Around 79% of the 1.4 million pregnant women living with HIV in 2016 worldwide received antiretroviral therapy (ART) during their pregnancy to prevent mother-to-child transmission (MTCT) . Most received a three-drug regimen, as recommended by WHO for all HIV-positive pregnant women since 2013, with tenofovir (TDF) and emtricitabine (FTC) and efavirenz (EFV) as first-line . Widespread antenatal and postnatal ART along with other interventions has reduced HIV MTCT rates to ‘elimination’ levels in some high prevalence settings , and to around less than 1% in Western Europe [3–6] and 1–4% in Eastern Europe [7,8]. However, combination ART (cART) has been associated with an increased risk of some adverse pregnancy outcomes, including preterm delivery (PTD) and small-for-gestational age (SGA), as compared with mono/dual therapy [9–12].
Results of studies vary with respect to the safest ART regimens/component drugs in pregnancy. Boosted protease inhibitors and particularly ritonavir-boosted lopinavir (LPV/r) have been associated with an increased risk of PTD , while results from the PROMISE trial led to a focus on the safety of TDF. In this trial, which took place in India, Malawi, South Africa, Tanzania, Uganda, Zambia and Zimbabwe, LPV/r given with a TDF-FTC backbone was associated with a higher risk of delivery less than 34 weeks and neonatal death by 14 days than when given with a zidovudine (ZDV) - lamivudine (3TC) backbone among women starting ART in pregnancy . In contrast, population-based data from Botswana (a context with high prevalence of adverse pregnancy outcomes overall) have been reassuring with regard to the safety of TDF-containing regimens, with no difference in PTD rates among women starting TDF-FTC-EFV vs. other ART regimen in pregnancy , although a lower risk of SGA among pregnancies exposed to TDF-FTC-EFV vs. TDF-FTC-LPV/r or TDF-FTC-NVP from conception [14,15]. Similarly, U.S. data do not indicate an increased risk of adverse pregnancy outcomes with TDF-FTC-LPV/r compared with ZDV-3TC-LPV/r , while a recent meta-analysis found no increased risk of a range of adverse pregnancy, maternal and infant outcomes among women on TDF-containing regimens and a lower risk of PTD and stillbirth .
Causes of adverse pregnancy outcomes are complex and overlapping, with severity of HIV infection and other factors such as malnutrition, maternal age, IDU and coinfections implicated in increasing risk as well as specific ART regimens. This may explain the conflicting findings between studies conducted in different populations, alongside other factors such as timing of ART initiation. The majority of HIV-positive pregnant women in Europe are now on ART at conception [3,18], and this proportion is increasing in high prevalence settings with adoption of treat all approaches. However, almost half of people living with HIV worldwide in 2016 were not yet on treatment ; data regarding the safest ART regimens for those newly initiating treatment during pregnancy therefore remain important.
Our aim was to investigate whether specific NRTI backbones were associated with risk of adverse pregnancy outcomes among women starting ART during pregnancy, in resource-rich and middle-income settings in Western and Eastern Europe.
Materials and methods
We conducted a pooled analysis of pregnancies in HIV-positive women from observational studies participating in the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC).
Singleton pregnancies ending in a live birth in 2008–2014 conceived off treatment and in which a single cART regimen was initiated were eligible for inclusion in this study. cART was defined as three or four antiretroviral drugs, including at least two NRTIs, started within a 7-day period. We took this approach to minimize treatment bias by timing of ART initiation and to explore the safety of ART regimens started during pregnancy, given differences in outcomes reported by timing of initiation . The combination of TDF with either 3TC or FTC is referred to as TDF-XTC throughout.
Exclusion criteria were reported duration of ART less than 2 weeks (n = 148); enrolment in a country with less than 10 eligible pregnancies (n = 12); ART switches or substitutions [defined as at least five antiretrovirals received in pregnancy, or four antiretrovirals if difference of >7 days in start dates] (n = 495); missing data on gestation at delivery (n = 64).
