Prevention of perinatal HIV transmission in an area of high HIV prevalence in the United States

Abstract

Objective:

To evaluate the uptake of perinatal HIV preventive interventions by risk of perinatal HIV transmission in mother-infant pairs in a high HIV prevalence area in the United States (US).

Study Design:

This was a retrospective cohort study of mother-infant pairs with perinatal HIV exposure during 2013–2017 managed at a subspecialty pediatric HIV program in Washington, DC. We collected demographics, maternal HIV history, delivery mode, maternal and infant antiretroviral drug (ARV) use, and infant’s HIV test results. We compared the uptake of recommended preventive interventions in low-risk (mothers on ARVs with viral suppression) and high-risk (mothers without ARVs or viral suppression) mother-infant pairs using Pearson’s Chi-square, Fisher’s exact, Wilcoxon rank sum tests, and logistic regression.

Results:

We analyzed 551 HIV-exposed infants and 542 mothers living with HIV. The majority of mothers received ARVs (95.5%), had HIV RNA ≤1,000 copies/mL before delivery (81.9%), and received intrapartum zidovudine (65.5%). The majority of all HIV-exposed infants was low-risk (82.6%) and received postpartum ARVs (98.9%). Among low-risk infants, 53.2% were delivered via cesarean delivery, and 62.9% and 96.5% were administered intrapartum and postpartum zidovudine, respectively. Among high-risk infants, 84.4% were delivered via cesarean delivery, 78.1% received intrapartum zidovudine, and 62.5% received combination ARVs. Nine high-risk infants acquired HIV perinatally.

Conclusion:

In an area of high HIV prevalence in the US, a large proportion of low-risk HIV-exposed infants received intrapartum zidovudine and was delivered via cesarean delivery. We also observed missed opportunities for the prevention of perinatal HIV transmission.

Introduction

With the implementation of strategies to prevent perinatal HIV transmission, the incidence of perinatally acquired HIV has decreased dramatically in the United States (US).¹ These strategies include universal prenatal HIV screening,^{2, 3} advancement of antiretroviral therapy (ART) for pregnant women living with HIV^2–5 and infant antiretroviral drug (ARV) prophylaxis,^{5, 6} cesarean delivery for women with elevated plasma HIV-1 RNA viral load,^{2, 7} and replacement of breastfeeding with exclusive formula feeding.² Approximately 5,000 women living with HIV give birth annually in the US,⁸ and only 32 infants (or 0.8 per 100,000 live births) were diagnosed with perinatally acquired HIV nationally in 2018.⁹ The rate of perinatal transmission of HIV has significantly declined from an estimated 1,630 perinatal HIV infections in the US in 1993,¹⁰ highlighting the overall success of national approaches to the prevention of perinatal HIV.

US guidelines for the prevention of perinatal HIV transmission are developed, maintained, and updated annually by the Department of Health and Human Services (HHS) Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission.¹¹ The management of maternal ART and ARV regimens for infants is based on maternal factors that affect the risk of perinatal HIV transmission. “Low risk” is defined as infants who are born to women living with HIV who received ART during pregnancy with sustained virologic suppression near delivery without concerns for non-adherence to antenatal ART. “Higher risk” is defined as infants born to women living with HIV who did not receive or had poor adherence to antenatal ART, received only intrapartum ARVs, had detectable HIV RNA near delivery, or had acute or primary HIV infection during pregnancy or breastfeeding. The current recommendation for postnatal management of infants at low risk of HIV transmission is to prescribe oral zidovudine (ZDV) for 4 weeks,¹¹ instead of 6 weeks which was recommended prior to 2014.¹² Combination infant ARV regimens are recommended for infants at higher risk of HIV transmission, and include either a dual regimen with 6 weeks of ZDV plus three doses of nevirapine (NVP); or a triple regimen with ZDV plus lamivudine (3TC) plus NVP or raltegravir (RAL).^{11, 13} The HHS perinatal HIV management guidelines were significantly modified in 2014. For women living with HIV on ART with an HIV RNA ≤1,000 copies/mL in late pregnancy and near delivery, the 2014 guidelines no longer recommended administration of maternal intrapartum intravenous (IV) ZDV.¹² Currently, data are limited on the actual implementation of these changes and how obstetric and pediatric care in the real-world setting is aligned with the HHS perinatal HIV prevention guidelines.¹⁴

