The median birth weight was 3120 g (interquartile range, 2750–3470). A total of 16.9% (n = 2 missing birth weights) of neonates had LBW and 18.7% were SGA (Table 5). The proportions of neonates born preterm were 7.5%, 27.3%, and 11.8% for those whose earliest dolutegravir exposures started in the first, second, and third trimesters, respectively.
Antiretroviral Pregnancy Registry
In the APR cohort, among the 255 live-born neonates (including 9 sets of twins) with prenatal exposure to dolutegravir, birth defects occurred in 7 (2.7%) neonates. Of the 121 neonates first exposed to dolutegravir at conception, 3 (2.5%) were reported to have abnormalities: a male neonate with bilateral polydactyly postaxial to both hands who was also exposed to darunavir/ritonavir; a female neonate with an ectopic right kidney who was also exposed to emtricitabine, lamivudine, raltegravir, and tenofovir disoproxil fumarate at conception, darunavir/ritonavir during the second trimester, and zidovudine during the third trimester; and a male neonate with endocardial fibroelastosis who was also exposed to abacavir and lamivudine. Ages of the mothers (ethnicity) at delivery were 26 years (black), 26 years (black), and 19 years (Hispanic), respectively. Of the 40 neonates with first exposure after conception and during the first trimester, 2 (5.0%) were reported to have abnormalities: a male neonate with polydactyly on the ulnar side and syndactyly on the second, third, and fourth fingers who was also exposed to tenofovir disoproxil fumarate and emtricitabine and a male neonate with talipes equinovarus also exposed to abacavir, lamivudine, and raltegravir. Ages of the mothers (ethnicity) at delivery were 22 years (black) and 24 years (Asian), respectively. Of the 94 neonates with first exposure during the second or third trimester, 2 (2.1%) were reported to have abnormalities: a female neonate with hypoglossia–hypodactylia syndrome with dolutegravir exposure during the third trimester who was also exposed to darunavir/ritonavir, tenofovir disoproxil fumarate, and emtricitabine during the second trimester as well as zidovudine in the third trimester and a female neonate with Down syndrome who was exposed to dolutegravir, abacavir, and lamivudine during the second trimester. Ages of the mothers (ethnicity) at delivery were 31 years (black) and 38 years (Hispanic), respectively. No neural tube defects or central nervous system defects were reported.
European Pregnancy and Paediatric HIV Cohort Collaboration
Data on congenital abnormalities in the EPPICC studies were available for 81 of 84 live-born and stillborn neonates (twin/singleton pregnancies). Overall, abnormalities were recorded in 4 neonates [4.9%; 95% confidence interval (CI): 1.4 to 12.2]: 3 from the Italian cohort and 1 from the Swiss cohort. Of the 42 neonates first exposed to dolutegravir during the first trimester, 3 male neonates (7.1%) were reported to have abnormalities: 1 neonate with a patent foramen ovale with small left-to-right interatrial shunting, who was first exposed to dolutegravir from conception and also exposed to lamivudine and abacavir; 1 neonate with bilateral hexadactyly and hypospadias, who was first exposed to dolutegravir at week 3 and also exposed to lamivudine/abacavir and emtricitabine/tenofovir disoproxil fumarate; and 1 neonate with ankyloglossia (tongue-tie), who was first exposed to dolutegravir at week 12 and was also exposed to darunavir/ritonavir, emtricitabine/tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, and raltegravir. Ages of the mothers (ethnicity) at delivery were 38 years (black African), 40 years (white), and 31 years (white), respectively. Of the 24 neonates first exposed to dolutegravir during the second trimester (week 14), 1 (4.2%) male neonate was also exposed to lamivudine and abacavir and presented with hyperpigmentation on his back. His mother was of black African ethnicity and was aged 34 years. No central nervous system defects were reported.