Seven studies across eight countries in Western and Eastern Europe had pregnancies meeting the inclusion criteria. Anonymous individual-level data were pooled using a standard operating procedure based on HIV Cohorts Data Exchange Protocol (hicdep.org) data specification. The studies participating in the data merger were each responsible for ensuring that appropriate ethics approvals were in place, and for compliance with data protection requirements. Variables included sociodemographic, clinical and treatment factors, and pregnancy and neonatal outcomes.
PTD was defined as delivery at less than 37 completed weeks gestation and very PTD at less than 34 weeks. SGA was defined as less than 10th percentile according to INTERGROWTH standards [21,22]. Gestational age was predominantly determined by ultrasound (coverage of >95% in Ukraine  and in Western European countries). Neonatal death was defined as within the first 28 days.
Univariable comparisons of categorical variables were assessed using chi-squared or Fisher exact tests. The Wilcoxon–Mann–Whitney rank sum test was used to compare continuous variables. Adjusted prevalence ratios (aPRs) were estimated by fitting Poisson regression models with robust estimates to investigate associations between NRTI backbone and PTD, very PTD and SGA, adjusted a priori for potential confounders (for PTD models: calendar year and country of delivery, parity, maternal IDU history, CD4+ cell count, maternal age, third agent in the ART regimen; for SGA model: all variables included in the PTD models and infant sex and ART duration).
Outcomes were also assessed in subanalyses restricted to pregnancies initiated on a LPV/r-containing regimen (which increases TDF blood levels when coadministered). These models were conducted on a complete case basis and adjusted for the variables included in the main model. Statistical analyses were carried out using STATA v15 software (Stata Corp, College Station, Texas, USA).
Maternal characteristics and pregnancy outcomes
Of 7193 pregnancies included in these analyses, 45% (3207) were in the UK and Ireland, 44% (3134) in Ukraine and 7% (469) in Russia, with smaller numbers in Belgium, Romania, Spain and Switzerland (Table 1). Overall, 52% of pregnancies were in women newly diagnosed with HIV during that pregnancy, 37% in Black women (ranging from 77% (2469/3199) in the UK/Ireland to none in Russia and 0.6% (2/3116) in Ukraine) and 7% were in women with a history of IDU (ranging from 11% in Ukraine (355/3125) and 9% in Russia (41/454) to 2% in UK and Ireland (49/2948) and none in Belgium and Switzerland). Median first CD4+ cell count in pregnancy was 396 cells/μl [interquartile range (IQR) 260–559] with no difference by timing of HIV diagnosis (before/during pregnancy, P = 0.186). ART was started at median 22.9 gestation weeks (IQR 18.9–25.7) and received for median 15.7 weeks by delivery (IQR 12.3–19.6).
Overall 10% (n = 722) of deliveries were preterm and 3.4% (n = 246) were very preterm; 11.1% (785/7089) of infants were SGA. There were 92 (1.3%) infants who were both preterm and SGA, representing 11.7% (92/785) of the SGA group and 13% (92/707) of the PTD group (birthweight missing for 15 preterm infants). Rates of PTD and SGA differed by country (supplementary Table A, http://links.lww.com/QAD/B382). The rate of low birthweight (<2500 g) among term infants was 6.7% (431/6471). The unadjusted MTCT rate was 1.11% (95% CI 0.85–1.42) [HIV status known for 77% (5511/7193) infants]. There were 21 neonatal deaths among 6689 infants with data available, giving a neonatal mortality rate (NMR) of 3.1 per 1000 live births. Of the 21 neonates who died, 13 were preterm (10/13 <34 weeks) and three were SGA (2/3 preterm). The NMR among very preterm, preterm and SGA infants was 40.7, 18.0 and 3.8 per 1000 live births, respectively.