Washington, District of Columbia (DC) represents one of the “hotspots” of the national HIV epidemic with an overall HIV prevalence of 1.8% in 2018.^{15, 16} Women living with HIV constitute over a quarter (26.1%) of adults living with HIV in DC.¹⁶ Children’s National Hospital, located in DC, serves as a major referral center for perinatally HIV-exposed infants (HEI), providing HIV counseling, testing, and treatment services to an estimated 95% of affected mother-infant pairs in the metropolitan DC area including suburban Maryland and Virginia.¹⁴ In this study, we aimed to evaluate the uptake of HHS recommended perinatal HIV preventive interventions in the metropolitan DC area by comparing delivery mode and receipt of maternal and infant ARVs between mother-infant pairs at low risk with those at higher risk for perinatal HIV transmission.

Methods

Study design

We conducted a retrospective cohort analysis of mother-infant pairs with perinatal HIV exposure evaluated at the Special Immunology Services (SIS) in Children’s National Hospital, between January 2013 and December 2017. SIS follows HEI from birth to 18 months of age, with virologic testing with HIV DNA and/or RNA polymerase chain reaction (PCR) per HHS guidelines.^{11, 13} All HEI evaluated at least once at SIS were included in the data analysis. The study was approved by the Institutional Review Board with informed consent waived.

We classified all HEI into two cohorts of “low-risk” or “high-risk”. “Low-risk” criteria included being born to a woman living with HIV who reported adherence to ART and maintained viral suppression near delivery with HIV RNA ≤1,000 copies/mL. “High-risk” criteria included being born to a woman living with HIV with poor ART adherence and/or without viral suppression near delivery (e.g., HIV RNA >1,000 copies/mL). In accordance with the HHS perinatal HIV guidelines, the infant’s HIV status was considered negative if perinatal HIV infection was definitively excluded in non-breastfed infants with at least two negative HIV nucleic acid amplification tests: one at age ≥1 month and the other at age ≥4 months.^{11, 13}

Data collection

We extracted data from the SIS clinical database on HEI generated from the infant’s electronic medical records (EMR) and maternal referral forms from the delivery hospitals. Collected data included maternal demographics (age, race), timing of maternal HIV diagnosis, antenatal ART regimen near the time of delivery, HIV RNA near the time of delivery, intrapartum ZDV use and delivery mode. Infant data included gestational age at delivery, sex, postnatal ARV regimen and duration, HIV test results, and biological father’s HIV status. De-identified study data were managed using Research Electronic Data Capture (REDCap) program.¹⁷

Data analysis

We used Pearson’s Chi-square test or Fisher’s exact test to compare categorical variables, and Wilcoxon rank-sum for continuous variables. We applied logistic regression to estimate the odds of cesarean delivery. To reduce the effect of possible confounding variables in this study, we adjusted the odds of having a cesarean delivery for variables with p<0.10 in unadjusted analysis. A p<0.05 was considered statistically significant. Analyses were performed using SAS (SAS Institute, Cary, North Carolina), version 9.4.

Results

Data from mother-infant pairs (551 HEIs and their 542 mothers) were included in the analysis. The infants were delivered at 34 known regional healthcare facilities in DC (45.5%), Maryland (46.5%), Virginia (6.0%) and other states (0.9%); the remaining infants (1.1%) were delivered at home or at unknown facilities. The median maternal age at the time of the delivery was 31 years (interquartile range (IQR) 26–36 years), the majority of mothers were African-American (n=379; 68.8%) or African (n=136; 24.7%) (Table 1). The majority of mothers received antenatal ART (n=526; 95.5%), comprised most frequently of dual nucleoside reverse transcriptase inhibitors (NRTIs) (n=490; 93.1%) with a boosted protease inhibitor (PI) (n=293; 55.7%). The remainder of the mothers were prescribed ART with a dual NRTI backbone combined with a non-nucleoside reverse transcriptase inhibitor (NNRTI) (n=98; 18.6%) or integrase strand transfer inhibitor (INSTI) (n=76; 14.4%), and a few mothers received a combination of two NRTIs, INSTI and a boosted PI (n=5; 1.0%). Eight mothers (1.5%) received ART without a dual NRTI backbone, and 28 mothers (5.3%) had an unknown ART regimen. After excluding 53 pregnancies with unknown ART regimens and/or an unknown prior treatment history that would influence the appropriate selection of ARVs, 392/473 (82.9%) of pregnant women were prescribed ARV regimens corresponding to the relevant HHS guidelines designation of preferred or alternative drugs.^{18, 19} The remaining women were prescribed ART regimens recommended for use under special circumstances (n=4; 0.8%), with insufficient evidence of use during pregnancy (n=53; 11.2%), not recommended for use during pregnancy (n=23; 4.9%), and one not mentioned in the relevant HHS perinatal HIV guidelines.

