Introduction
It is now widely accepted that antiretroviral therapy (ART) in pregnancy is associated with increased risk of preterm delivery (PTD), but questions remain about the exact nature of this association, for example the roles of timing of ART initiation (preconception or postconception) and maternal immunological status (e.g. CD4+ cell count) and the extent to which specific drugs or regimens are involved in this association [1–4]. Pregnant women on protease inhibitor regimens may be at higher risk of PTD [5–8]. Limited data on mechanisms suggest that protease inhibitors may reduce progesterone levels in pregnancy [9], leading to foetal growth restriction. Progesterone may also play an important role in PTD [10,11]. Certain antiretroviral drugs, namely ritonavir (RTV), widely used as a booster for other protease inhibitor and the nucleoside ‘backbone’ tenofovir (TDF)/emtricitabine (FTC) may also interact with protease inhibitors and increase PTD risk [12,13]. Most recently, assessment of individual ART regimens has been recommended to better understand the differences and causes of adverse perinatal outcomes between ART [14,15].
In a previous analysis of data from the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC) based on pregnancies delivered between 1990 and 2005 [6], we showed an increased rate of PTD in women on combination ART (cART) (14%) vs. mono/dual therapy (10%). Since then, new antiretroviral drugs have been licenced and the drug combinations used routinely during pregnancy have changed substantially, with mono/dual therapy no longer used. In addition, an increasing proportion of women are conceiving on ART [16].
In this article, we examine whether pregnant women on a regimen that includes a protease inhibitor boosted with RTV (PI/r) are at higher risk of delivering preterm compared with pregnant women on an nonnucleoside reverse transcriptase inhibitors (NNRTI)-based regimen and whether this risk varies by ART use at conception, CD4+ cell count (high vs. low) and ART drug combination.
Methods
Study population
The NSHPC is a national surveillance study that collects comprehensive population-based data on all HIV-positive pregnant women and their children seen for care in the United Kingdom and Ireland. Information on pregnancy and delivery is collected from obstetric respondents in all maternity units, and HIV-exposed infants are followed up through their paediatrician to establish infection status. Full methodological details have been described elsewhere [17,18]. The NSHPC has received ethical approval from the London Multi-Centre Research Ethics Committee (MREC/04/2/009).
Inclusion criteria
We included pregnancies with known gestational age resulting in a singleton live birth delivered between 2007 and 2015 in women diagnosed with HIV before delivery and reported to the NSHPC by March 2016. To investigate the association of PTD with ART class, we compared pregnancies exposed to a PI/r-based regimen with those exposed to an NNRTI-based regimen and distinguished RTV-boosted lopinavir (LPV/r), the predominant protease inhibitor in our study, from other protease inhibitor to avoid results being driven by LPV/r. We defined a PI/r-based regimen as a regimen that included a protease inhibitor, RTV booster and two nucleoside reverse transcriptase inhibitor (NRTI) drugs (the ‘backbone’); similarly, an NNRTI-based regimen included an NNRTI and two NRTIs. We excluded 211 pregnancies with no or ‘unspecified’ data on ART, 145 with ART started less than 28 days before delivery and 192 pregnancies exposed to mono/dual regimens, 90 to integrase inhibitors, 77 to unboosted protease inhibitor and 1510 to more than one antiretroviral drug combination during the pregnancy. We further excluded 1371 earlier pregnancies in women with repeated pregnancies, keeping only the most recent one.
Definitions
Gestational age at delivery, in completed gestational weeks, was reported by the respondent based on expected date of delivery. We defined PTD as a delivery at less than 37 weeks, moderate PTD (MPTD) as delivery at 34–36 weeks and very PTD (VPTD) as delivery at less than 34 weeks [13]. Small for gestational age (SGA) was defined according to United States sex-specific standards [19]. Baseline CD4+ cell count was defined as the first CD4+ cell count reported in pregnancy. We grouped maternal country of origin into six main world regions according to UN classification; Western Europe and Westernised Countries + Eastern Europe (WEWC + EE), East Africa, Middle/Southern Africa, West Africa, Caribbean and others.
