), and other (n = 14). Women who were excluded from the analysis
were more likely to have been in A5175 (p<0.001), older (median age 29 versus 27 years old;
p = 0.046), more likely to be from Asia and Central/South America (p<0.001), more likely to
have been on NNRTI-based ART (p = 0.01), and had higher median CD4+ cell count upon
entry into the parent study (168 versus 146 cells/mm3; p = 0.047). Of the 253 women included
in our analysis, 114 (45%) were from HPTN 052, 89 (35%) were from A5208, and 50 (20%)
were from A5175. Baseline characteristics by parent study are presented in Table 1. The
majority of women were African in origin and were taking an NNRTI-based ART regimen prior to
pregnancy. Of the women taking an NNRTI-based regimen, 97 (73%) and 30 (23%) were on
an EFV-or NVP-based combination, respectively. Another 118 (47%) were taking PI-based
ART, and 8 (3%) on 3-NRTIs at conception. The median pre-pregnancy CD4+ cell count was
higher among women in HPTN 052 (median 593 cells/mm3 [interquartile range (IQR): 441±
764 cells/mm3] versus 383 [IQR: 292±458] in A5175 and 321 [IQR: 233±445] in A5208). This
was expected since HPTN 052 enrolled women with screening CD4+ between 350 and 550
cells/mm3, while the screening CD4+ criterion for A5208 and A5175 were <200 and <300
Of the 253 pregnancies, there were 160 (63%) live births (Table 2). Of the 160 live births, 84
(53%) occurred prior to 37 weeks completed gestation and 76 (47%) were term. The overall
median gestational age (GA) of live births was 35 weeks and 5 days (IQR: 35.1, 38.1). The
median GA at birth among those women on a PI-based ART regimen was 36.5 weeks (IQR:
35.1, 38.1); among women on an NNRTI-based regimen was 37 weeks (IQR: 35.3, 38.1); and
among women on NRTIs was 36.4 weeks (IQR: 34.4, 37.4). The median birth weight among
the 68 live-born infants with a recorded birth weight was 2900 g (IQR: 2500±3400 g). The
proportion of births after 20 weeks that resulted in a stillbirth was 11 (4%). Fifty-one (20%)
pregnancies were recorded as spontaneous abortions and 28 (11%) were elective terminations.
Associations with non-live birth
Baseline characteristics by live birth versus other birth outcome are summarized in Table 3.
The median pre-pregnancy CD4+ cell count was significantly higher among women with live
births: median 451 cells/mm3 [IQR: 321±615 cells/mm3] versus 399 [276±559] in non-live
births; p = 0.045. Maternal age at study entry, number of prior pregnancies, pre-pregnancy
BMI, pre-pregnancy hemoglobin grade, pre-pregnancy CD4+ cell count, pre-pregnancy HIV
RNA suppression (< = 400 copies/mL), pre-pregnancy ART class, any detectable HIV RNA
(>400 copies/mL), and any use of either an NNRTI or PI were not significantly associated
with non-live birth in Cox proportional hazards regression models adjusted for region and
parent study (Fig 1); there were no significant multivariable models. In a post hoc analysis
where the multivariable Cox model was adjusted for region, parent study, and pre-pregnancy
ART class, older age was not significantly associated with non-live birth [HR 1.25 per 5 years
older; 95% CI: 0.997±1.57; p = 0.07 (Table 4)]. ªA sensitivity analysis that removed 28 elective
terminations was performed. Older age became significantly associated with non-live birth
[HR 1.42 per 5 years older; 95% CI: 1.08±1.87; p = 0.012]º.
Associations with preterm live birth
In Cox proportional hazards regression analysis of time to preterm live birth adjusted for
region and parent study, we found no factors to be significantly associated with preterm birth
among women with a live birth (Fig 2); there were no significant multivariable models. In a
post hoc analysis where the multivariable Cox model was adjusted for region, parent study,
and pre-pregnancy ART class, maternal age 25±30 years compared to age 18±24 was
4 / 12
HPTN 052 did not collect height and weight (for body mass index), CD8+ cell count, or hepatitis B serology; creatinine grading depends upon weight and is thus also
missing from HPTN052 cohort. A5175 and A5208 did not uniformly collect hepatitis B serology. ACTG A5208 did not collect alcohol or illicit drug use.
