TABLE 1.

Included Studies

Study No.	Author, year, country	Study Design	Population	Exposure	Outcome	Results	Quality
A. cART v. no cART
1	Suy et al. (2006) (32) Spain	Prospective, matched observational cohort, 2001–03 (HIV-negative pregnant women), 1985–2003 (HIV-positive pregnant women)	HIV-positive and negative pregnant women	HIV	Preeclampsia and stillbirth	472 HIV-positive women available for analysis. 76% had no ARV exposure prior to pregnancy, and 59% had no ARV exposure during pregnancy. Of those using ARVs during pregnancy, 25% used ARVs at an optimal dose. HIV-positive women had a higher incidence of preeclampsia than HIV-negative women (109.8/1000 deliveries versus 28.6/1000 deliveries, OR 4.3, 95% CI 1.9–9.0). After adjustment, use of cART was independently associated with development of preeclampsia among 9 women with HIV (aOR 8.9, 95% CI 1.7–45.5).	Fair
2	Machado et al. (2014) (25) Latin America and Caribbean	Prospective observational cohort analysis (2002–2009)	HIV-positive pregnant women	cART, including PI v. single/dual/triple ARV therapy	HDP diagnosed after 20 weeks’ of gestation	1513 pregnancies available, 73 cases of HDP (4.8%, 95% CI: 3.8–6%), 2.3% had preeclampsia/eclampsia (95% CI 1.7–3.2%) On bivariate analysis, use of cART or any PI regimen at conception was associated with HDP (7.1% v. 4.3%, p = 0.04), including preeclampsia/eclampsia (4.4% v. 1.8, p < 0.01); this trend did not persist with ARV initiation in 1st trimester (6.6 v. 4.2 % for gestational hypertension, p = 0.07; 3.6% v. 1.9% for preeclampsia/eclampsia, p = 0.07)	Good
3	Sansone et al. (2016)(15) Italy	Retrospective cohort analysis, single site (1989–2015)	HIV-positive and negative pregnant women	HIV, cART	Preeclampsia with severe features, early onset preeclampsia with severe features, and preterm birth	453 HIV-positive pregnant women available for analysis. 66.4% received cART during pregnancy, while 22.0% used single (AZT) or dual ARV (AZT and 3TC) therapy When compared with HIV- negative women, HIV- positive women had higher incidences of preeclampsia (10.2% v 4.1%, aOR 2.03, 95% CI 1.26–3.28) and preeclampsia with severe features (4.0% v 2.0%, aOR 2.03, 95% CI 1.26–3.28). HIV-positive women using cART had a higher incidence of preeclampsia when compared to seronegative women (13.0% v 4.1%, aOR 3.52, 95% CI 2.51–4.94) and HIV-positive women not using cART (13.0% v. 4.6%, aOR 3.08, 95% CI 1.34–5.07). HIV-positive women not using cART had similar incidences of preeclampsia when compared with HIV- negative women (4.6% v. 4.1%, aOR 1.14, 95% CI 0.53–2.44)	Good
4	Stoner et al. (2016) (27) Zambia	Multicenter retrospective case-control study (2006–2012)	HIV-positive and negative pregnant women	HIV, cART	Pregnancy-induced hypertension	249,771 women included for analysis, of whom 5354 women met criteria for pregnancy-induced hypertension (701 had preeclampsia, 394 had eclampsia). HIV-positive women using cART had a higher adjusted odds for pregnancy-induced hypertension when compared with HIV- positive women not on cART (aOR 1.27, 95% CI 1.04–1.55). This finding was unrelated to timing of initiation of cART. HIV-positive women who were untreated had a lower adjusted odds for pregnancy-induced hypertension when compared with HIV- negative women (aOR 0.75, 95% CI 0.61–0.93).	Good