Table 1.

Maternal and infant characteristics by perinatal HIV transmission risk category.

Characteristic†	Total HEI‡ (n=551)	Low-risk HEI (n=455)	High-risk HEI (n=96)	p-value§
Maternal Characteristics
Median age, years (Q1, Q3)	31 (26, 36)	31, (26, 36)	28, (24, 33)	0.0004
Race/ethnicity, n (%):
African	136 (24.7%)	116 (25.5%)	20 (20.8%)	0.1391
African-American	379 (68.8%)	313 (68.8%)	66 (68.7%)
Asian	4 (0.7%)	3 (0.7%)	1 (1.0%)
Caucasian	8 (1.4%)	4 (0.9%)	4 (4.2%)
Hispanic	19 (3.4%)	15 (3.3%)	4 (4.2%)
HIV VL at delivery, n (%):
Undetectable (<20 copies/mL)	391 (71.0%)	388 (85.3%)	3 (3.1%)	NA
20–50 copies/mL	15 (2.7%)	15 (3.3%)	0 (0%)
>50–400 copies/mL	36 (6.5%)	35 (7.7%)	1 (1.0%)
>400–1,000 copies/mL	9 (1.6%)	6 (1.3%)	3 (3.1%)
>1000 copies/mL	51 (9.3%)	0 (0%)	51 (53.1%)
Unknown	49 (8.9%)	11 (2.4%)	38 (39.6%)
Median years since HIV diagnosis (Q1, Q3)	4 (1, 9)	5 (2, 10)	2 (0, 8)	0.0004
HIV diagnosed during pregnancy, n (%)	120 (21.8%)	85 (18.7%)	35 (36.4%)	NA
Received antenatal ART, n (%)	526 (95.5%)	453 (99.6%)	73 (76.0%)	<.0001
Delivery mode, n (%):
Cesarean delivery (CD)	323 (58.6%)	242 (53.2%)	81 (84.4%)	<.0001
Vaginal	225 (40.8%)	211 (46.4%)	14 (14.6%)
Received intrapartum ZDV, n (%)	361 (65.5%)	286 (62.9%)	75 (78.1%)	0.0001
Infant Characteristics
Female sex, n (%)	264 (47.9%)	221 (48.6%)	43 (44.8%)	0.5005
Median birth gestational age, weeks (Q1, Q3)	38 (37, 39)	39 (38, 40)	38 (36, 38)	<.0001
ARV prophylaxis¶, n (%):				<.0001
ZDV only	472 (85.7%)	439 (96.5%)	33 (34.4%)
Dual ARV	33 (6.0%)	8 (1.8%)	25 (26.0%)
Triple ARV	40 (7.3%)	5 (1.1%)	35 (36.5%)
Duration of ARV prophylaxis, n (%):
≤4 weeks	267 (48.5%)	262 (57.6%)	5 (5.2%)	<.0001
>4 weeks	253 (45.9%)	174 (38.2%)	79 (82.3%)
Final HIV status, n (%):
HIV-uninfected	479 (86.9%)	405 (89.0%)	74 (77.1%)	<.0001
HIV-infected	9 (1.6%)	0 (0.0%)	9 (9.4%)
Unknown	63 (11.4%)	50 (11.0%)	13 (13.5%)
Biological father’s HIV status, n (%):				<.0001
HIV-infected	72 (13.0%)	59 (13.0%)	13 (13.5%)
HIV-uninfected	247 (44.8%)	231 (50.8%)	16 (16.7%)
Unknown	232 (42.1%)	165 (36.3%)	67 (69.8%)

^†Some characteristics were not available for all participants in addition to those specifically noted as unknown above, including maternal age (n=32, 5.8%), race/ethnicity (n=5; 0.9%), years since HIV diagnosis (n=34; 6.2%), HIV diagnosis during pregnancy (n=9; 1.6%), delivery mode (n=5; 0.9%), intrapartum ZDV (n=52; 9.4%), birth gestational age (n=63; 11.4%), infant ARV prophylaxis (n=6; 1.1%), duration of ARV prophylaxis (n=31; 5.6%).

