Adverse Birth Outcomes in Botswana Among Women With Vertically or Horizontally Acquired Human Immunodeficiency Virus

Abstract

Background

Women with vertically acquired HIV (VHIV) may have a greater risk of adverse birth outcomes than women with horizontally acquired HIV (HHIV).

Methods

The Tsepamo study performed birth outcomes surveillance at 8 government delivery sites in Botswana from July 2014 through March 2019. Pregnant women diagnosed with HIV before their 11th birthday received VHIV status, and other women had HHIV. Small for gestational age (SGA), preterm delivery (PTD), stillbirth, and neonatal death were compared using χ2 and Fisher’s exact tests. Log-binomial regression models determined risk ratios (RRs).

Results

VHIV women (n = 402) aged 15–27 years were identified over 4 years of surveillance and compared with HHIV women (n = 8465) of the same age. VHIV women were more likely to use nevirapine (NVP)-based antiretroviral treatment (ART) in pregnancy and to have SGA and very SGA infants, but less likely to have very PTD infants. In unadjusted analyses, VHIV women had a higher risk of any adverse birth outcome combined (RR = 1.21, 95% confidence interval [CI], 1.08–1.36). After adjusting for potential confounders, particularly use of NVP-based regimens, the risk of adverse birth outcomes among VHIV and HHIV women was similar.

Conclusions

NVP-based ART is a primary and modifiable risk factor for adverse birth outcomes. Updating ART regimens could improve birth outcomes for women with HIV.

Globally, an estimated 37.9 million people are living with human immunodeficiency virus (HIV), including 1.7 million children [1]. Because several sub-Saharan African countries, including Botswana, are disproportionately impacted by HIV, substantial increases in the availability and safety of antiretroviral therapy (ART) have resulted in improved health of individuals living with HIV [2, 3]. More children who acquired HIV in utero or at birth are living to reproductive age. As a result, infant outcomes from pregnant women with vertically acquired HIV (VHIV) may differ when compared with women with horizontally acquired HIV (HHIV) [4].

Past studies compared adverse birth outcomes between VHIV and HHIV women and concluded that the proportions of various adverse birth outcomes, such as preterm delivery (PTD) and low birth weight, were not significantly different [5, 6]. However, information on potential adverse birth outcomes among VHIV women is not well known in high HIV prevalence settings. Botswana, with an estimated HIV prevalence of 20.3% among adults aged 15–49 years and approximately 95% of women delivering in a hospital or clinic facility, is an ideal location for evaluation of the potential differences in birth outcomes between VHIV and HHIV women [1, 7]. In addition, Botswana has a free countrywide HIV treatment program, and more than 95% of pregnant women living with HIV are receiving ART [2].

Despite the efforts to prevent maternal-to-child HIV transmission in Botswana, it is currently unknown whether infants from mothers who had VHIV have greater risk of experiencing adverse birth outcomes compared with infants from mothers who had HHIV. Therefore, given these relatively ideal study conditions in Botswana, we compared adverse birth outcomes between VHIV and HHIV women in a nationwide birth outcomes surveillance study.

METHODS

Study Population

Data were compiled from the ongoing Tsepamo observational surveillance study between July 2014 and June 2018. The Tsepamo study contained obstetric records of women who delivered live-born or stillborn infants at 8 government maternity wards in Botswana. These maternity wards included the Princess Marina Hospital in Gaborone, Nyangabgwe Referral Hospital in Francistown, Letsholathebe II Memorial Hospital in Maun, Sekgoma Memorial Hospital in Serowe, Selebi-Phikwe Hospital in Selebi-Phikwe, Mahalapye Hospital in Mahalapye, Scottish Livingstone Hospital in Molepolole, and Ghanzi Primary Hospital in Ghanzi. These institutions accounted for approximately 45% of all births in Botswana during the surveillance period [8]. Births were excluded if they occurred before arrival at the hospital or at a gestational age of less than 24 weeks. For the current analysis, only women with singleton births were included. Those with twins or triplets were excluded because of known associations between multiple births and adverse birth outcomes [9].