5 / 12
(N = 127)
(N = 8)
significantly associated with increased hazard of preterm birth [HR 2.49; 95% CI: 1.18±5.26;
p = 0.017] (Table 4).
In this analysis of women in resource-limited settings who conceived while taking ART in a
clinical trial, adverse pregnancy outcomes were common. Only 30% of women who became
pregnant delivered a live-born infant at term. Approximately half of the live-born infants were
preterm. The proportion of pregnancies that ended in a stillbirth was 4%, which is
considerably higher than reported stillbirth rates in other African countries,[
] and 20% of
pregnancies ended in a spontaneous abortion. In understanding the results of this analysis, it is
important to note that women enrolled in these clinical trials had mandatory and frequent
testing for pregnancy. It is likely that the frequent pregnancy testing detected spontaneous
abortions that might have otherwise been missed if women had not been followed as closely.
No specific antiretroviral regimen was associated with more adverse birth outcomes.
We were surprised at the high proportion of adverse pregnancy outcomes. In the recent
PROMISE trial (IMPAACT 1077BF/1077FF), which compared two PI-containing ART
regimens to non-suppressive zidovudine prophylaxis, they also found high rates of adverse birth
outcomes with 33.7% of pregnancies reaching the combined outcome of preterm birth, low
birthweight, stillbirth, or abortion[
]. Since the PROMISE trial only enrolled women after 14
weeks gestation (median gestational age at enrollment: 26 weeks), it is likely that many of the
spontaneous and elective terminations that we saw in the present analysis were not detected in
PROMISE. Our rates of spontaneous abortion do not differ substantially from rates seen in the
few studies that assess miscarriage rates in the general population[
The stillbirth numbers we observed were substantially higher than what has been reported
in other African populations[
]; however, these other studies were not restricted to
HIVinfected women on ART. Among studies of HIV-infected women on preconception ART, our
stillbirth proportions remain consistent, but also unacceptably high. Chen and colleagues
reported overall stillbirth rates of 4.6% among 9504 births to HIV-infected women in
Botswana, but a 6.3% stillbirth rate among women who conceived on ART which is similar to
what we found. The etiologies of antepartum and intrapartum stillbirths are very different
] and many of these risk factors were not available in our study or in Chen's study;
knowledge of these risk factors will impact interventions to mitigate risk of stillbirth. Maternal
comorbidities in pregnancy, such as preeclampsia and gestational hypertension, are also known
risk factors for stillbirth [
] and may be higher in HIV-infected women on ART[
proportion of women who delivered a preterm birth in our study was substantially higher than
other studies and this may be, in part, due to lack of ultrasound dating and reliance on last
menstrual period (LMP) for to determine an estimated gestational age.
6 / 12
Pre-pregnancy HIV RNA among those not suppressed (log10copies/mL)
Pre-pregnancy hemoglobin grade
Pre-pregnancy creatinine grade
Pre-pregnancy body mass index (BMI, kg/m2)
Pre-pregnancy hepatitis B infection
Pre-pregnancy use of alcohol or illicit drugs
Number of previous pregnancies
Number of pregnancies per woman during the study period
IQR = interquartile range
Fisher's Exact Test; See Table 1 caption for information on missing data.
PLOS ONE | https://doi.org/10.1371/journal.pone.0199555
7 / 12
Fig 1. Cox proportional hazard models of time to non-live birth pregnancy outcomes (adjusted for region and parent study).
It is possible that adverse birth outcomes among HIV-infected women may be related to
chronic inflammation. Inflammation is known to be associated with stillbirth, preterm births,
and intrauterine growth restriction[
]. Many patients who are stable on ART continue to
have chronic residual immune activation, and this may be contributing to higher rates of
adverse pregnancy outcomes among HIV-infected women in resource-limited settings who,
until recently, have started ART later in their HIV infections.