^‡A total of 542 mothers delivered 551 infants.

^§For categorical variables, Pearson’s chi-square test is used unless the expected cell size is small (i.e. <5), where Fisher’s exact test is used instead; for continuous variables, Wilcoxon rank sum test is used.

^¶Dual ARV refers to ZDV plus three doses of nevirapine. Triple ARV refers to ZDV plus lamivudine (3TC) plus nevirapine (NVP) or raltegravir (RAL).

Acronyms: ART, antiretroviral therapy; ARV, antiretroviral drug; CD, cesarean delivery; HEI, HIV-exposed infant; NA, not applicable due to these variables being part of the definitions for risk categorization for HEIs; VL, viral load; ZDV, zidovudine;.

The majority of HEIs (n=455; 82.6%) were low-risk for perinatal HIV transmission (Table 1). Three infants with unknown perinatal HIV transmission risk were presumed to be high-risk. A majority of the low-risk infants were born to mothers with HIV RNA <20 copies/mL (n=388; 85.3%) (Table 1). Compared with mothers of low-risk HEIs, mothers of high-risk HEIs were younger (28 vs 31 years; p=0.0004) and most had unknown or elevated HIV RNA >1,000 copies/mL (92.7% vs 2.4%; p<0.0001) (Table 1).

More than half of all HEIs were delivered via cesarean delivery (n=323; 58.6%) and the majority of these infants were considered to be low-risk (n=242/323; 74.9%) (Table 1). Most mothers who had cesarean delivery also received intrapartum ZDV (n=229; 70.9%) (data not shown). After excluding deliveries in 2013, prior to 2014 HHS recommendations reserving intrapartum ZDV for women with HIV RNA >1,000 copies/mL,¹² 61.5% (281/457) of mothers received intrapartum ZDV between 2014 and 2017 (data not shown). Compared to low-risk, a higher proportion of high-risk HEIs received intrapartum ZDV (62.9% vs 78.1%; p=0.0001).

High-risk HEIs had slightly lower median gestational age at delivery (38 vs 39 weeks; p<0.0001) and higher proportions of fathers with unknown HIV status compared with low-risk HEIs (69.8% vs 36.3%; p<0.0001) (Table 1). Mothers of high-risk HEIs had higher percentages of being diagnosed with HIV during the recent pregnancy (36.4% vs 18.7%; p<0.0001), lower antenatal ART use (76.0% vs 99.6%; p<0.0001), and a shorter duration of time since HIV diagnosis (2 vs 5 years; p=0.0004) (Table 1). Of the 35 high-risk HEIs born to women diagnosed with HIV during pregnancy, six (17.1%) were born to women who seroconverted during pregnancy (data not shown). The timing of seroconversion for the remaining women was unknown.

Most HEIs received postpartum ARVs (n=545; 98.9%), with the majority (n=472; 85.7%) receiving only ZDV and only 13.3% (n=73) receiving combination ARV regimens. Six infants did not receive ARVs due to not receiving a prescription (n=1), maternal decision (n=1), delayed maternal HIV diagnosis (n=2), and other unknown reasons (n=2). Compared to low-risk HEIs, more high-risk HEIs received combination ARV regimens (62.5% vs 2.9%; p<0.0001) for a longer (>4 weeks) duration of time (82.3% vs 38.2%; p<0.0001) (Table 1). Approximately one-third (n=33; 34.4%) of high-risk HEIs received only ZDV and five (5.2%) high-risk HEIs received ≤4 weeks of ARVs (Table 1). One high-risk HEI who received ≤4 weeks of ARVs was diagnosed with HIV infection during the first month of life and subsequently initiated ART. The remaining high-risk HEIs received only ZDV or ≤4 weeks of ARVs due to insufficient prescription or unknown reasons.