5	Sebitloane, Moodley, & Sartorius (2017) (35) South Africa	Retrospective, case-control study (2011–2013)	HIV-positive and HIV-negative pregnant women who had a maternal death	HIV	Death due to HDP	640 deaths due to HDP, 32.5% occurred among HIV-positive women. When compared with HIV- negative women, HIV- positive women had a lower risk of maternal death due to HDP (RR 0.57, 95% CI, 0.41–0.64). HIV-positive women not using cART had a lower risk of having HDP when compared with HIV- negative women (RR 0.68, 95% CI 0.57–0.82) HDP was more likely to be cause of death among patients with AIDS receiving cART when compared with patients with AIDS not receiving cART (RR 1.15, 95% CI 1.02–1.29). Patients with AIDS not receiving cART were less likely to have HDP as underlying cause of death compared to HIV- positive women who were not using cART (RR 0.67, 95% CI 0.57–0.79)	Fair
B. Type of ARV used in cART
1	McGowan et al. (1999) (38) USA	Single-site retrospective cohort analysis (1996–1998)	HIV-positive pregnant women	cART	Pregnancy-induced hypertension	30 women included, of whom 4 had pregnancy- induced hypertension (13%). Use of PI was noted in all cases of pregnancy-induced hypertension, though 3 subjects were non-adherent.	Poor
2	Wimalasundera et al. (2002) (3) UK	Retrospective case-control analysis of two hospitals (1990–2001)	Pregnant women	HIV	Preeclampsia	9/214 (4.2%) HIV-positive women were diagnosed with preeclampsia v. 12/214 HIV-negative controls (6%). The incidence of preeclampsia was lower among HIV-positive women who were untreated (0%, OR 15.3, 95% CI 0.9–270) or in the mono-or-dual therapy group (1%, OR 15.3, 95% CI 1.1–73) when compared with women who took triple therapy ARVs (8/76, 11%). When compared to HIV- negative women, no difference in incidence of preeclampsia among HIV-positive women who were untreated (p = 0.07) or on ARVs (0.2).	Fair
3	Boer et al. (2007) (28) Netherlands	Retrospective cohort Analysis (1997–2003)	HIV-positive pregnant women on cART and HIV- negative women	HIV, cART with or without use of PI	Preeclampsia	143 HIV infected women- infant pairs and 196 matched controls available for analysis. No difference in incidence of preeclampsia among HIV-positive women using cART v. negative women (2.8 v 1%) Incidence of preeclampsia 3.2% among 93 women on cART with PI and 2.0% among 50 women on cART without PI (ns).	Fair
4	Williams et al. (2009) (39) USA	Case series, single site (1997–2007)	Pregnant women with perinatally- acquired HIV using cART	N/A	Antepartum, intrapartum, and postpartum complications.	10 women with 13 pregnancies. Total of 3 pregnancies complicated by preeclampsia (23%) Medications used included 3TC, ABC, LPV/r, DDI, AZT, IDV/r, and NFV.	Poor
5	Boyajian et al. (2012) (8) Canada	Single-site retrospective matched cohort analysis at a single hospital in Toronto (2003–2010)	HIV-positive pregnant women using cART and HIV-negative pregnant women	HIV, cART	Preeclampsia	Total of 91 HIV-positive women available for analysis. Incidence of preeclampsia 3.3% v. 5.1% in HIV- positive on cART v. HIV- negative pregnant women (aOR 0.59, 95% CI 0.11–3.08). When compared with HIV-negative women, HIV-positive women had higher incidence of thrombocytopenia (5.5% v. 1.5%, OR 3.91, 95% CI 1.11–13.76) and elevated liver enzymes (13.2% v. 5.1%, OR 2.81, 95% CI 1.27–6.23) despite no difference in incidence of severe preeclampsia. Subgroup analysis demonstrated that women who began cART prior to conception or during pregnancy did not have a difference in incidence of preeclampsia (p = 0.56). There was no difference in risk of preeclampsia among women using PIs v. those on other ARV regimens (p > 0.99).	Fair