Data Extraction

As stated in previous studies, deidentified data were obtained from maternal obstetric records [7, 8, 10]. For all women living HIV, the date of HIV diagnosis, most recent CD4 cell count, and antiretroviral history, such as ART start date, regimen, and any switch or discontinuation during pregnancy, were collected. Additional extracted data included maternal demographics, maternal medical history, maternal HIV status, medications and antibiotics taken during pregnancy, self-reported smoking and alcohol use, outpatient antenatal care, and inpatient care during labor and delivery. All data were collected at the time of discharge from the postnatal ward. Infant data were collected from the maternal obstetric records and included gender, birth weight, delivery complication, and admission to the neonatal unit. Diagnoses were recorded by the treating physician or midwife with the exception of anemia, defined as hemoglobin ≤10 g/dL, and hypertension, defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg in pregnancy [7].

Exposures

VHIV and HHIV status was determined by the self-reported dates of HIV diagnosis. Pregnant women diagnosed as living with HIV before their 11th birthday were classified as women with VHIV; all other women were considered likely to have been women with HHIV. The age at HIV infection was calculated by subtracting the date of first reported HIV diagnosis from the delivery date and then subtracting this difference from the age at delivery. To reduce confounding by age, only women with HHIV within the same age range at delivery (15–27 years) as women with VHIV were included in the study.

Outcomes

The primary outcomes consisted of 2 endpoints: adverse birth and severe adverse birth outcomes. Adverse birth outcomes included stillbirth, PTD, small for gestational age (SGA), and neonatal death. Severe adverse birth outcomes consisted of stillbirth, very PTD, very SGA, and neonatal death. Stillbirth was defined as fetal death (summed Apgar score of 0); PTD was defined as deliveries less than 37 weeks gestational age; and very PTD as deliveries less than 32 weeks gestational age. Nurses estimated and documented the gestational age during delivery by using the last menstrual period recorded at the first antenatal visit and confirmed the estimate using ultrasonography [8, 10]. When the date of the last menstrual period could not be accurately estimated or confirmed with an ultrasound, midwives used fundal height measurements. Based on the Intergrowth-21 norms (defined for 24–42 weeks gestational age), infants were categorized as SGA if they weighed less than the tenth percentile birth weight by gestational age and as very SGA if they weighed less than the third percentile birth weight by gestational age [11, 12]. Neonatal death was defined as infant death prior to leaving the hospital within 28 days of delivery. The proportions of the aforementioned outcomes were individually assessed among VHIV and HHIV women.

Statistical Analyses

Fisher exact and χ² tests were used to compare outcomes of VHIV and HHIV women. Wilcoxon rank sum tests were used to compare the median and interquartile range (IQR) of continuous maternal information. For risk of each birth outcome, log-binomial regression models were used to determine unadjusted risk ratios (RRs) and adjusted risk ratios (aRRs). The covariates for adjusted analyses were selected based on prior knowledge from similar studies [7, 8, 10]. Selected covariates included maternal age, parity, education, low maternal birth weight (first recorded weight during pregnancy <50 kg), self-reported smoking or alcohol use during pregnancy, and initial ART prescribed or continued during pregnancy. Women who changed or terminated their initial ART prescribed or continued during pregnancy or had unspecified ART regimens were excluded from analyses that evaluated specific ART regimens. Due to the missing values for recent CD4 cell count, this variable was only included in models for the sensitivity analyses. P values were generated using 2-sided tests with an α = 0.05 significance level. Statistical analyses were performed using SAS University Edition software (SAS Institute, Cary, NC).

Ethical Approval

Institutional approval for this study was granted by the Health Research and Development Committee in Botswana and by the institutional review board of Harvard T. H. Chan School of Public Health in Boston, Massachusetts. Maternal consent was waived as data were collected anonymously and via chart abstraction.