Trends in nucleoside reverse transcriptase inhibitor backbones and antiretroviral therapy regimens over time
In 71% (5122/7193) of pregnancies, the ART regimen included ZDV-3TC, in 16% (1122/7193) TDF-XTC and in 10% (711/7193) 3TC and abacavir (ABC). Use of ZDV-3TC declined over time, with an increasing use of other regimens, particularly TDF-containing backbones (Fig. 1). The most commonly used third agent was ritonavir-boosted LPV/r, used in 77% (5558/7193) of regimens overall, of which 81% (4527/5558) contained a ZDV-3TC backbone (Fig. 2). Of regimens based on other protease inhibitors, 30% (283/934) contained a ZDV-3TC backbone and 49% (456/934) a TDF-XTC backbone. NNRTIs were used in 7% (517/7193) of pregnancies overall [most commonly nevirapine (NVP), which accounted for 416 of 517 NNRTI-based regimens]. Use of antiretrovirals varied substantially by country with LPV/r-based regimens most commonly used in Ukraine and Russia, see supplementary table A, http://links.lww.com/QAD/B382.
Nucleoside reverse transcriptase inhibitor backbone and preterm delivery risk
Overall, PTD rates for the four most commonly used regimens were 10.2% (461/4527) for LPV/r-ZDV-3TC; 10.0% (46/461) for LPV/r-ABC-3TC; 11.6% (53/457) for LPV/r-TDF-XTC; 11.2% (51/456) for other PI-TDF-XTC. There was no difference in PTD rate according to inclusion in the complete case analysis [PTD rate was 10.2% (626/6123) in included vs. 9.0% (96/1070) in excluded pregnancies, P = 0.209]. However, there was a slight difference in NRTI backbones received: ZDV-3TC was received in 71.8% of included pregnancies vs. 67.7% excluded; ABC-3TC in 9.5% included pregnancies vs. 12.1% excluded; TDF-XTC in 15.4% of included vs. 16.8% excluded; other NRTI backbone in 3% in both groups (P = 0.023). In the main model adjusting for third agent and other factors (Table 2, N = 6123), there was no association between NRTI backbone and PTD. Pregnancies in women with a CD4+ cell count less than 200 vs. at least 350 cells/μl, aged 30–39 vs. 21–29 years, and with an IDU history were more likely to be delivered preterm, as were pregnancies in which a LPV/r-based ART regimen was received.
In the subanalysis among 4720 pregnancies on LPV/r and adjusted as for the main model, NRTI backbone remained unassociated with PTD risk (aPR 1.03 95% CI 0.74–1.43, P = 0.873 for ABC-3TC, aPR 1.16 95% CI 0.85–1.57, P = 0.351 for TDF-XTC and aPR 0.59 95% CI 0.28–1.24 P = 0.166 for other NRTI backbone, all vs. ZDV-3TC).
Very PTD rates less than 34 weeks were 3.4% (173/5122) for ZDV-3TC, 2.8% (20/711) for ABC-3TC, 3.7% (42/1122) for TDF-XTC and 4.6% (11/238) for other NRTI backbones. There was no indication of an association between NRTI backbone in adjusted analyses (aPR 0.93, 95% CI 0.54–1.60, P = 0.790 for ABC-3TC, aPR 1.27, 95% CI 0.84–1.91, P = 0.259 for TDF-XTC and aPR 1.22, 95% CI 0.61–2.42, P = 0.569 for other NRTI backbone, all vs. ZDV-3TC), and no increased risk of very PTD with LPV/r vs. other protease inhibitors (aPR 1.17 95% CI 0.75–1.82, P = 0.498).
Nucleoside reverse transcriptase inhibitor backbone and small-for-gestational age
The SGA rate was the same among the 5780 pregnancies included in the complete case analysis and those excluded (both 20.9%, 1209/5780 and 273/1309). However, the distribution of NRTI backbones was significantly different between the two groups (P < 0.001): comparing included with excluded pregnancies, ZDV-3TC was received in a greater proportion of the former (72.2 vs. 67.0%) and ABC-3TC and TDF-XTC in smaller proportions (9.7 vs. 10.5% and 14.8 vs. 19.0%, respectively), with no difference in other NRTI backbones (3.3 vs. 3.4%). Infants exposed in utero to ABC-3TC or TDF-XTC were less likely to be SGA than those exposed to ZDV-3TC in both unadjusted and adjusted analyses (Table 3, N = 5780). Although LPV/r was associated with SGA in unadjusted analyses, there was no difference by third agent after adjusting for NRTI backbone and the other factors in the multivariable model. Increased risk of SGA was also observed in infants born to nulliparous women and those whose mothers had a history of IDU.