The 2 separate analyses using data from APR and EPPICC account for many of the prospectively collected, prenatal exposures of dolutegravir to date. For most pregnancies included in these analyses (APR, 65%; EPPICC, 58%), dolutegravir was initiated during or before the first trimester (including 158 outcomes after dolutegravir exposure at conception), thus providing important safety information for use of dolutegravir-based regimens during early pregnancy. More than 90% of pregnancies from both data sets resulted in live births. Induced and spontaneous abortions primarily were reported in women exposed to dolutegravir during their first trimester of pregnancy (as expected, because most abortions occur in the first trimester).15,16 Rates of both induced and spontaneous abortions among APR (2.3% and 4.2%, respectively) and EPPICC (both 1.2%) cohorts who received dolutegravir are lower than recent estimates among general populations for these outcomes; however, neither study is designed to capture early pregnancy loss or termination prevalence.17–19
Of the 231 singleton live births in the APR data set without defects and with prenatal exposure to dolutegravir, 10.4% were delivered at <37 weeks (preterm) and 12.6% had birth weights <2500 g. Of the 79 singleton live births and 1 stillbirth in the EPPICC data set, 13.8% were delivered preterm, 16.9% of neonates had LBW (1500–2499 g; none were <1500 g at birth), and 18.7% were SGA. Congenital abnormalities occurred in 2.7% and 4.9% (95% CI: 1.4 to 12.2) of live births from APR and EPPICC, respectively, with most anomalies being polydactyly, a common birth defect.20 Congenital upper-extremity abnormalities comprise approximately 10% of all birth defects21; by contrast, the birth prevalence rate of radial polydactyly is approximately 25 per 100,000 births.22 The risk factors associated with polydactyly include race/ethnicity (predominance of postaxial polydactyly in people of African descent),23 male sex,24 birth order,25 and maternal smoking.26
The preterm delivery rate of 14% of the 79 pregnancies assessed in women exposed to dolutegravir-containing regimens from EPPICC was similar to that reported among women living with HIV infection who delivered during the same period in the United Kingdom—the country accounting for approximately 60% of the studied women. In a recent analysis of data from the UK and Ireland National Study of HIV in Pregnancy and Childhood regarding pregnant women taking protease inhibitor–based or non-nucleoside reverse transcriptase inhibitor–based ARV treatment regimens who delivered neonates between 2007 and 2015, the preterm delivery rate was 11.5% for women taking ARV therapy at conception with CD4+ counts ≤350 cells/µL.27 The 10.4% preterm delivery rate in the APR cohort is similar to rates reported in overall populations in North America (10.6%; excluding Mexico)28 and worldwide (11.1%; approximately 14.9 million preterm deliveries).29 However, a meta-analysis of prospective and retrospective cohort studies conducted across developed and developing countries found that women with HIV infection were at increased risk of preterm delivery (summary odds ratio 1.56; 95% CI: 1.49 to 1.63) when compared with their uninfected counterparts.30
Approximately 10% of the women in the EPPICC cohort were vertically infected themselves, and an additional 9% were coinfected with hepatitis C virus (HCV)/HIV. These proportions are higher than expected considering the larger cohort populations of pregnant women with HIV infection living in Western Europe from which they are drawn.12,31 They most likely reflect the preferential use of dolutegravir in specific groups of women. Factors such as coinfection with HCV/HIV may also be associated with worse pregnancy outcomes.31
The observed LBW prevalence among singleton live births without defects in APR (10.6%) was higher than reported US rates in the general population (8.2%) in 201632 but lower than expected compared with a recent analysis of APR birth outcomes through 2011 reporting birth weight <2500 g was 15.9%.33 Although 5 cases were reported, the prevalence of VLBW (<1500 g) after dolutegravir exposure (2.2%) was similar to earlier APR data (2.1%) but higher than the 2016 prevalence of the general US population (1.4%).32 Overall, a meta-analysis of reports comparing pregnancy outcomes in women with or without HIV found that those living with HIV infection are at increased risk of delivering a neonate with LBW compared with their uninfected counterparts (summary odds ratio 1.73; 95% CI: 1.64 to 1.82).30
Birth defect numbers were comparable across APR (7 of 255) and EPPICC (4 of 81) data sets. CIs relating to EPPICC data were large, reflecting the small sample size, and that considerable heterogeneity was observed across cohorts (eg, age, region, CD4+ count, timing of dolutegravir exposure). When applying the EUROCAT classification of birth defects to EPPICC (which excludes isolated tongue-tie and hyperpigmentation on the back), the rate decreased to 2.5%. Through January 31, 2018, among APR reports with any ARV exposure during pregnancy, 516 birth defects were identified of the 18,660 live births, with a prevalence of 2.8 birth defects per 100 live births (95% CI: 2.5 to 3.0).34 This proportion was not substantially higher than the 3.0 and 4.6 per 100 live births reported in other similar US population-based databases, ie, MACDP and the Texas Birth Defects Registry, respectively.35,36 In the APR, ≥200 first-trimester exposures to any individual drug are needed to estimate the overall prevalence of birth defects, a statistical threshold the present assessment of dolutegravir pregnancy exposure does not meet.
There are multiple limitations with these 2 analyses. It is also possible that birth defects may go unrecognized or be differentially reported. Unlike the APR, data relating to birth defects from participating studies in EPPICC are not reviewed by a teratologist. Conclusions based on the proportions of induced and spontaneous abortions were limited because some cohorts included patients first enrolled in the cohort later in the pregnancy than when most abortions occur. First-trimester exposures in both cohorts are not large enough for definitive conclusions. Conclusions about regional differences in pregnancy outcomes between the 2 studies are limited because the APR and EPPICC cohorts included 18 (6.8%) and 61 (60.4%) patients from the United Kingdom/Ireland, respectively, and it is possible that the some of the 18 participants may have been included in both cohorts. Similarly, because the EPPICC cohort included participants from 6 cohorts in different countries, differences in study design could affect overall conclusions of pregnancy outcomes in Western Europe. Further postmarketing surveillance within EPPICC is ongoing.