RESULTS

Of the 28 836 women living with HIV identified between July 2014 and March 2019, 1712 (5.9%) were missing the following essential data and were excluded: maternal age, timing of their first HIV diagnosis (ie, before pregnancy, during pregnancy, or after delivery), or HIV diagnosis date (Figure 1). Among the remaining 27 124 (94.1%) women, 3 (0.0011%) were excluded for suspected inaccurate HIV diagnosis date. As women with VHIV (aged 15–27 years) were generally younger than women with HHIV (aged 13–51 years), 18 124 (66.8%) women with HHIV were excluded from this analysis as they were outside the age range of women with VHIV. Finally, 4 (0.015%) women were excluded for suspected inaccurate delivery date or implausible VHIV diagnosis, 125 (0.46%) were excluded for delivering twins, and 1 (0.0037%) was excluded for delivering triplets. In the final analysis, the current study consisted of 402 (1.5%) women with VHIV and 8465 (31.2%) women with HHIV.

Figure 1.

Flow chart of the study population. ^aVHIV status is for women diagnosed as living with HIV before age 11 years. ^bHHIV status is for women diagnosed as living with HIV during or after age 11 years. Abbreviations: HIV, human immunodeficiency virus; VHIV, vertically acquired HIV; HHIV, horizontally acquired HIV.

For the 8867 women, the median age at VHIV diagnosis was 6 years (IQR, 0–9), and the median age at HHIV diagnosis was 22 years (IQR, 19–24; Table 1). The median age at delivery for women with VHIV was 20 years (IQR, 18–22) and for women with HHIV it was 24 years (IQR, 21–26). VHIV and HHIV women had the same median number of antenatal care visits (9 visits). Women with VHIV were more likely to have obtained a tertiary or secondary education (93.8% vs 89.3%) and more likely to be nulliparous (82.1% vs 38.8%). Women with VHIV were also more likely to be classified as having low maternal weight (24.6% vs 15.7%). Women with HHIV were more likely to be multiparous (25.9% vs 4.0%) and to have consumed alcohol or smoked during pregnancy (10.1% vs 6.2%). Last, women with VHIV were more likely to be on nevirapine (NVP)–based ART (34.1% vs 4.8%) and to have a recorded duration of initial ART prescribed or continued during pregnancy use longer than 5 years (71.9% vs 8.1%).

Table 1.

Baseline Maternal Characteristics by Mode of Human Immunodeficiency Virus Acquisition