6	Powis et al. (2013) (34) Botswana	Secondary analysis of a randomized controlled trial (2006–2008)	HIV-positive, cART-naïve, preeclamptic pregnant women	ABC/AZT/3TC or AZT/3TC + LPV/r or observation with initiation of AZT/3TC/NVP when CD4 < 200 cells/mm3	Change in level of PlGF and sFLT-1 after cART initiation; preeclampsia	722 women available for analysis. 11 developed preeclampsia VL > 100,000 was associated with preeclampsia (OR 5.8, 95% CI 1.8–19.4), even after adjusting for CD4 count, cART regimen, and gestational age at cART initiation. Among women who developed preeclampsia, there were lower PlGF and higher sFlT-1 levels prior to initiation of cART. VL > 100,000 and PlGF were associated with preeclampsia after adjusting for sFlt-1.	Poor
7	Machado et al. (2014) (25)	See Part A, No. 2 for details
C. Other studies
1	Mattar et al. (2004) (37) Brazil	Single-site retrospective cohort analysis (2000–2002)	HIV-positive pregnant women using ARVs, HIV- negative pregnant women.	HIV	Preeclampsia	1/123 HIV-positive women (0.8%) had preeclampsia v 182/1708 (10.6%) women without HIV. Among HIV-positive women, 22/123 (17.9%) using ARV monotherapy, 78/123 using cART (63.4%).	Poor
2	Tuomala et al. (2005) (47) USA	Multicenter, prospective cohort (1990–2002)	HIV-positive pregnant women with singleton gestations	N/A	HELLP, gestational hypertension, preeclampsia, eclampsia	2286 women included for analysis. Low prevalence of HDP, precluding analysis.	Poor
3	Bodkin, Klopper, & Langley (2006) (22) South Africa	Single-site retrospective cohort analysis (2003)	HIV-positive and negative pregnant women	HIV	Eclampsia and pregnancy-induced hypertension	204 HIV-positive women and 1336 HIV-negative women available for analysis. No significant difference in incidence of eclampsia (2.83 v. 0.99%, p = 0.44). Higher, nonsignificant incidence of pregnancy- induced hypertension among HIV-positive women (16.98% v. 9.90%)	Fair
4	Kourtis et al. (2006) (24) USA	Retrospective cohort Analysis (1994–2008)	HIV-positive and HIV-negative pregnant women	cART	Hospitalization for preeclampsia	In 1994, among 6143 HIV- positive women, 9.9% developed preeclampsia/hypertension v. 7.3% among HIV- negative women (aOR 1.13, 95% CI 0.82–1.56) In 2003, among 6235 HIV- positive women, 9.9% developed preeclampsia/hypertension v. 8.9% among HIV- negative women (aOR 1.00, 95% CI 0.82–1.21).	Good
5	Bera (2009) (29) South Africa	Retrospective cohort analysis, single site (2006–2008)	HIV-positive pregnant women initiating cART	N/A	Maternal death, preeclampsia, eclampsia, and HELLP	385 women included. 96.4% started EFV-based ART, 4.2% were on NVP- based regimen, and 2.6% of women were on AZT- based regimen. IRIS occurred in 7% women. 7.5% of women developed preeclampsia, 10.3% developed eclampsia and 3.4% developed HELLP.	Poor
6	Haeri et al. (2009) (7) USA	Retrospective cohort analysis at two sites (2000–2007)	HIV-positive pregnant women using cART and HIV-negative pregnant women	HIV, cART	Gestational hypertension and preeclampsia	47,126 deliveries, with 188 deliveries among HIV- positive women. Total of 151 HIV-positive pregnant women on cART included for analysis Gestational hypertension (1 v 4%, p = 0.04) and preeclampsia (6 v. 12%, p = 0.04) less common among HIV-positive women, when compared with HIV-negative women. However, when controlling for risk factors for preeclampsia, these findings become nonsignificant.	Good