Sixty-three HEIs (11.4%) were lost to follow-up and had an unknown final HIV status. Nine (1.6%) infants were diagnosed with perinatal HIV infection, all of whom were high-risk HEIs. Seven of the 9 infants with perinatal HIV infection were born to women whose HIV diagnosis was known by the time of delivery. Despite these seven infants meeting high-risk criteria, only three were initiated on combination ARV regimens prior to being diagnosed with perinatal HIV infection (Table 2). One infant with perinatal HIV was breastfed by a woman who did not know her diagnosis at the time (Table 2). Of the nine infants diagnosed with perinatal HIV infection, four were estimated to be infected in utero, one was estimated to be infected through intrapartum transmission, and the timeline for infection could not be estimated for the remaining four.

Table 2.

Characteristics of HIV-infected infants (2013–2017).

Year of birth	Timing of maternal HIV diagnosis†	Maternal antenatal ART	Maternal VL peri-delivery	Delivery mode	Maternal intrapartum ZDV	Perinatal HIV risk category	Neonatal ARV prophylaxis	Infant age at HIV diagnosis	Factors attributing to perinatal HIV (author’s comments)
2013	Likely during 2nd or 3rd trimester	Unknown	Unknown	Vaginal	Unknown	Unknown (high)	None	5 months old	Maternal seroconversion during pregnancy, lack of prenatal care
2013	3rd trimester	Yes	Unknown	CD	Yes	High	ZDV	1 month old	Maternal seroconversion during pregnancy, late start of antenatal ART
2015‡	3rd trimester	Yes	UD	Vaginal	No	High	ZDV	Birth	Late maternal HIV diagnosis during pregnancy and late start of antenatal ART
2016	Before pregnancy	Unknown	Unknown	Vaginal	Unknown	High	ZDV	16 months old	Lack of prenatal care, poor adherence to neonatal ARV prophylaxis, infant received ZDV instead of combination ARV
2016	At delivery	Unknown	>1000 copies/mL	Vaginal	No	High	Combination ARV	6 days old	Lack of prenatal care
2016	2nd trimester	Yes	>1,000 copies/mL	CD	Yes	High	Combination ARV	2 months old	Late start of prenatal care and antenatal ART
2017	Before pregnancy	Yes	UD	CD	Unknown	High	ZDV	Birth	Poor adherence during 1st trimester due to hyperemesis
2017	Before pregnancy	Yes	~800 copies/mL	CD	Yes	High	Combination ARV	Birth	Late start of prenatal care and antenatal ART
2017	6 weeks postpartum	No	Unknown	Vaginal	No	Unknown (High)	None	7 months old	Lack of prenatal maternal HIV testing, breastfeeding prior to maternal HIV diagnosis

^†8 of these women living with HIV were African or African-American.

^‡Transferred after birth from North Carolina.

Acronyms: ART, antiretroviral therapy; ARV, antiretroviral drug; CD, cesarean delivery; UD, undetectable; VL, viral load; ZDV, zidovudine

Due to the high rates of cesarean deliveries observed in our cohort, we evaluated the factors associated with cesarean delivery. Although the majority of cesarean deliveries occurred in mothers with low HIV RNA ≤1,000 copies/mL (n=238, 73.7%) (data not shown), HEIs born to women with unknown or >1,000 copies/mL HIV RNA had a higher odds of cesarean delivery compared to HEIs born to women with an undetectable HIV RNA (i.e.: <20 copies/mL) (adjusted OR 3.09; 95% CI 0.66, 14.47). Interestingly, HEIs born to women with HIV RNA 20–50 copies/mL and >400–1,000 copies/mL had a lower odds of cesarean delivery compared to HEIs born to women with an undetectable HIV RNA (adjusted OR 0.88; 95% CI 0.31, 2.53 and adjusted 0.27; 95% CI 0.06, 1.29, respectively). The significance of this result is unclear due to the small sample size of only 15 and 9 HEIs in the respective categories. Mothers of high-risk HEIs had higher proportions (84.4% vs 53.2%; p<0.0001) of cesarean delivery compared to low-risk infants, but the odds of cesarean delivery were not associated with HIV transmission risk (adjusted OR 2.51; 95% CI 0.54, 11.59) (Table 3). Aligned with guidelines recommending intrapartum ZDV in women with HIV RNA >1,000 copies/mL,¹¹ the receipt of intrapartum ZDV was observed to be associated with a higher odds of caesarean delivery (adjusted OR 1.81; 95% CI 1.17, 2.81). Compared to early preterm deliveries (≤34 weeks of gestation; n=31), term deliveries (>37 weeks of gestation; n=313) had lower odds of cesarean delivery (adjusted OR 0.72; 95% CI 0.27, 1.92). The odds of cesarean delivery was the same when comparing maternal age and race, timing of maternal HIV diagnosis (prior to or during pregnancy), antenatal maternal ART use, delivery facility location, and year of delivery (2013 or after 2013) (Table 3).