In the model restricted to 4482 pregnancies with LPV/r, NRTI backbone was no longer associated with risk of SGA (aPR 0.73, 95% CI 0.52–1.03, P = 0.076 for ABC+3TC, aPR 0.75, 95% CI 0.53–1.06, P = 0.100 for TDF-XTC and aPR 1.08, 95% CI 0.65–1.79, P = 0.763 for other NRTI backbone, all vs. ZDV-3TC).
In this pooled analysis of over 5700 pregnancies in HIV-positive women delivering in Europe in 2008–2014 who started ART during pregnancy, we found no increased PTD risk among those initiating a TDF-containing regimen and a decreased risk of SGA in newborns exposed in utero to TDF-XTC or ABC-3TC compared with those exposed to ZDV-3TC. The use of ART regimens changed substantially over time, with TDF-containing backbones accounting for an increasing proportion of regimens overall in more recent years, used mostly in combination with protease inhibitors other than LPV/r and accounting for over 20% of regimens in 2014.
Among pregnancies on LPV/r-based regimens, those with a TDF-XTC backbone had a slightly higher unadjusted PTD rate than other regimens (11.6% vs. around 10%); however, the former were initiated earlier in pregnancy, increasing the opportunity for PTD after ART initiation, and included a greater proportion of Black African women, a factor independently associated with shorter gestation . In analyses adjusting for country, year and other factors, we found no association between NRTI backbone and PTD or very PTD. This is in contrast with the PROMISE study  but in line with other studies that have found no difference or a reduced risk of PTD with TDF-containing regimens [14,25,26] and a recent meta-analysis that found TDF to be associated with a 10% reduction in PTD overall (RR 0.90, 95% CI 0.81–0.99 vs. non-TDF containing ART regimens) . In a subanalysis of pregnancies with LPV/r, there remained no association between NRTI backbone and PTD. Our findings add to the evidence base supporting the safety of TDF-XTC in pregnancy with respect to gestation length.
LPV/r was associated with an increased risk of PTD overall (aPR 1.32), an association previously reported in the UK and Ireland in women starting LPV/r preconception but not antenatally  and in a 2000–2012 Ukraine analyses in which only 4% of pregnancies were conceived on ART, with cART (89% LPV/r-based) associated with a 40% increased risk of PTD compared with zidovudine monotherapy . However, in a study in Uganda, there was no difference in PTD risk between women randomized to LPV/r-ZDV-3TC and EFV-ZDV-3TC at 12–28 weeks (16 and 15% delivered preterm, respectively) . Although its use is declining in western Europe, LPV/r is still used widely in pregnancy in Ukraine and Russia where other risk factors for PTD (e.g. IDU history and smoking) are also more prevalent in HIV-positive women , and is a second-line option in high prevalence settings .
Of the 1099 singleton infants in our study exposed to TDF-XTC in utero, 8.6% were SGA compared with 11.7% exposed to ZDV-3TC, corresponding to a 35% reduced risk of SGA in adjusted analyses. The number of pregnancies in which ABC-3TC was initiated was smaller, but a reduced risk of SGA was also detected in these pregnancies vs. those with ZDV-3TC in main (although not sensitivity) analyses. A meta-analysis of five previous studies found no association between TDF-containing ART and low birthweight (risk ratio 0.91, 95% 0.80–1.04) or weight-for-age Z scores at birth (mean difference -0.00 95% CI -0.11 to 0.11) . However, a reduced risk of SGA with TDF-XTC backbone has previously been reported in national surveillance data from Botswana, in which 1461 infants exposed to TDF-FTC-EFV in utero (started antenatally) had a 50% reduced risk of SGA compared with infants exposed to other three-drug ART regimens, predominantly ZDV-3TC-NVP . In a further analysis from Botswana, where ART was initiated before conception, SGA risk was also lower with TDF-FTC-EFV than all other three-drug ART regimens, although the reduced risk was not specific to TDF-XTC regimens per se [adjusted risk ratio of 1.62 (1.29–2.03) for TDF-FTC-LPV/r vs. TDF-FTC-EFV] . In our study, LPV/r was associated with SGA in unadjusted analyses but not after adjusting for NRTI backbone and other factors.