7	Aebi-Popp et al. (2010) (48) Switzerland	Prospective observational cohort (2003–2008)	HIV-positive pregnant women	HIV, cART	Preeclampsia or “arterial hypertension”	266 HIV-positive women. 35.5% ARV naïve at conception, 1.9% at time of delivery. 62.9% had CD4 > 350 at time of delivery, with VL < 50 among 78.7% of population. 45–57% of population on PI-boosted regimen. Almost 20–40% of population stopped ARVs during pregnancy. Overall prevalence of preeclampsia was 2.6%.	Poor
8	Parekh et al. (2011) (33) Botswana	Multicenter retrospective case-control study (2007–2010)	HIV-positive and negative pregnant women who gave birth at greater than 26 weeks’ gestation	HIV, cART	Hypertension during pregnancy (i.e. one blood pressure > 140/90 mmHg measured at any antenatal visit)	16,219 pregnancies included for analysis, of which 4,347 were affected by HIV. Among HIV- positive women, 67.8% on AZT monotherapy, 8% on cART, 18.1% “continued” HAART, and 16.1% did not use ARVs. For cART regimen, majority used AZT, 3TC, and NVP. After adjusting for maternal age, marital status, and nulliparity, HIV was associated with increased odds for hypertension when compared with HIV- negative women (aOR 1.19, 95% CI 1.02–1.39). When compared with HIV- positive women using other ARVs, cART use prior to conception was independently associated with hypertension during pregnancy (aOR 1.34, 95% CI 1.00–1.77).	Fair
9	Shapiro et al. (2012) (36) Botswana	Prospective case-control, single-site study (2010)	HIV-positive and negative pregnant women with stillbirths > 19w	HIV, cART	Preeclampsia, hypertension in pregnancy	66 HIV-positive women and 33 HIV-negative women. 42% of HIV positive women were on cART at time of stillbirth, 81% from prior to pregnancy and 19% who started during pregnancy. 23% started AZT at greater than 28 weeks’ gestation. Nonsignificant difference in incidence of both pregnancy-induced hypertension (54% v. 47% v. 51%) and preeclampsia/eclampsia (23% v. 19% v. 22%) among HIV-infected women using cART v. not using cART v. HIV- negative women.	Poor
10	Ngene et al. (2013)(30) South Africa	Prospective cohort, single site (2010–2011)	Pregnant women or women up to 42 days post-partum, admitted to ICU	HIV	Hypoxic- ischaemic brain injury, death, or preeclampsia	82 patients in ICU, 31 were HIV positive. 8 were on cART while 10 were receiving AZT monotherapy. HIV-positive women had lower incidence of eclampsia (9.7 v. 31.0%) and severe preeclampsia (3.2 v. 14.3%) when compared with HIV- negative women.	Poor
11	Hall et al. (2014)(9) South Africa	Prospective, single-site cohort analysis (2007–2011)	HIV-positive and HIV- negative pregnant women	HIV	Preeclampsia, gestational hypertension	1093 HIV-positive and 1173 HIV-negative pregnancies included for analysis. 200 women were using cART, 865 using AZT monotherapy with intrapartum NVP; 28 cases had no medication reported. Lower incidences of preeclampsia (3.2 v 4.9%, OR 0.65, 95% CI 0.42–0.99) and gestational hypertension (1.6 v. 3.1%, OR 0.53, 95% CI 0.30–0.94) among HIV-positive v. HIV-negative women. No significant differences noted when stratifying HIV-positive women by CD4 count. On multivariable regression modelling, HIV was associated with a reduced odds of preeclampsia (aOR 0.46, 95% CI 0.28–0.76) and gestational hypertension (aOR 0.42, 95% CI 0.22–0.80).	Good
12	Landi et al. (2014) (21) Italy	Prospective observational cohort study, two sites (2004–2012)	HIV-positive and negative pregnant women with singleton gestations	HIV	Gestational hypertension and preeclampsia	126 HIV-positive women, 140 HIV-negative women included in the analysis. 35.7% of cART initiation was before pregnancy, and 64.3% occurred after the first trimester. Lower incidences of gestational hypertension and preeclampsia among HIV-positive v. HIV- negative women (2.38% v. 10%, p = 0.01). Initiating cART before pregnancy was not associated with an increased incidence of gestational hypertension and preeclampsia (4.4 v 1.2%, p = 0.26).	Fair