Table 3.

Factors associated with cesarean delivery (CD) for women living with HIV.

Variable†	OR (95%CI)	p-value	Adjusted OR (95% CI) ‡	p-value
Maternal Factors
Maternal age
<25 years of age	Reference	0.147
25–30 years of age	0.59 (0.35, 0.99)		-	-
>30 years of age	0.82 (0.50, 1.34)
Unknown	0.56 (0.25, 1.27)
Maternal race/ethnicity
African/African-American	Reference	0.160	-	-
All others	1.72 (0.81, 3.68)
HIV VL before delivery
<20 copies/mL	Reference	<.0001	Reference	0.09
20–50 copies/mL	1.04 (0.37, 2.91)		0.88 (0.31, 2.53)
>50–400 copies/mL	1.60 (0.79, 3.26)		1.33 (0.62, 2.86)
>400–1,000 copies/mL	0.45 (0.11, 1.84)		0.27 (0.06, 1.29)
>1,000 copies/mL or unknown	5.50 (3.02, 10.02)		3.09 (0.66, 14.47)
Timing of HIV diagnosis
Before pregnancy	Reference	0.408
During pregnancy	1.29 (0.84, 1.97)		-	-
Unknown	0.79 (0.33, 1.90)
Maternal antenatal ART
No	Reference	0.181	-	-
Yes	0.54 (0.22, 1.33)
Delivery facility location
DC	Reference	0.344
Maryland	1.34 (0.94, 1.93)		-	-
Virginia	1.64 (0.71, 3.78)
Others	1.07 (0.50, 2.30)
Intrapartum IV ZDV
No	Reference	0.0004	Reference	0.008
Yes	2.07 (1.39, 3.09)		1.81 (1.17, 2.81)
Year of Delivery
2013	Reference	0.462	-	-
After 2013	0.84 (0.53, 1.33)
Infant factors
Birth gestational age
Early preterm (<34 weeks)	Reference	0.018	Reference	0.416
Late preterm (35–<38 weeks)	1.0 (0.35, 2.87)		1.12 (0.35, 3.57)
Term (≥38 weeks)	0.46 (0.19, 1.12)		0.72 (0.27, 1.92)
HIV transmission risk
Low-risk	Reference	<.0001	Reference	0.239
High-risk	4.86 (2.67, 8.83)		2.51 (0.54, 11.59)

^†Some characteristics were not available for all participants in addition to those specifically noted as unknown above.

^‡Results are adjusted for all factors with p<0.1 in unadjusted models.

Acronyms: ARV, antiretroviral drug; ART, antiretroviral therapy; CD, cesarean delivery; VL, viral load; ZDV, zidovudine.

When evaluating the dynamics of preventive practice from 2013 to 2017 by risk categories, the prevalence of cesarean delivery remained relatively consistent throughout the five-year period (Figure 1). There were no annual variations in the geometric mean HIV RNA in mothers near the time of delivery between 2013 and 2017 (data not shown) for both low-risk and high-risk HEIs. We used the lower limit of detection for HIV RNA measurements (i.e.: log₁₀ 1.3) for women with an undetectable viral load. Annual intrapartum ZDV use remained stable in high-risk infants and decreased from 85.3% in 2013 to 46.2% in 2017 for low-risk infants (Figure 1). The proportion of high-risk infants delivered annually remained at approximately 20% between 2013 and 2017, with the exception of a decline in 2014 to 9.8% (data not shown). The proportion of HEIs receiving >4 weeks ARVs remained unchanged among high-risk infants, but declined among low-risk infants from 90.7% in 2013 to 17.0% in 2017 (Figure 1).

