Highlight
– MTN-042/DELIVER randomized pregnant, HIV-negative women to dapivirine vaginal ring (DVR) or daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) and followed 545 infants to 12 months.
– Composite infant safety events (serious adverse events or grade ≥3 adverse events) occurred but were not attributed to study product; no maternal or infant HIV infections were observed.
– Findings support DVR and oral PrEP as pregnancy options to prevent maternal HIV acquisition, with continued pharmacovigilance recommended.
Background
Pregnancy is a period of increased biological and behavioural vulnerability to HIV acquisition in high-burden settings. New maternal HIV infections during pregnancy and breastfeeding not only endanger maternal health but also increase the risk of vertical transmission. Pre-exposure prophylaxis (PrEP) with oral tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) is an efficacious HIV prevention strategy in diverse populations, and the dapivirine vaginal ring (DVR) offers an alternative, topical modality with lower systemic exposure. However, evidence on fetal and infant safety after prenatal exposure, particularly for DVR, has been limited. Rigorous safety data are essential to inform guidelines and clinical decision-making for offering PrEP options to pregnant women at substantial risk of HIV.
Study design
Overview
MTN-042/DELIVER was an open-label, randomized, phase 3b safety study conducted at clinical research sites in Malawi, South Africa, Uganda, and Zimbabwe. HIV-negative, healthy pregnant women aged 18–40 years were enrolled in three gestational cohorts to capture different windows of in-utero exposure: cohort 1 at 36–37 weeks, cohort 2 at 30–35 weeks, and cohort 3 at 12–29 weeks’ gestation. Randomization ratios were 2:1 (DVR:oral PrEP) for cohorts 1 and 2 and 4:1 for cohort 3, reflecting escalating exposure windows and a prioritization of DVR data collection.
Interventions and follow-up
Participants received either the dapivirine 25 mg vaginal ring or daily oral TDF/FTC (TDF 300 mg + FTC 200 mg). All liveborn infants of enrolled maternal participants were included in the primary infant analysis. Infant clinical assessments occurred at <2 weeks, 6 weeks, 6 months, and 12 months of age. The prespecified primary infant composite safety outcome comprised serious adverse events (SAEs) and grade 3 or higher adverse events. Additional endpoints included birth outcomes (livebirth, stillbirth, prematurity), the timing and frequency of adverse events across visits, growth trajectories to 12 months, congenital anomalies, and infant/maternal HIV status. The trial is registered at ClinicalTrials.gov (NCT03965923).
Key findings
Population and exposure
Between Feb 7, 2020, and May 13, 2024, 545 infants were followed in the primary analysis set: 147 in cohort 1, 154 in cohort 2, and 244 in cohort 3. Mean durations of in-utero exposure were 23.3 days (cohort 1), 59.7 days (cohort 2), and 113.8 days (cohort 3), providing a range of gestational exposure windows.
Birth outcomes and overall survival
Of 550 reported pregnancy outcomes, 545 (99%) were livebirths. This high livebirth proportion is reassuring and aligns with expectations in similar clinical trial settings. The publication reports no maternal or infant HIV transmissions during follow-up.
Infant safety events: composite outcome
In the DVR arm (n=398 infants), 66 infants (17%) experienced at least one serious adverse event. In the oral PrEP arm (n=147 infants), 15 infants (10%) experienced an SAE. Grade 3 or higher adverse events occurred in 95/398 (24%) infants in the DVR group and 29/147 (20%) in the oral PrEP group. Importantly, the trial investigators adjudicated that none of the composite events were related to in-utero exposure to study product.
Timing and nature of events
Of 81 new-onset SAEs reported across groups, 41 (51%) occurred by the 6-week visit, indicating a front-loaded distribution of severe events in early neonatal life. Eleven congenital anomalies were reported; ten (91%) were diagnosed by 6 months. The paper does not attribute these anomalies to study products, and event timing is consistent with routine perinatal diagnoses.
Growth and other safety signals
The authors evaluated growth through 12 months and report no product-related growth deficits. The absence of HIV acquisitions in mothers and infants further supports the maternal and infant safety profile within the trial period.