Statistical analysis
First, we examined the overall associations of PTD with LPV/r-based, other PI/r-based and NNRTI-based regimens using logistic regression and multinomial logistic regression to investigate whether this association varied by MPTD and VPTD. To minimize bias by indication for treatment, we further excluded 105 pregnancies in women with a history of injecting drug use (IDU) and 1296 pregnancies (26 with a history of IDU) with no data on CD4+ cell count and conducted stratified analyses on the remaining 4968 pregnancies divided into four subgroups: no ART at conception and baseline CD4+ cell count 350 cells/μl or less (979); no ART at conception and baseline CD4+ cell count more than 350 cells/μl (1334); ART at conception and baseline CD4+ cell count 350 cells/μl or less (504); ART at conception and baseline CD4+ cell count more than 350 cells/μl (1881). Finally, we explored these stratified associations by drug-specific regimen (rather than ART class). We included any drug combinations received in at least 5% of pregnancies and selected the combination with the lowest PTD rate as the baseline for comparison.
Analyses were adjusted for potential confounders identified a priori based on previous literature [6,12,20]: that is year of delivery (continuous), maternal age at delivery (divided into quartiles), parity (primiparous vs. multiparous), IDU history, antenatal CD4+ cell count (≤350, >350 cells/μl), ART at conception and maternal country of origin.
Results were considered statistically significant at a P value of less than 0.05. Differences in proportions were tested for statistical significance using the chi-square test. Statistical analyses were performed using Stata version 13.1 (StataCorp, College Station, Texas, USA).
Role of the funding source
The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Results
The final dataset included 6073 pregnancies, mainly in women from sub-Saharan Africa (4445/6073, 73.2%) and of median age of 33 years [interquartile range (IQR) 29–36]; 3090 (50.9%) pregnancies were conceived on ART, whereas the remainder started ART on average at 19.1 gestational weeks (15.7–22.1). Median CD4+ cell count at baseline was 440 (IQR 311–596) cells/μl, and in 3272 pregnancies (68.5% of the 4777 pregnancies with available CD4+ cell count), it was above 350 cells/μl. Of these CD4+ cell counts, 42.4% were measured in the first, 45.3% in the second and 12.4% in the third trimester. CD4+ cell count was missing in 1296 pregnancies; these pregnancies tended to be at the beginning of study (P = 0.007), but there was no difference in PTD rate (P = 0.27) or use of ART class (P = 0.51) compared with pregnancies with available CD4+ cell count. PI/r-based regimens were the most common accounting for 4184 (68.9%) pregnancies, of which 2368 (39.0%) received LPV/r; the remaining 1889 (31.1%) pregnancies received a NNRTI-based [mainly efavirenz (EFV) and nevirapine (NVP)] regimen. The number of women receiving LPV/r in pregnancy was particularly high at the start of the study period, but the number swiftly declined subsequently (Fig. 1) due to changes in commissioning and adult treatment guidelines. Overall, the PTD rate was 10.4% (629/6073) and the VPTD rate was 3.8% (228/6073). Women receiving LPV/r had higher PTD rates than women receiving other PI/r-based or NNRTI-based regimens (Table 1).
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Fig. 1: Proportion of pregnancies on nonnucleoside reverse transcriptase inhibitor-based, ritonavir-boosted lopinavir-based and other ritonavir-boosted protease inhibitor-based regimens by calendar year.
Table 1: Characteristics of all pregnancies by nonnucleoside reverse transcriptase inhibitor-based, ritonavir-boosted lopinavir-based and other protease inhibitor-based regimens.