Our study is unique because of the follow-up from before conception, monthly recording
of LMP, and frequent urine pregnancy tests that allows for diagnosis of pregnancy in the first
8 / 12
Fig 2. Cox proportional hazard models of time to preterm live birth pregnancy outcomes (adjusted for region and parent study).
trimester, which many studies lack. This is also an improvement over simple reliance on LMP
recollection and likely accounts for the high numbers of spontaneous abortions and elective
terminations that we were able to capture. Another strength is the accurate recording of
antiretroviral drug regimens and the switching of regimens, as well as discontinuation of regimens;
we observed no impact of certain antiretrovirals on adverse birth outcomes.
Because the parent studies were designed to measure HIV outcomes and not obstetrical
outcomes, our analysis has several important limitations. A reliable gestational age
determination is critical to assessing pregnancy outcomes; dating based solely on LMP is notoriously
]. However, we note that all three protocols assessed LMP at each visit, a practice
that we expect would make patient recollection more reliable. Additionally, although relying
on dating of pregnancies by LMP alone is a weakness, there is no reason to think that the
estimated gestational age at delivery would be systematically biased one way or another for the
overall outcomes. An additional weakness is the small sample size and missing birthweight
data that prevented us from being able to detect even moderate differences in birth outcomes
or birthweights among specific antiretroviral regimens. We would have liked to have collected
more detailed information on the types of preterm birth (spontaneous versus indicated) and
stillbirth (pre-labor/macerated versus intrapartum/fresh) in our cohort. The underlying
etiologies for spontaneous preterm birth and indicated preterm birth differ substantially and must
be understood with regard to HIV-infected pregnant women who are on ART before making
9 / 12
conclusions about causality[
]. Finally, because of the multiple inclusion and exclusion
criteria for the three included studies, our results may not be generalizable to a larger population of
pregnant HIV infected women.
Since the introduction of Option B+ in many resource-limited settings, the number of
infants who are perinatally-infected with HIV has fallen precipitously, but the relationship
between HIV infection, timing of initiation of ART, and actual ART regimens on adverse
pregnancy outcomes remain elusive, for the most part, because of the lack of well-designed studies
that are focused on pregnancy outcomes as a primary outcome.
In our study, adverse pregnancy outcomes including stillbirth and preterm birth were high
among an HIV-infected population of women who were on ART at the time of conception.
Studies that more accurately capture gestational age at birth, indications for preterm births,
and maternal birth history, while examining commonly used ART regimens, timing of ART
administration in the pre- and post-conception period, as well as immune status at the time of
initiation of ART are urgently needed to inform the management of HIV infection in
S1 Table. List of ethics boards that approved the studies.
S2 Table. Deidentified study data file.
We thank the staff who worked tirelessly on these studies and the patients who generously
participated in them.
Conceptualization: Elizabeth M. Stringer, Karin Nielsen-Saines, Susan Cu-uvin, Judith S.
Data curation: Michelle A. Kendall, Xingye Wu.
Formal analysis: Michelle A. Kendall, Xingye Wu.
Investigation: Shahin Lockman, Thomas B. Campbell.
Methodology: Elizabeth M. Stringer, Shahin Lockman, Thomas B. Campbell, Karin
Saines, Judith S. Currier.
Writing ± original draft: Elizabeth M. Stringer, Shahin Lockman, Susan Cu-uvin, Judith S.
Writing ± review & editing: Elizabeth M. Stringer, Shahin Lockman, Thomas B. Campbell,
Karin Nielsen-Saines, Fred Sawe, Susan Cu-uvin, Judith S. Currier.
10 / 12
Infection in Pregnant Women, Mothers, and Children in the Global Plan Era. J Acquir Immune Defic
Syndr. 2017; 75 Suppl 1:S7±S16.
11 / 12
1. Luo C , Hirnschall G , Rodrigues J , Romano S , Essajee S , Rogers B , et al. Translating Technical Support Into Country Action: The Role of the Interagency Task Team on the Prevention and Treatment of HIV
2. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection . Geneva: World Health Organization.; 2013 .