Figure 1. Proportions of a) low-risk and b) high-risk infants that received intrapartum zidovudine (ZDV), had cesarean delivery (CD), received >4 weeks of antiretroviral (ARV) prophylaxis, received combination ARV prophylaxis (2013–2017).

The top panel (a) shows the proportion of low-risk infants born from 2013 to 2017 who received intrapartum ZDV (clear bars), had CD (solid grey bars), received >4 weeks duration of ARV prophylaxis (diagonal black stripes), and received combination ARV (solid black bars). The bottom panel (b) shows the proportion of high-risk infants born from 2013 to 2017 who received intrapartum ZDV (clear bars), had CD (solid grey bars), received >4 weeks duration of ARV prophylaxis (diagonal black stripes), and received combination ARV prophylaxis (solid black bars).

Abbreviations: ARV, antiretroviral; CD, cesarean delivery; LR, low-risk; HR, high-risk; ZDV, zidovudine.

Discussion

Our study reports data on recent clinical practice of management to prevent perinatal HIV transmission in an area of high HIV prevalence in the US. In our cohort of mother-infant pairs with perinatal HIV exposure from metropolitan DC, the majority was at low risk for perinatal HIV transmission and received recommended maternal ART and infant postpartum ARVs. Consistent with HHS guidelines and national data on the use of ARVs among HEIs in the US between 1990–2015,²⁰ high-risk HEIs were more likely to receive combination ARVs compared to low-risk HEIs in our study. However, one-third of high-risk HEIs did not receive combination ARVs, representing missed opportunities for neonatal prevention of perinatally acquired HIV.

The composition and duration of infant ARVs was not consistently associated with the perinatal HIV transmission risk, with some low-risk HEIs receiving combination ARVs and some high-risk HEIs receiving suboptimal regimens. While certain factors such as parental substance abuse and unstable housing,²¹ and short duration of maternal ART²² may affect the decision to initiate an infant on combination ARVs, every effort must be made to optimize ARV regimens among high-risk HEIs. Our findings highlight the need to further optimize ARV regimens among high-risk HEIs and reduce the use of unnecessary ARV exposure among low-risk HEIs.

Cesarean delivery for pregnant women with HIV RNA >1,000 copies/mL has been recommended by both the HHS and American College of Obstetricians and Gynecologists since 2000.^{23, 24} Despite these guidelines recommending cesarean delivery and intrapartum ZDV only for women with HIV RNA >1,000 copies/mL near the time of delivery, a large proportion of low-risk infants were delivered via cesarean delivery and were exposed to intrapartum ZDV. Discordance of clinical practice with the national perinatal HIV prevention guidelines has been reported in earlier studies in the US. A large study of 8,054 deliveries for women living with HIV in the US found only 32.7% of HIV-exposed uninfected infants born between 2005 and 2008 received all recommended interventions to prevent perinatal HIV transmission (defined in the cited manuscript as receiving prenatal care, early maternal HIV testing, prenatal ARV prescription, intrapartum ARV prescription, infant ARV prescription, scheduled cesarean delivery for women with HIV RNA >1,000 copies/mL before labor, and no breastfeeding),²⁵ and only two-thirds of pregnant women with unknown or elevated HIV RNA had cesarean deliveries in Philadelphia between 2005 and 2013.²⁶

The overall proportion of cesarean deliveries in our cohort of women living with HIV (58.1%) was significantly higher compared to the DC, Maryland and Virginia rates of 32.2%, 33.9% and 32.6% respectively among all live births in 2017.²⁷ Although most women in our cohort had HIV RNA ≤1,000 copies/mL around delivery, we observed a higher rate of cesarean deliveries compared to two published US studies evaluating cesarean delivery rates among pregnant women living with HIV during the time periods of 1998–2013 (47%) and 1990–2015 (45%).^{20, 28} The latter study included a cohort of HEIs born between 2007–2015 with a comparable cesarean delivery rate to our study (56%).²⁰ However, this cohort was developed using a trigger-based design to detect infants with ART adverse events,²⁹ whereas our study included all referred HEIs. Studies from Europe reported that cesarean deliveries were frequently performed among women living with HIV due to non-HIV related reasons such as obstetrical concerns.^{30, 31} The higher rates of cesarean delivery among women living with HIV in resource-rich settings needs further investigation, given an increased risk of cesarean-related complications among women living with HIV compared to HIV-uninfected women.^32–34