Among 5711 infants with available birth-weight data, 1004 (17.6%) were SGA at delivery. Sixteen infants (0.26% of 6073), all born full-term, were HIV-infected. Ten infants (0.16%), eight of whom were VPTD, one MPTD and one full-term, died within the first 28 days. Congenital abnormalities were reported in 2.9% (171/5867) of infants. Compared with full-term infants, preterm infants were more likely to have a congenital abnormality [40/595 (6.7%) vs. 131/5272 (2.5%), P < 0.001] and more likely to be SGA compared with full-term infants [(137/594) (23.1%) vs. (867/5117) (16.9%), < 0.001].
After adjustment for other risk factors associated with PTD, overall analysis suggested an association of PTD with LPV/r, low CD4+ cell count (≤350 cells/μl), ART at conception and older maternal age (>36 years) (Table 2). Multinomial analysis suggested very PTD was associated with LPV/r, low CD4+, ART at conception, older age and history of IDU and moderate PTD with LPV/r and mother originating in the Caribbean. (SDC Table 1, https://links.lww.com/QAD/B189).
Table 2: Associations of preterm delivery with nonnucleoside reverse transcriptase inhibitor-based, ritonavir-boosted lopinavir-based and other protease inhibitor-based regimens.
Association of preterm delivery with antiretroviral therapy class stratified by antiretroviral therapy at conception and CD4+ cell count
The highest rate of PTD (13.7%) was observed in women on ART at conception and low CD4+ cell count (≤350 cells/μl) and the lowest PTD rate (8.8%) in those on ART at conception with high CD4+ cell counts (>350 cells/μl) (SDC Table 2a and b, https://links.lww.com/QAD/B189). Stratified analysis suggested that irrespective of baseline CD4+, PTD risk increased in women conceiving on LPV/r (Fig. 2). Women who conceived on other PI/r-regimens were also at higher PTD risk when CD4+ cell count 350 cells/μl or less but no clear pattern was observed when CD4+ cell count more than 350 cells/μl [e.g. PTD rates varied widely between PI/r-based regimens from 4.9% in women who conceived on RTV-boosted atazanavir (ATV/r) + TDF/FTC to 13.4% in women who conceived on RTV-boosted darunavir (DRV/r) + TDF/FTC].
Fig. 2: Associations of preterm delivery with nonnucleoside reverse transcriptase inhibitor-based, ritonavir-boosted lopinavir-based and other ritonavir-boosted protease inhibitor-based antenatal regimens stratified by CD4+ and antiretroviral therapy at conception adjusted for maternal age and origin, parity and year of delivery and sorted by size of estimated effect.
Where ART was initiated after conception, no significant associations between PTD and LPV/r-based or other PI/r-based regimens were observed irrespective of CD4+ cell count (Fig. 2). Despite exclusion from our analyses of women starting ART less than 28 days before delivery, some women were included who initiated ART beyond defined gestational age cut-offs for PTD (particularly very or MPTD) and were therefore not exposed to ART during the period that they were at risk for PTD. We therefore conducted a sensitivity analysis excluding women starting ART at least 28 gestational weeks (n = 91), but results did not vary and no significant associations were observed (SDC Table 4, https://links.lww.com/QAD/B189).
Association of preterm delivery with antiretroviral therapy by drug combinations
Among the PI/r-regimens, the most frequent combinations were LPV/r + zidovudine (ZDV) /lamivudine (3TC) (1325/4698, 28.2%) and ATV/r + TDF/FTC (535/4698, 11.4%) and among the NNRTI-regimens were EFV + TDF/FTC (495/4698, 10.5%) and NVP + 3TC/abacavir (ABC) (288/4698, 6.1%) (SDC Table 3, https://links.lww.com/QAD/B189). Thirty women with a CD4+ cell count more than 350 cells/μl who started NVP in pregnancy were excluded from the analysis as NVP initiation is not recommended when CD4+ cell count more than 250 cells/μl.
The highest PTD rates (21.2 and 21.1%, respectively) were observed in women with CD4+ cell count 350 cells/μl or less, namely in those who did conceive on LPV/r + TDF/FTC and in those who did not conceive on ART and received DRV/r + TDF/FTC in pregnancy.