Characteristic	Vertically Acquired HIV (n = 402) (%)	Horizontally Acquired HIV (n = 8465) (%)
Maternal age, median (IQR), y	20 (18–22)	24 (21–26)
Age of first diagnosis, median (IQR), y	6 (0–9)	22 (19–24)
Education
Primary/none	20 (5.0)	722 (8.5)
Secondary/tertiary education	377 (93.8)	7562 (89.3)
Missing	5 (1.2)	181 (2.1)
Occupation
Salaried	49 (12.2)	2042 (24.1)
Nonsalaried/Housewife	289 (71.9)	5 (65.8)
Student	47 (11.7)	477 (5.6)
Missing	17 (4.2)	375 (4.4)
Marital statusa
Single	387 (96.3)	8067 (95.3)
Married	3 (0.75)	148 (1.7)
Divorced/Widowed	0	5 (0.06)
Missing	12 (3.0)	245 (2.9)
Nationalitya
Botswana citizen	400 (99.5)	8269 (97.7)
Other	0	167 (2.0)
Missing	2 (0.5)	29 (0.3)
Clinical visits during pregnancy (interquartile range)	9 (7–12)	9 (6–12)
Parity
Nulliparous	330 (82.1)	3283 (38.8)
Primiparous	53 (13.2)	2925 (34.5)
Multiparous (2–4 births)	16 (4.0)	2189 (25.9)
Grand multiparous (≥5 births)	1 (0.3)	45 (0.5)
Missing	2 (0.5)	23 (0.3)
Anemia during pregnancyb
Yes	99 (24.6)	2339 (27.6)
No	163 (40.5)	2885 (34.1)
Missing	140 (34.8)	3241 (38.3)
Hypertension during pregnancyc
Yes	53 (13.2)	1164 (13.8)
No	341 (84.8)	6879 (81.3)
Missing	8 (2.0)	422 (5.0)
Low maternal weight (<50 kg)
Yes	99 (24.6)	1327 (15.7)
No	284 (70.6)	6592 (77.9)
Missing	19 (4.7)	546 (6.4)
Smoke/Alcohol use during pregnancy
Yes	25 (6.2)	859 (10.1)
No	342 (85.1)	6761 (79.9)
Missing	35 (8.7)	845 (10.0)
Antibiotic use in pregnancy
Yes	201 (50.0)	3885 (45.9)
No	194 (48.3)	4201 (49.6)
Missing	7 (1.7)	379 (4.5)
CD4 cell count, cells/mm3
<200	3 (0.7)	192 (2.3)
200–349	13 (3.2)	483 (5.7)
350–499	21 (5.2)	643 (7.6)
≥500	51 (12.7)	928 (11.0)
Missing	314 (78.1)	6219 (73.5)
Initial ART prescribed/continued during pregnancy
Nevirapine-containing ART	137 (34.1)	405 (4.8)
Efavirenz-containing ART	111 (27.6)	4458 (52.7)
Dolutegravir-containing ART	67 (16.7)	2438 (28.8)
Lopinavir-containing ART	56 (13.9)	149 (1.8)
Missing	31 (7.7)	1015 (12.0)
Duration of ART, y
>2	59 (14.7)	5354 (63.3)
2–5	24 (6.0)	1428 (16.9)
>5	289 (71.9)	687 (8.1)
Missing	30 (7.5)	996 (11.8)

Percentages may not add to 100% due to rounding.

Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus.

^aFisher exact test used.

^bAnemia is defined as hemoglobin measurement ≤10 g/dL.

^cHypertension defined as any systolic blood pressure ≥140 mm Hg or any diastolic blood pressure ≥90 mm Hg.

The pregnancy characteristics and delivery outcomes among VHIV and HHIV women are shown in Table 2. The proportions with adverse birth outcomes were similar among VHIV (PTD, 19.7%; stillbirth, 1.2%; and neonatal death, 1.0%) and HHIV women (PTD, 23.8%; stillbirth, 2.5%; and neonatal death, 1.6%; all P values > .05). However, compared with women with HHIV, women with VHIV experienced greater levels of SGA (27.1% vs 18.4%, P < .0001) and very SGA (10.9% vs 7.1%, P = .003) but a lower proportion of very PTD (2.2% vs 4.8%, P = .01). Crude and adjusted relative risks for adverse birth outcomes between VHIV and HHIV women were generated. To reduce potential bias of the relationship between women with VHIV and SGA and very PTD, we constructed a multivariable model that included maternal age, education, parity, low maternal birth weight, smoking and alcohol use during pregnancy, and initial ART prescribed or continued during pregnancy. After adjusting for these variables and excluding women who changed or terminated their ART regimen during pregnancy, the aRR among women with VHIV for SGA was 1.18 (95% CI, 0.97–1.43), for VSGA was 1.05 (95% CI, 0.74–1.50), and for very PTD was 0.41 (95% CI, 0.18–0.95).

Table 2.