In accordance with the HHS guidelines and similar to other US studies, our findings suggest that women with an elevated or unknown HIV RNA were three times more likely than women with an undetectable HIV RNA to undergo a cesarean delivery.^{11, 28} Interestingly, after adjusting for HIV RNA, intrapartum ZDV and gestational age, being at high-risk for perinatal HIV transmission was no longer associated with an increased odds of cesarean delivery, confirming that being high-risk alone was an inadequate rationale for a cesarean delivery. Multiple factors contribute to the reasons for cesarean delivery including maternal age,³⁵ detectable maternal HIV RNA, ^{28, 30} parity, birth complications³⁰ or maternal preference.³⁶

The proportion of high-risk mother-infants pairs with perinatal HIV exposure did not decrease and remained stable over the five year period, and we had 63 infants (11.4%; 50 low-risk, 13 high-risk) who did not receive final HIV testing. Loss to follow-up and high-risk HIV exposure both represent missed opportunities for perinatal HIV prevention and highlight the need for continued focus on the prevention of perinatally acquired HIV in the US. Efforts to retain HIV-exposed infants in care for repeat testing and evaluation are essential in preventing perinatal HIV transmission. Additionally, the lack of information on the father’s HIV status in high-risk HEIs observed in our study may be linked to a lack of paternal involvement, which has been associated with low birth weight and preterm delivery.³⁷ Further research is needed to understand the role of fathers of HEI in the cascade of testing and care for the prevention of perinatal HIV transmission.

Although not the main objective of this study, we observed similar proportions of pregnant women living with HIV receiving ART consisting of three drugs from two ARV classes compared to study from the Pediatric HIV/AIDS Cohort Study (PHACS) on ART coverage during pregnancy from 18 clinical research sites in the US (90.7% vs 87.9%, respectively).¹⁸ When applying categorizations of ARV regimens and individual ARVs used in relevant HHS guidelines, we observed a significantly higher use of preferred or alternative ARV regimens (82.9%) during pregnancy compared to the PHACS study (49.5%).¹⁸ This difference is likely due to several factors including the more recent five year timeline in our study (2013–2017) compared to PHACS (2006–2016), with more ARV pharmacokinetic and dosing data available in pregnancy, and consequent reclassification of several ARVs from “insufficient evidence” to “preferred” or “alternative” in regular updates of the HHS guidelines.^{11, 13}

Indeed, compared to an estimated 17 year time gap between the publication of research evidence and the implementation of related public health approaches into clinical practice globally,³⁸ the HIV field has moved at a considerably faster pace in both domains of treatment and prevention. Barriers to guideline implementation are complex, and include among others, physicians’ knowledge, attitudes and external factors including patient preferences and environmental-related factors.³⁹

Our study had some limitations. First, as we did not have access to maternal medical records, we were unable to verify indications for cesarean delivery by obstetricians. Maternal data was collected from the delivery hospital referral, infant discharge summaries (when available), and self-reported information to guide infant care. Second, we did not systematically analyze data on the rationale for the selection of infant ARVs by referring providers and did not collect the data on ART regimens of maternal ART that mothers received throughout the pregnancy and its relationship to maternal HIV infection. Nevertheless, our analysis represents a recent large sample cohort analysis of pregnant women living with HIV and their children in a “hotspot” for the US HIV epidemic ¹⁵, and provides a unique insight into the areas for improvement in the practical application of the US HHS perinatal HIV management guidelines.

Conclusions

In our study of mother-infant pairs with perinatal HIV exposure from an area of high HIV prevalence in the US, the majority of the perinatal HIV exposures represented low-risk scenarios for perinatal HIV transmission. We report, however, high rates of cesarean deliveries and intrapartum ZDV use among mother-infant pairs at low-risk for perinatal HIV transmission, and steadily high rates of high-risk HEIs with missed opportunities for intrapartum and infant prophylaxis to prevent HIV transmission. Prospective evaluation of regional and national barriers to best clinical practices in accordance to the current HHS guidelines is warranted to further advance towards the elimination of perinatal HIV transmission in the US.