Results from stratified analyses did not show any clear trend in PTD risk according to ART class and drug combination. Among women with CD4+ cell count more than 350 cells/μl, PTD risk was three-fold higher when conceiving on DRV/r + TDF/FTC or LPV/r + TDF/FTC than when conceiving on ATV/r + TDF/FTC. However, in women with CD4+ cell count 350 cells/μl or less PTD risk was higher in women conceiving on ATV/r + TDF/FTC than with any other drug combinations (Fig. 3).
Fig. 3: Associations of preterm delivery with most frequently used antenatal ritonavir-boosted protease inhibitor-based and nonnucleoside reverse transcriptase inhibitor-based regimens stratified for CD4+ and antiretroviral therapy at conception adjusted for maternal age and origin, parity and year of delivery and sorted by size of estimated effect.3TC, lamivudine; ABC, abacavir; ATV, atazanavir; DRV, darunavir; EFV, efavirenz; FTC, emtricitabine; LPV, lopinavir; NVP, nevirapine; r, ritonavir boosted; TDF, tenofovir; ZDV, zidovudine.
Discussion
In this national surveillance study, preterm births accounted for around 10% of all included singletons. An association between RTV-boosted protease inhibitors and PTD was observed, but this was not consistent across all protease inhibitors. Among women who conceived on ART, we found an increased risk of PTD in women on LPV/r compared with women who conceived on an NNRTI-based (mainly EFV and NVP) regimen even after taking into account other factors associated with PTD and irrespective of whether CD4+ cell count was above or below 350 cells/μl. The associations between other protease inhibitor-based (mainly ATV/r and DRV/r) regimens and PTD risk were complex, with significant associations seen in some subgroups but not in others. There was no trend in PTD across TDF-containing regimens and no clear pattern when considering the most common drug combinations. Overall, PTD risk was higher in women who conceived on ART, had low CD4+ cell count and were older (>36 years), with VPTD risk also increased in women with a history of IDU.
Our findings on PTD associated with LPV/r are consistent with other studies, although there are differences. The PROMISE randomized clinical trial [10] reported significant higher PTD risk in the LPV/r + TDF + FTC arm compared with the LPV/r + 3TC/ZDV or mono ZDV + single dose NVP arms although all participants initiated ART in pregnancy with CD4+ cell count more than 350 cells/μl. Conversely, the main findings of a surveillance study in Botswana [21] suggested that PTD risk was higher in women conceiving on LPV/r + ZDV/3TC than in women conceiving on LPV/r + TDF/FTC, although the authors could not adjust or stratify analysis by CD4+ cell count. When considering women with CD4+ cell count more than 350 cells/μl (Supplementary Online Content [21]) those on LPV/r + TDF/FTC tended to have higher PTD risk than those on LPV/r + ZDV/3TC (EFV + TDF/FTC as the reference). It is therefore difficult to compare these results with our findings. A further study [22] that had randomized Ugandan women to LPV/r or EFV-based ART at 12–28 weeks gestation found no significant different in PTD risk between LPV/r-based and EFV-based ART. In our study, the association between LPV/r and PTD was only seen among women on ART at conception and not among those starting treatment in pregnancy.
Overall, we found that women who conceived on ART were at higher risk of PTD than those starting ART in pregnancy. The size of our dataset and availability of CD4+ data meant we could stratify women who conceived on ART by CD4+ group, finding that PTD rate was much higher (13.7%) in women with CD4+ cell count 350 cells/μl or less than in women with CD4+ cell count more than 350 cells/μl (8.8%). This is an important result as a recent systematic review and meta-analysis [4] that summarized findings from 11 studies showed an increased risk of PTD with preconception initiation of ART but authors could not differentiate between women with low and high CD4+ cell count because of lack of data. Similarly, a very recent study using data of HIV-infected women delivering in a hospital in Malawi between 2012 and 2015 [23], a period marking the implementation of Option B+, found that women conceiving on ART were at lower risk of delivering PTD compared with those starting ART in pregnancy. However, analyses were not adjusted for CD4+ cell count (data not available) and the Option B+ regimen did not include protease inhibitors.