Delivery Characteristics and Birth Outcomes by Mode of Human Immunodeficiency Virus Acquisition

Adverse Birth Outcome	Vertically Acquired HIV Infants (n = 402) (%)	Horizontally Acquired HIV Infants (n = 8465) (%)	P Value	RR (95% CI)	aRRa (95% CI)
Median gestational age, median (IQR),b wk	39 (37–40)	39 (37–40)	.91	…	…
Preterm deliveryc	…	…	.64	0.95 (0.80–1.17)	0.94 (0.72–1.21)
Yes	79 (19.7)	1748 (23.8)	…	…	…
No	310 (77.1)	6454 (76.3)	…	…	…
Missing	13 (3.2)	263 (3.1)	…	…	…
Very preterm deliveryd	…	…	.01	0.47 (0.24–0.90)	0.41 (0.18–0.95)
Yes	9 (2.2)	407 (4.8)	…	…	…
No	380 (94.5)	7795 (92.1)	…	…	…
Missing	13 (3.2)	263 (3.1)	…	…	…
Stillbirth	…	…	.12	0.50 (0.21–1.21)	0.53 (0.19–1.52)
Yes	5 (1.2)	210 (2.5)	…	…	…
No	397 (98.8)	8254 (97.5)	…	…	…
Missing	0	1 (0.01)	…	…	…
Neonatal deathe	…	…	.31	0.60 (0.22–1.62)	0.62 (0.18–2.14)
Yes	4 (1.0)	138 (1.6)	…	…	…
No	392 (97.5)	8102 (95.7)	…	…	…
Missing	6 (1.5)	225 (2.7)	…	…	…
Median birth weight, median (IQR),b kg	2.86 (2.56–3.20)	3.0 (2.66–3.30)	<.0001	…	…
SGA	…	…	<.0001	1.47 (1.24–1.73)	1.18 (0.97–1.43)
Yes	109 (27.1)	1559 (18.4)	…	…	…
No	278 (69.2)	6564 (77.5)	…	…	…
Missing	15 (3.7)	342 (4.0)	…	…	…
Very SGA	…	…	.003	1.55 (1.16–2.06)	1.05 (0.74–1.50)
Yes	44 (10.9)	597 (7.1)	…	…	…
No	343 (85.3)	7526 (88.9)	…	…	…
Missing	15 (3.7)	342 (4.0)	…	…	…

Percentages may not add to 100% due to rounding.

Abbreviations: aRR, adjusted risk ratio CI, confidence interval; HIV, human immunodeficiency virus; IQR, interquartile range; SGA, small for gestational age (<10th percentile of birth weight by gestational age); very SGA, very small for gestational age (<3rd percentile of birth weight by gestational age); RR, risk ratio.

^aAdjusted for maternal age, education, parity, low maternal weight, smoking or alcohol use, and initial antiretroviral therapy regimen prescribed or continued during pregnancy excluding women who changed or terminated treatment during pregnancy (women with horizontally acquired HIV = 180; women with vertically acquired HIV = 25).

^bWilcoxon rank sum test used.

^cPreterm delivery is delivery <37 weeks gestational age.

^dVery preterm delivery is delivery <32 weeks gestational age.

^eNeonatal death is <28 days infant death.

To further estimate the effect of initial ART regimen prescribed or continued during pregnancy on the association between women with VHIV and any adverse or severe adverse birth outcome, unadjusted log-binomial regression models were developed. Compared with women with HHIV, women with VHIV had an increased risk of any adverse birth outcome (RR = 1.21; 95% CI, 1.08–1.36; Table 3). As observed in the crude relationship between women with VHIV and the separate adverse birth outcomes, SGA and VGSA, when adjusted for ART regimen (NVP-based), the RR was substantially reduced (aRR = 1.08; 95% CI, 0.94–1.23). The adjusted associations between NVP-based ART and any adverse or severe adverse birth outcome were 1.34 (95% CI, 1.30–1.49) and 1.72 (95% CI, 1.40–2.11), respectively. Separate sensitivity analyses that included duration of ART use, calendar year of delivery, and hypertension during pregnancy did not affect the overall reported associations. When recent CD4 cell count was included, the association for SGA became significant; however, this could be driven by its availability and utility.

Table 3.