Interpretation and clinical implications
MTN-042/DELIVER offers some of the most robust randomized data to date on infant outcomes after maternal use of DVR and oral TDF/FTC PrEP during pregnancy. Key implications include:
- General infant safety: Although SAEs and grade ≥3 AEs occurred, these were not attributed to the study products. Observed event rates were within ranges seen in perinatal cohorts in similar settings, and the lack of product-related signals is clinically reassuring.
- Supporting choice of PrEP in pregnancy: Together with maternal safety data, these findings support offering either the DVR or oral TDF/FTC as pregnancy PrEP options to women at substantial HIV risk. DVR’s low systemic exposure provides a biologically plausible basis for limited fetal exposure, while extensive clinical experience with TDF/FTC in HIV treatment supports its safety profile.
- No HIV infections: The absence of maternal or infant HIV infections during follow-up is important, though the study was not designed or powered to compare efficacy between modalities; the result is nevertheless reassuring regarding real-world potential to reduce maternal acquisition.
Strengths and limitations
Strengths
- Randomized design across multiple African sites enhances internal validity and relevance to high-burden settings.
- Enrollment across three gestational windows captured a range of fetal exposures to study products.
- Systematic infant follow-up to 12 months enabled detection of early and some later adverse outcomes, including congenital anomalies and growth patterns.
Limitations and considerations
- Open-label design: Knowledge of assignment could influence care-seeking or reporting of events, although objective endpoints (e.g., congenital anomalies, growth) are less susceptible to bias.
- Randomization ratios favored the DVR arm, resulting in unequal group sizes and limited precision for head-to-head safety comparisons. The trial was not primarily powered to detect small differences in infant SAE rates between arms.
- Follow-up limited to 12 months: While this window captures many early events, longer-term neurodevelopmental outcomes and later-onset effects require surveillance beyond infancy.
- Contextual factors: Background rates of neonatal morbidity and health system differences across sites influence event rates and generalizability; heterogeneity by site was not a primary focus of the report.
Biological plausibility and mechanistic notes
Dapivirine is a non-nucleoside reverse transcriptase inhibitor delivered locally via a silicone ring; systemic levels are substantially lower than those achieved with oral antiretrovirals, reducing the biologically plausible risk of fetal toxicity. TDF/FTC are nucleos(t)ide agents with extensive experience in pregnancy as components of antiretroviral therapy, and observational data as well as randomized trials of PrEP have not demonstrated major teratogenic signals. The absence of product-related signals in DELIVER is therefore consistent with mechanistic expectations.
Expert commentary and guideline context
Clinical adoption of PrEP in pregnancy has been incremental, partly because of concerns about fetal safety and partly due to limited service integration. MTN-042/DELIVER fills a major evidence gap by providing randomized infant safety data spanning early and mid-gestation exposures. Clinicians and policy-makers should integrate these findings with existing guideline recommendations and local epidemiology to expand access to PrEP options for pregnant women at substantial risk.
Conclusions and next steps
MTN-042/DELIVER demonstrates that in-utero exposure to the DVR and oral TDF/FTC PrEP was not associated with infant safety signals attributable to product exposure through 12 months of life. These data support counseling pregnant women about both modalities as prevention options when HIV risk is high. Continued pharmacovigilance, including longer-term neurodevelopmental follow-up and larger post-marketing surveillance, will strengthen confidence in safety and inform implementation strategies. Operational research is also needed to optimize delivery, adherence support, and informed choice in antenatal care settings.
Funding and trial registration
The study was funded by the US National Institutes of Health. ClinicalTrials.gov registration: NCT03965923.
References
1. Fairlie L, Szydlo DW, Mayo A, et al.; MTN-042 study team. Safety outcomes among infants whose mothers used the dapivirine vaginal ring or oral PrEP during pregnancy (MTN-042/DELIVER): a randomised phase 3b study. Lancet HIV. 2025 Nov;12(11):e763-e773. doi:10.1016/S2352-3018(25)00261-9.
2. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367:399-410. doi:10.1056/NEJMoa1108524.
Thumbnail image prompt
A warm, clinical scene: a nurse in clinical scrubs cradling a healthy newborn in a bright clinic room, with a translucent overlay showing a small vaginal ring and a strip of pills; soft natural lighting, calm expressions, tones of teal and soft orange to convey clinical rigor and reassurance.