The association of PTD with ART is likely to be multifactorial. Untreated HIV infection is associated with a Th1 to Th2 immunological shift, as is normal pregnancy. As ART reverses this ‘normal’ shift in pregnant patients with HIV [24], it has been postulated that this might be associated with increased PTD risk. Biologically, this effect, altering the balance of cytokines, might be expected to have most impact where ART was initiated during pregnancy. However, the data presented here and by others [1,5,25] point to a greater effect of ART on PTD risk if initiated prior to conception.
Most consistent in the literature has been the association of PTD with protease inhibitors. A Canadian study [26] reported the odds ratio of PTD with boosted protease inhibitors to be twice that of unboosted protease inhibitor, raising the question of the direct impact of the booster as well as an indirect effect via higher drug concentrations. Data are lacking on the effect of full dose RTV (600-mg twice daily) on PTD. However, a pattern emerges from our data of lower PTD with boosted ATV (100-mg RTV daily) compared with LPV (100-mg RTV twice daily) and darunavir (RTV 100 mg daily or twice daily). In the PROMISE study [13], LPV/r dose was increased for the third trimester resulting in exposure to RTV 150 mg twice daily. We excluded women on unboosted protease inhibitors from our analysis, as the small number precluded statistical comparison with other groups; the PTD rate in this group was 5.2%. Protease inhibitors are associated with reduced levels of progesterone [9], possibly by reducing prolactin levels and increasing placental expression of the prolactin-regulated, progesterone-inactivating enzyme 20-α-hydroxysteroid dehydrogenase [27] and a study of topical cervical progesterone in HIV has been proposed to explore whether this improves perinatal outcomes [11], but it is clear that more research is needed, including to understand the effect of protease inhibitor exposure throughout pregnancy on progesterone levels. The PROMISE study focused attention on the role of nucleosides/nucleotides; one interpretation of the PROMISE results is that TDF/FTC is associated, at least when administered with LPV/r, with increased PTD risk. In our study, an increased PTD risk was seen when TDF/FTC were administered with LPV/r but not with ATV/r (possibly due to lower ATV/r concentrations with TDF) nor with NNRTIs, suggesting that TDF/FTC per se are not associated with PTD risk. An alternative hypothesis could be that ZDV-based therapies are associated with lower risk of PTD, supported by data from the PROMISE [13] and MmaBana [7] studies (ABC/ZDV/3TC) and by data from the NSHPC on ZDV monotherapy and ZDV/3TC dual therapy [2]. In another clinical trial conducted in Uganda the backbone to both arms (EFV vs. LPV/r) was ZDV + 3TC, with no significant difference in PTD observed (16.2% with LPV/r vs. 14.7% with EFV) [22]. Finally, restoration of immune function with treatment may unmask otherwise hidden risks for PTD. A resurgence in risk of preeclampsia has been reported in the cART era, whereas mothers on ZDV monotherapy had lower than expected rates [28]. This might be considered a form of immune reconstitution inflammatory syndrome and would not necessarily be class specific, as such an effect would correlate with overall regimen efficacy.
