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, http://links.lww.com/QAD/B189).
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, http://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].
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, http://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, http://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).
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  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  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 ) 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  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  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 , 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 , 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  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 , 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 , possibly by reducing prolactin levels and increasing placental expression of the prolactin-regulated, progesterone-inactivating enzyme 20-α-hydroxysteroid dehydrogenase  and a study of topical cervical progesterone in HIV has been proposed to explore whether this improves perinatal outcomes , 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  and MmaBana  studies (ABC/ZDV/3TC) and by data from the NSHPC on ZDV monotherapy and ZDV/3TC dual therapy . 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) . 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 . 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 . 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 , and the implications of PTD for infant morbidity and mortality in such settings . 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.
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 . 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.
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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