HIV-positive women of childbearing potential, pregnant women, and their health care professionals should follow recommendations on dolutegravir use.9,37,38 In the United Kingdom and Ireland, the percentage of pregnant women exposed to dolutegravir-based regimens has increased >10-fold from 0.3% in 2015 to 3.3% in 2016.39 Even with this analysis of pregnancies with first-trimester exposure to dolutegravir combined from APR and EPPICC, the expanding use of dolutegravir, together with the potential safety signal of neural tube defects reported with dolutegravir exposure at the time of conception from Botswana,9 highlights the importance for continuing the prospective monitoring of pregnant women and their infants through APR and EPPICC. Following recommendations from global, US, and European agencies,9,37,38 conceptions on dolutegravir may decline, but continued monitoring is critical. Our assessment of these collective 198 birth outcomes after first-trimester dolutegravir exposure from 2 prospective registries (APR, 156 outcomes; EPPICC, 42 outcomes) and data cited from 3 other studies with 104 pregnancy outcomes identified no birth defect signal, either in defect prevalence or in defect-type clustering.40–42 In addition, among birth defects reported after dolutegravir exposure during pregnancy or at the time of conception, none involved the neural tube. These findings may provide some reassurance to women whose pregnancies have already been exposed to dolutegravir or who have limited therapeutic options.
All listed authors meet the criteria for authorship set forth by the International Committee of Medical Journal Editors. Both V.V. and C.T. were involved in design of the study, data analysis, manuscript development, and manuscript approval. At the time of publication, the APR is funded by 27 pharmaceutical manufacturers of the 49 proprietary and more than 70 generic ARV medications monitored by APR. This study was funded by ViiV Healthcare. Writing and editorial assistance was provided under the direction of the authors by Jeffrey Stumpf and Sherri Damlo, MedThink SciCom, and was funded by ViiV Healthcare.
Author contributors: From APR: Jessica D. Albano, MPH, PhD, Mandy Bowen, BS, Taylor Cook, BS, Syneos Health, Wilmington, NC; Harmony Garges, MD, MPH, ViiV Healthcare Global Medical Sciences, Research Triangle Park, NC; Leigh Ragone, MS, ViiV Healthcare, Research Triangle Park, NC; Angela E. Scheuerle, MD, University of Texas Southwestern Medical Center, Department of Pediatrics, Dallas, TX; Hugh Tilson, MD, DrPH, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC; Yuming Xue, PhD, Syneos Health, Raleigh, NC; and Nadja Vielot, PhD, MSPH, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC. From EPPICC: Karoline Aebi-Popp, MD, Department of Infectious Diseases, Bern University Hospital, Bern, Switzerland (Swiss Mother and Child HIV Cohort Study); David Burger, PharmD, and Angela Colbers, PhD, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands (PANNA Network); Marco Floridia, MD, National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy (Italian Group on Surveillance on Antiretroviral Treatment in Pregnancy); Carlo Giaquinto, MD, PENTA Foundation, Padua, Italy; Tessa Goetghebuer, MD, PhD, Hospital St Pierre, Brussels, Belgium (European Collaborative Study on HIV-infected pregnant women and their children); Helen Peters, MSc, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom (UK and Ireland National Study of HIV in Pregnancy and Childhood); Anton Pozniak, MD, Chelsea & Westminster Hospital, London, United Kingdom (NEAT-ID); Antoni Soriano-Arandes, MSc, PhD, Paediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d’Hebron, Barcelona, Spain (NENEXP study); and Milena Sovric, PhD, Munich University Hospital, Munich, Germany (NEAT-ID).
The EPPICC/PANNA study groups acknowledge Graziella Favarato (EPPICC, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom); Rebecca Sconza, Kate Francis, Anna Horn, and Pat Tookey (UK and Ireland National Study of HIV in Pregnancy and Childhood, London, United Kingdom); Marc Delforge, Evelyne Van Der Kelen, and Deborah Konopnicki (Saint-Pierre University Hospital, Brussels, Belgium); Katharina Weizsäcker (Klinik für Geburtsmedizin; Charité Universitätsmedizin, Berlin, Germany); Carmen Hidalgo Tenorio (Hospital Universitario Virgen de las Nieves Granada, Granada, Spain); Reinout van Crevel (Radboud University Medical Center, Nijmegen, The Netherlands); Giulia Masuelli, Arsenio Spinillo, Alessandra Meloni, and Cosimo Polizzi (Italian Group on Surveillance on Antiretroviral Treatment in Pregnancy); Antoni Noguera-Julian and Claudia Fortuny (Hospital Universitari Sant Joan de Déu, Barcelona, Spain), Pere Soler-Palacín and Natalia Mendoza (Hospital Universitari Vall d’Hebron, Barcelona, Spain), Antonio Mur (Hospital Universitari del Mar, Barcelona, Spain); Lourdes García (Consorci Sanitari del Maresme, Barcelona, Spain); and Alexandra Scherrer (Swiss Mother and Child HIV Cohort Study, Zurich, Switzerland).The authors thank all the patients for participating in the studies.
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