The size of the NSHPC dataset allowed us to stratify analyses by CD4+ cell count and ART at conception to minimize bias in treatment indication, as well as to investigate PTD risk associated with the most commonly prescribed regimens in the United Kingdom between 2007 and 2015. However, our study had some limitations. There was some systematic bias as we excluded a-priori women exposed to ART for less than 28 days before delivery. In this group, the PTD rate was extremely high (42/145, 29.0%) and the reasons behind this are likely to be complex and deserve separate investigation. We could not adjust for maternal HIV disease stage prior to conception or nadir CD4+ cell count (because data not collected by NSHPC) or other coinfections, which may increase the risk of PTD or determine ART regimen choice. Until recently, ART was prescribed outside of the context of pregnancy to women with immune deficiency and/or low CD4+ cell count. Women starting treatment before conception in earlier years were more likely to have started because of HIV disease and may therefore have risk factors for adverse pregnancy outcome not present in women first starting ART during pregnancy [15,16]. This scenario (and thus residual confounding) may be particularly relevant to women who conceived on LPV/r (as LPV/r was more frequently prescribed in earlier years of the study) and DRV/r. DRV-based regimens were recommended second-line in UK guidelines between 2008 and 2012, implying higher prevalence of previous severe maternal HIV disease and/or virological failure. Pregnant women living with HIV in the United Kingdom/Ireland have risk factors for PTD in common with the general population, such as older maternal age and IDU, or coming from communities at increased PTD risk, such as women originating in the CRB [29]. However, we were not able to adjust our analyses for other important PTD risk factors such previous PTD, maternal BMI, smoking and socio-economic status because the NSHPC does not collect this information.
Our data support a link between the initiation of LPV/r-based ART prior to pregnancy and subsequent PTD, which should be factored into treatment guidelines. Although rarely prescribed in the United Kingdom now, LPV/r-based regimens are still used by large numbers of pregnant women living with HIV in Eastern Europe [30,31]. Our findings also show increased PTD risk among women on other specific regimens at conception with CD4+ cell counts above 350 cells/μl. This is of particular relevance given the rapid growth in the number of women with HIV conceiving on ART expected in lower and middle-income settings with current guidelines to initiate ART at any CD4+ cell count [32], and the implications of PTD for infant morbidity and mortality in such settings [33]. The public health approach to HIV treatment in lower and middle-income settings precludes an individualized approach to ART according to women's childbearing potential/intent and PTD risk, and the safest regimens for all women therefore need to be identified and included in guidelines.
Conclusion
Our data support a link between the initiation of RTV-boosted/LPV-based ART preconception and PTD in subsequent pregnancies. These and other data associating the preconception choice of ART with pregnancy outcomes have implications for adult and not just pregnancy treatment guidelines given that increasing numbers of pregnancies worldwide are conceived on ART [34]. Although the benefits of ART for pregnant women living with HIV and their infants are clear, data on safety and pharmacokinetics in pregnancy are lacking, particularly for newer drugs and classes and continued monitoring of PTD risk is needed.
Acknowledgements
The national surveillance of obstetric and paediatric HIV is undertaken through the National Study of HIV in Pregnancy and Childhood (NSHPC), in collaboration with Public Health England. The authors gratefully acknowledge the contribution of the midwives, obstetricians, genitourinary physicians, paediatricians, clinical nurse specialists and all other colleagues who report to the NSHPC through the British Paediatric Surveillance Unit of the Royal College of Paediatrics and Child Health and the obstetric reporting scheme. We wish to thank Icina Shakes (former Study Assistant), Anna Horn (Study Assistant), Rebecca Sconza and Kate Francis (Research Assistants) for their essential contributions to the NSHPC.
The National Study of HIV in Pregnancy and Childhood receives funding from Public Health England, including the National Health Service Infectious Diseases in Pregnancy Screening Programme. The funding body had no input into the conduct of this analysis.
Author contributions: Conceptualization: G.F., C.L.T., C.T., P.T. and H.B.; Data curation: H.P.; Formal analysis: G.F.; Funding acquisition: C.T. and P.T.; Investigation: G.F., C.L.T., H.B., H.P., P.T., G.T. and C.T.; Writing – original draft preparation: G.F., C.L.T., C.T. and G.T.; Writing – review and editing: G.F., C.L.T., H.B., H.P., P.T., G.T. and C.T.
Conflicts of interest
C.T. and P.T. have received funding from AbbVie; C.T. has received funding from ViiV and participated in an Advisory Board for ViiV. C.L.T. has received consultancy fees from WHO and Public Health England. The other authors have no conflicts of interest to disclose.
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