Crude and Adjusted Risk Ratios for Any Adverse or Any Severe Adverse Birth Outcome

	Any Adverse Birth Outcomea		Any Severe Adverse Birth Outcomeb
Variable	RR (95% CI)	aRRc (95% CI)	RR (95% CI)	aRRc (95% CI)
Vertically acquired HIV	1.21 (1.08–1.36)	1.08 (0.94–1.23)	1.11 (0.87–1.42)	0.83 (0.61–1.13)
Horizontally acquired HIV	Reference	Reference	Reference	Reference
Maternal age (years)	0.999 (0.998–1.00)	1.00 (0.98–1.01)	1.013 (1.01–1.015)	1.01 (0.99–1.04)
Parity
Nulliparous	Reference	Reference	Reference	Reference
Primiparous	0.90 (0.88–0.92)	0.90 (0.83–0.98)	0.93 (0.90–0.97)	0.73 (0.62–0.86)
Multiparous	0.96 (0.94–0.98)	0.90 (0.82–0.99)	1.00 (0.96–1.04)	0.67 (0.55–0.81)
Grand multiparous	1.05 (1.01–1.10)	1.03 (0.71–1.50)	1.04 (0.96–1.13)	1.18 (0.61–2.31)
Education
Primary/none	Reference	Reference	Reference	Reference
Secondary/Tertiary	0.83 (0.80–0.85)	0.91 (0.81–1.02)	0.82 (0.78–0.87)	0.94 (0.74–1.21)
Low maternal weight
No	Reference	Reference	Reference	Reference
Yes	1.44 (1.41–1.47)	1.42 (1.32–1.52)	1.45 (1.38–1.51)	1.48 (1.28–1.72)
Smoke/ alcohol use during pregnancy
No	Reference	Reference	Reference	Reference
Yes	1.04 (1.01–1.07)	1.05 (0.96–1.16)	1.13 (1.07–1.19)	0.98 (0.79–1.20)
Initial ART prescribed/cont. during pregnancy
Efavirenz-containing ART	Reference	Reference	Reference	Reference
Nevirapine-containing ART	1.25 (1.21–1.30)	1.34 (1.30–1.49)	1.52 (1.42–1.64)	1.72 (1.40–2.11)
Dolutegravir-containing ART	0.96 (0.92–1.00)	0.99 (0.92–1.06)	0.94 (0.86–1.02)	0.81 (0.70–0.96)
Lopinavir-containing ART	1.26 (1.17–1.35)	1.19 (1.00–1.41)	1.37 (1.19–1.58)	1.16 (0.79–1.71)

Abbreviations: aRR, adjusted risk ratio; ART, antiretroviral therapy; CI, confidence interval; HIV, human immunodeficiency virus; RR, risk ratio.

^aAny adverse outcomes include preterm delivery (<37 weeks gestational age), small for gestational age (<10th percentile of birth weight by gestational age), neonatal death (infant death <28 days), and stillbirth (summed Apgar score of 0).

^bAny severe adverse outcomes include very preterm delivery (<32 weeks), very small for gestational age (<3rd percentile of birth weight by gestational age), neonatal death, and stillbirth.

^cAdjusted for maternal age, education, parity, low maternal weight, smoking or alcohol use, and initial antiretroviral therapy regimen prescribed or continued during pregnancy excluding women who changed or terminated treatment during pregnancy (women with horizontally acquired HIV = 180; women with vertically acquired HIV = 25).

DISCUSSION

With the increased availability and safety of ART, a greater number of children who vertically acquired HIV infection live to reproductive age, especially in sub-Saharan Africa [4]. To our knowledge, in this study, we are among the first to evaluate adverse birth outcomes among women with VHIV from an African cohort. While our unadjusted results showed that women with VHIV were significantly more likely to have SGA and significantly less likely to have very PTD infants when compared with women with HHIV, these unadjusted associations were biased by the use of NVP-based ART during pregnancy. Women with VHIV were more likely to be on an ART regimen that contained NVP (34.1% vs 4.8%), which is known to be associated with adverse birth outcomes such as SGA, VSGA, and very PTD [10, 13, 14]. After adjusting for NVP-based ART, the observed unadjusted association became null for SGA and VSGA.