Although women starting ART in pregnancy have been found in other studies to have lower PTD risk than those conceiving on ART , confounding by ART indication complicates these comparisons with important differences in risk by immunological status . Lifelong continuation of ART initiated in pregnancy (and therefore taken from conception in subsequent pregnancies) means that the broader safety profile of ART regimens need to be considered for women starting ART during pregnancy, including where – as with LPV/r – there is evidence of differential risk by timing of ART initiation . An improved understanding of mechanisms by which ART may influence the risk of adverse pregnancy outcomes (which may include derangement of progesterone and/or estradiol levels [30,31]) is needed to inform treatment guidelines for women starting ART within and outside of the context of pregnancy.
In the present study, PTD risk was higher in the 14% of pregnancies with a first antenatal CD4+ cell count less than 200 cells/μl; approximately half of these women were already diagnosed before conception. This reflects CD4+ cell eligibility cut-offs for treatment in earlier years (e.g. <350 cells/μl in UK 2008 guidelines  and in Ukraine up to 2015 ), low ART coverage in Ukraine and possible disengagement from HIV care of previously diagnosed women , and highlights the potential impact of a treat-all approach on improving pregnancy outcomes.
IDU history is an established risk factor for adverse pregnancy outcomes  and was associated with a two-fold increased risk of PTD and 50% increased risk of SGA in this study. One in ten women from Eastern European cohorts had an IDU history, vs. less than 2% in the UK/Ireland, reflecting the different epidemiology of HIV in western and Eastern Europe [9,35,36]. Given barriers to testing and treatment services experienced by some women who inject drugs , they may continue to be an important group among those initiating ART during pregnancy in future years.
Analyses exploring the role of timing of ART initiation or duration of ART in relation to PTD risk are prone to selection bias because pregnancies delivered preterm have by definition less opportunity to start ART in the later weeks . For this reason, we did not explore ART duration in PTD analyses.
Our exclusion of 148 pregnancies with less than 2 weeks of ART may have resulted in underestimation of the overall PTD rate, while exclusion of 495 pregnancies with ART switch may have resulted in selection bias if the reason for switch was related to the ART regimen received as well as risk of PTD or SGA (reason for switch was not consistently available). In addition, we did not have information available on some important confounders, for example smoking, BMI, history of adverse pregnancy outcomes, concurrent infections in pregnancy, ART adherence; the uneven distribution of these factors between countries as well as changes in national and international ART guidelines may have resulted in residual and uncontrolled confounding. Our study dataset was dominated by the UK/Ireland and Ukraine, and overall findings may not be generalizable to countries with smaller numbers of included pregnancies. Although the third agents used became more diverse over time, LPV/r-based regimens predominated overall and the proportion of pregnancies with NNRTI-based (and particularly EFV-based) regimens was limited.
In this pooled analysis of pregnancies in HIV-positive women in Europe from 2008 to 2014, there was no evidence of an association between NRTI backbone and PTD. Infants exposed to ABC-3TC or TDF-XTC in utero were significantly less likely to be born SGA than those exposed to ZDV-3TC. Taken together, results support the safety of TDF-XTC backbones initiated in pregnancy, with respect to gestation length and birthweight, as recommended first-line in WHO guidelines.