13	Reitter et al. (2014)(49) Germany	Prospective cohort study (2002–2012)	HIV-positive pregnant women	N/A	Preeclampsia or hypertension	330 pregnant women enrolled, 5 women (1.5%) developed preeclampsia or hypertension. 33.3% of the total sample of HIV- positive women were using a PI, 26.6% were using a triple NRTI regimen, and 21.2% had NNRTI + NRTI regimen.	Poor
14	Ewing et al. (2016)(26) USA	Retrospective cross-sectional cohort using the Nationwide Inpatient Sample (2004–2011)	Pregnant HIV - positive and HIV - negative women hospitalized for antenatal care and delivery	HIV	Multiple outcomes, of which preeclampsia/HDP were included	In 2004, preeclampsia/HDP affected 13.6% of HIV- positive women (n = 7107) v. 9.5% of HIV-negative patients (n = 4,675,615) (aOR 1.08, 95% CI 0.64–1.88). In 2011, preeclampsia/HDP affected 18.9% of HIV- positive women (n = 4751) v. 11.4% of all HIV- negative women (4,180,200) (aOR 1.44, 95% CI 1.16–1.80).	Good
15	Maharaj, Moodley, & Chuturgoon (2016) (31) South Africa	Prospective, observational cohort, single site (2013–2014)	HIV-positive and negative pregnant women	HIV using cART	Preeclampsia	193 women recruited; 98 women had preeclampsia with HIV using cART and 53 had preeclampsia without HIV. 95 women were normotensive (45 with HIV using cART and 50 without HIV). 1.9% of HIV-positive women had eclampsia v. 0% among HIV-negative women (ns).	Fair
16	Tooke et al. (2016)(23) South Africa	Single site retrospective case-control analysis (2011–2013)	Pregnant women delivering ELBW infants (<1000g)	HIV	Preeclampsia	46 HIV-positive women out of 195 ELBW births. 69.6% pregnancies affected by preeclampsia. When compared to HIV-positive women using cART < 4 weeks, those using cART > 4 weeks had a higher incidence of preeclampsia (24/29 v. 8/17, p = 0.01). Among HIV-positive women starting cART in pregnancy, those using it for > 4 weeks had a significantly higher incidence of preeclampsia (18/21) v. those who used it for < 4 weeks (8/17, p = 0.016).	Poor
17	Yudin et al. (2016)(50) Canada	Single-site retrospective cohort analysis (2002–2010)	HIV-positive pregnant women delivering at a single hospital in Toronto, ON	N/A	Chronic hypertension, gestational hypertension, and preeclampsia	142 HIV-positive women available for analysis. 94% using cART. 7 women (5%) had “hypertension as a complication in pregnancy”, 1 had chronic hypertension, 6 had gestational hypertension. 2 developed preeclampsia.	Poor

3TC: lamivudine; ABC: abacavir; AIDS: acquired immunodeficiency syndrome; ARV: antiretroviral medication; AZT: zidovudine; cART: combined antiretroviral therapy; DDI: didanosine; ELBW: extremely low birth weight; EFV: efavirenz; GGT: gamma-glutamyl transferase; HELLP: hemolysis, elevated liver enzymes, low platelet count syndrome; HDP: hypertensive disorders of pregnancy; IDV/r: indinavir/ritonavir; IRIS: immune reconstitution inflammatory syndrome; IUFD: intrauterine fetal demise; LPV/r: lopinavir/ritonavir; NNRTI: non-nucleoside reverse transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor; ns: nonsignificant; NVP: nevirapine; PI: protease inhibitor; PlGF: placental growth factor; sFlT-1: soluble fms-like tyrosine kinase-1; VL: viral load