3. World Health Organization. Guidelines on When to Start Antiretroviral Therapy and on Pre-exposure Prophylaxis for HIV . Geneva; 2015 .
4. Lorenzi P , Spicher VM , Laubereau B , Hirschel B , Kind C , Rudin C , et al. Antiretroviral therapies in pregnancy: maternal, fetal and neonatal effects. Swiss HIV Cohort Study, the Swiss Collaborative HIV and Pregnancy Study, and the Swiss Neonatal HIV Study . AIDS . 1998 ; 12 ( 18 ): F241±7 . PMID: 9875571
5. Lambert JS , Watts DH , Mofenson L , Stiehm ER , Harris DR , Bethel J , et al. Risk factors for preterm birth, low birth weight, and intrauterine growth retardation in infants born to HIV-infected pregnant women receiving zidovudine . Pediatric AIDS Clinical Trials Group 185 Team. AIDS . 2000 ; 14 ( 10 ): 1389 ± 99 .
6. Cotter AM , Garcia AG , Duthely ML , Luke B , O'Sullivan MJ . Is antiretroviral therapy during pregnancy associated with an increased risk of preterm delivery, low birth weight , or stillbirth? J Infect Dis . 2006 ; 193 ( 9 ): 1195 ± 201 . https://doi.org/10.1086/503045 PMID: 16586354
7. Thorne C , Patel D , Newell ML . Increased risk of adverse pregnancy outcomes in HIV-infected women treated with highly active antiretroviral therapy in Europe . AIDS . 2004 ;( 17 )18: 2337 ± 9 .
8. Kourtis AP , Schmid CH , Jamieson DJ , Lau J . Use of antiretroviral therapy in pregnant HIV-infected women and the risk of premature delivery: a meta-analysis . AIDS . 2007 ; 21 ( 5 ): 607 ± 15 . https://doi.org/ 10.1097/QAD.0b013e32802ef2f6 PMID: 17314523
9. Patel K , Shapiro DE , Brogly SB , Livingston EG , Stek AM , Bardeguez AD , et al. Prenatal protease inhibitor use and risk of preterm birth among HIV-infected women initiating antiretroviral drugs during pregnancy . J Infect Dis . 2010 ; 201 ( 7 ): 1035 ± 44 . https://doi.org/10.1086/651232 PMID: 20196654
10. Zash R , Souda S , Chen JY , Binda K , Dryden-Peterson S , Lockman S , et al. Reassuring Birth Outcomes With Tenofovir/Emtricitabine/Efavirenz Used for Prevention of Mother-to-Child Transmission of HIV in Botswana . J Acquir Immune Defic Syndr . 2016 ; 71 ( 4 ): 428 ± 36 . https://doi.org/10.1097/QAI. 0000000000000847 PMID: 26379069
11. Chen JY , Ribaudo HJ , Souda S , Parekh N , Ogwu A , Lockman S , et al. Highly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana . J Infect Dis . 2012 ; 206 ( 11 ): 1695 ± 705 . https://doi.org/10.1093/infdis/jis553 PMID: 23066160
12. Uthman OA , Nachega JB , Anderson J , Kanters S , Mills EJ , Renaud F , et al. Timing of initiation of antiretroviral therapy and adverse pregnancy outcomes: a systematic review and meta-analysis . Lancet HIV . 2017 ; 4(1):e21±e30 . https://doi.org/10.1016/S2352- 3018 ( 16 ) 30195 - 3 PMID: 27864000
13. Zash R , Jacobson DL , Diseko M , Mayondi G , Mmalane M , Essex M , et al. Comparative Safety of Antiretroviral Treatment Regimens in Pregnancy . JAMA Pediatr . 2017 ; 171 ( 10 ):e172222. https://doi.org/10. 1001/jamapediatrics. 2017 .2222 PMID: 28783807
14. Kourtis AP , Fowler MG . Antiretroviral use during pregnancy and risk of preterm delivery: more questions than answers . J Infect Dis . 2011 ; 204 ( 4 ): 493 ±4. https://doi.org/10.1093/infdis/jir318 PMID: 21791648