The reason for higher NVP use among women with VHIV is due to the historical evolution of Botswana’s HIV treatment guidelines: NVP-based ART was recommended for women of reproductive age from 2002 until 2012 but was continued for stable patients despite the change to efavirenz-based and dolutegravir-based regimens in 2012 and 2016, respectively [15]. Thus, women with VHIV who entered reproductive age taking NVP-based ART were disproportionately likely to receive this legacy ART regimen during pregnancy because most were on ART previously. Noted differences between women with VHIV and women with HHIV included social and behavioral factors, such as education and alcohol consumption or smoking. Therefore, we cannot entirely exclude these factors or other unmeasured confounders as possible contributors to the differences in adverse birth outcomes. In particular, it is possible that there are still inherent differences between women with VHIV and women with HHIV, particularly as viral load and changes in CD4 count during pregnancy may contribute to the observed differences in adverse birth outcomes. However, our results provide evidence that NVP may be one of the primary explanations for the excess adverse birth outcomes among women with VHIV and are supported by prior Tsepamo studies that demonstrated increased risk of adverse birth outcomes with NVP compared with updated ART [10, 14]. While we cannot explain the apparent reduction in very PTD among women with VHIV in our adjusted analyses, the number of events was small for the women with VHIV, and this finding may be the result of chance.

Previous studies of women with VHIV in pregnancy have also suggested no increased risk of adverse birth outcomes when compared with women with HHIV. Byrne et al compared adverse birth outcomes between VHIV and HHIV women in the United Kingdom and Ireland and reported no significant differences between the groups regarding preterm deliveries or low birth weight; however, this study was limited by a relatively small sample size [5]. Using the US Pediatric and HIV/AIDS Cohort Study with a larger sample size, Jao et al found that the proportion of adverse birth outcomes, such as PTD, SGA, and low birth weight, was similar among VHIV and HHIV women [6]. Our study adds to the literature by providing reassuring evidence that differences in adverse birth outcomes between VHIV and HHIV women were more likely to be related to use of older regimens. Supported by recent data that raise concerns about the risk of adverse birth outcomes, our findings emphasize the importance of updating older ART regimens [8].

The strengths of this study included a large sample size, a well-defined population of pregnant women living with HIV, the ability to age-stratify and control for other demographic factors, and an assessment of multiple adverse birth outcomes. However, this study had several limitations. Because we did not have complete birth records and, in some cases, clinicians may not have been aware of HIV diagnosis time and date, some women with VHIV could have been misclassified. However, we attempted to reduce the probability of this misclassification using a conservative VHIV definition (resulting in a median age at HIV diagnosis of 6 years). Moreover, multiple pregnancies from the same women were not noted in the Tsepamo dataset. Additionally, important factors, such as nadir CD4 cell count and HIV-RNA measurements, were missing from many of the women living with HIV and therefore not included in the final analyses. Finally, women who delivered prior to 24 weeks were not included in our surveillance, thus we cannot comment on this outcome.

In conclusion, we detected no increase in adverse birth outcomes among women with VHIV when accounting for potential risk factors, including greater exposure to older ART regimens during pregnancy among women with VHIV. This study provides insight on an understudied growing population of women with VHIV and suggests that updating legacy ART regimens in these women prior to pregnancy may improve birth outcomes.

Notes

Acknowledgments. We acknowledge the maternity nurses and hospital staff in Botswana; the Botswana Ministry of Health; and staff at the Botswana Harvard Partnership, especially the study research assistants Gosego Legase, Daphne Segobye, Mmapua Ofhestse, Tshephang Motlotlegi, Shally Morgan, Kebabonye Rabasiako, Tsaone Gaanakala, Edith Moseki, Cynthia Dube, Keemenao France, Onkabetse Mokgosiande, and Rosemary Moremi. We also acknowledge Kathy Brenner for assisting in manuscript development.

Financial support. This study was supported by the National Institutes of Health (R01HD080471).

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.