European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) Study Group author contributors:
Project team: Heather Bailey (EPPICC epidemiologist, UCL Great Ormond Street Institute of Child Health, UK); Tessa Goetghebuer (European Collaborative Study, Centre Hospitalier Universitaire Saint-Pierre, Belgium), Cosmina Gingaras (Victor Babes Hospital Cohort, Romania), Claudia Grawe (Swiss Mother and Child HIV Cohort Study, University of Zurich, Switzerland), Jose Tomas Ramos (Madrid Cohort of HIV-Infected Mother–Infant Pairs, Hospital Clínico, Pediatrics Department, Spain), Claire Thorne (EPPICC, UCL Great Ormond Street Institute of Child Health, UK).
Other writing group members (ordered alphabetically by cohort): Graziella Favarato (EPPICC data manager), Ruslan Malyuta, Alla Volokha (European Collaborative Study – Ukraine), Vladimir Rozenberg, Evgeny Voronin, Yulia Plotnikova (Irkutsk Cohort, Russia); Luis Prieto, (Madrid Cohort of HIV-Infected Mother–Infant Pairs); Natàlia Mendoza, Clàudia Fortuny, Lourdes García (NENEXP); Begoña Martinez de Tejada, Karoline Aebi-Popp (Swiss Mother and Child HIV Cohort Study); Helen Peters, Rebecca Sconza (UK and Ireland National Study of HIV in Pregnancy and Childhood).
All members of the project team participated in discussions about the study design, choice of statistical analyses and interpretation of the findings and were involved in the preparation and review of the final manuscript. Heather Bailey performed all statistical analyses. All members of the writing group were involved in the collection of data and interpretation of findings.
Other members of the EPPICC Study Group: P. Barlow, Y. Manigart, C. Gilles, M. Hainaut and T. Goetghebuer; Brichard, D. Van der Linden (European Collaborative Study: Western sites); T. Pilipenko, A. Zayats, S. Posokhova, T. Kaleeva, Y. Barishnikova, S. Servetsky, R. Teretsenko, A. Stelmah, G. Kiseleva, E. Dotsenko, O. A. Zalata, S. Solokha, M. P. Grazhdanov, E. Kulakovskaya, N. Bashkatova, V. Gigil, I. Raus, O. V. Yurchenko, I. Adeyanova, Z. Ruban, O. Govorun, O. Ostrovskaya, I. Kochergina, L. Kvasha, G. Kruglenko, N. Primak (European Collaborative Study – Ukraine); M.I. González-Tomé, M.L. Navarro, M.J. Mellado, L. Escosa, C. Fernández-McPhee, M.A. Roa, J Beceiro, I. Olabarrieta, E. Munõz, M. Gonzalez Tome (Madrid Cohort of HIV-Infected Mother–Infant Pairs); A. Noguera-Julian, C. Fortuny-Guasch, P. Soler-Palacín, M. Coll, V. Pineda, Ll Mayol, M. Mendez, N. Rovira, T. Vallmanya, A. Mur, L. Garcia, N. Rius, O. Calavia (NENEXP); K. Francis, A. Horn, P. Tookey (UK and Ireland National Study of HIV in Pregnancy and Childhood); L. Ene (‘Victor Babes’ Hospital Cohort, Romania); B. Martinez de Tejada, I. Hoesli, C. Kahlert, P. Paioni, C. Rudin, A Scherrer (Swiss Mother and Child HIV Cohort Study).
This work was funded by the EU Seventh Framework Programme (FP7/2007-2013) under EuroCoord grant agreement 260694. Some of this work was undertaken at UCL Great Ormond Street Institute of Child Health, which receives a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme.
Conflicts of interest
Claire Thorne reports personal fees from ViiV Healthcare, grants from ViiV Healthcare via PENTA Foundation, grants from AbbVie, outside the submitted work; the other authors have no conflicts of interest to disclose.
Some of these findings were previously presented as a poster at the 8th International Workshop on HIV Pediatrics, 15–16 July 2016, Durban, South Africa (p: 98).
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