15. Lockman S , Hughes MD , McIntyre J , Zheng Y , Chipato T , Conradie F , et al. Antiretroviral therapies in women after single-dose nevirapine exposure . N Engl J Med . 2010 ; 363 ( 16 ): 1499 ± 509 . https://doi.org/ 10.1056/NEJMoa0906626 PMID: 20942666
16. Campbell TB , Smeaton LM , Kumarasamy N , Flanigan T , Klingman KL , Firnhaber C , et al. Efficacy and safety of three antiretroviral regimens for initial treatment of HIV-1: a randomized clinical trial in diverse multinational settings . PLoS Med . 2012 ; 9 ( 8 ):e1001290. https://doi.org/10.1371/journal.pmed. 1001290 PMID: 22936892
17. Cohen MS , Chen YQ , McCauley M , Gamble T , Hosseinipour MC , Kumarasamy N , et al. Prevention of HIV-1 infection with early antiretroviral therapy . N Engl J Med . 2011 ; 365 ( 6 ): 493 ± 505 . https://doi.org/10. 1056/NEJMoa1105243 PMID: 21767103
18. Stringer EM , Vwalika B , Killam WP , Giganti MJ , Mbewe R , Chi BH , et al. Determinants of stillbirth in Zambia. Obstet Gynecol . 2011 ; 117 ( 5 ): 1151 ±9. https://doi.org/10.1097/AOG.0b013e3182167627 PMID: 21508755
19. Fowler MG , Qin M , Fiscus SA , Currier JS , Flynn PM , Chipato T , et al. Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention . N Engl J Med . 2016 ; 375 ( 18 ): 1726 ± 37 . https://doi.org/10.1056/ NEJMoa1511691 PMID: 27806243
20. Dellicour S , Aol G , Ouma P , Yan N , Bigogo G , Hamel MJ , et al. Weekly miscarriage rates in a community-based prospective cohort study in rural western Kenya . BMJ Open . 2016 ; 6 ( 4 ):e011088. https://doi. org/10.1136/bmjopen-2016 -011088 PMID: 27084287
21. Bailey PE , Andualem W , Brun M , Freedman L , Gbangbade S , Kante M , et al. Institutional maternal and perinatal deaths: a review of 40 low and middle income countries . BMC Pregnancy Childbirth . 2017 ; 17 ( 1 ): 295 . https://doi.org/10.1186/s12884-017 -1479-1 PMID: 28882128
22. Lawn JE , Blencowe H , Waiswa P , Amouzou A , Mathers C , Hogan D , et al. Stillbirths: rates, risk factors, and acceleration towards 2030 . Lancet. 2016 ; 387 ( 10018 ): 587 ± 603 . https://doi.org/10.1016/S0140- 6736 ( 15 ) 00837 - 5 PMID: 26794078
23. Jabeen M , Yakoob MY , Imdad A , Bhutta ZA . Impact of interventions to prevent and manage preeclampsia and eclampsia on stillbirths . BMC Public Health . 2011 ; 11 Suppl 3 : S6 .
24. Tooke L , Riemer L , Matjila M , Harrison M. Antiretrovirals causing severe pre-eclampsia . Pregnancy Hypertens . 2016 ; 6(4):266±8 . https://doi.org/10.1016/j.preghy. 2016 . 04 .006 PMID: 27939465
25. Gravett MG , Rubens CE , Nunes TM , Group GR. Global report on preterm birth and stillbirth (2 of 7): discovery science . BMC Pregnancy Childbirth . 2010 ; 10 Suppl 1 : S2 .
26. Campbell S , Warsof SL , Little D , DJ C. Routine ultrasound screening for the prediction of gestational age . Obstet Gynecol . 1985 ; 65 : 613 ± 20 . PMID: 3885105
27. Johnson KM , Zash R , Haviland MJ , Hacker MR , Luckett R , Diseko M , et al. Hypertensive disease in pregnancy in Botswana: Prevalence and impact on perinatal outcomes . Pregnancy Hypertens . 2016 ; 6 ( 4 ): 418 ± 22 . https://doi.org/10.1016/j.preghy. 2016 . 10 .002 PMID: 27939493