Highlights
– MTN‑042/DELIVER randomized pregnant, HIV‑negative women to the dapivirine vaginal ring (DVR) or daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) and followed infants to 12 months.
– Among 545 infants with in‑utero exposure, there were no infant or maternal HIV acquisitions and no infant adverse events attributed to study products.
– Serious adverse events (SAEs) and grade 3+ events were numerically higher in the DVR group (17% and 24%) versus oral PrEP (10% and 20%), but investigators reported none were related to product exposure.
Background
Pregnancy is a period of increased biological and social vulnerability to HIV acquisition in many high‑incidence settings. Preventing HIV in pregnant and breastfeeding women preserves maternal health and eliminates vertical transmission risk. Oral pre‑exposure prophylaxis (PrEP) with TDF/FTC has established efficacy for HIV prevention and observational data have generally supported its safety in pregnancy. The dapivirine vaginal ring (DVR) is a topical, woman‑controlled PrEP option that releases dapivirine locally with low systemic absorption; however, clinical data on in‑utero exposure and infant outcomes have been limited.
Study design
MTN‑042/DELIVER (ClinicalTrials.gov NCT03965923) was a randomized, controlled, open‑label, phase 3b study conducted at four research sites in Malawi, South Africa, Uganda, and Zimbabwe (Feb 7, 2020–May 13, 2024). Pregnant, healthy, HIV‑negative women aged 18–40 years were enrolled in three gestational cohorts: cohort 1 at 36–37 weeks, cohort 2 at 30–35 weeks, and cohort 3 at 12–29 weeks. Randomization ratios were 2:1 (DVR:oral PrEP) for cohorts 1 and 2 and 4:1 for cohort 3. The DVR contained 25 mg dapivirine; the oral PrEP regimen was daily TDF 300 mg plus FTC 200 mg. All infants born to enrolled mothers were included in the primary infant analysis and were assessed at <2 weeks, 6 weeks, 6 months, and 12 months of life.
The primary infant composite safety outcome included serious adverse events (SAEs) and grade 3 or higher adverse events. Secondary outcomes included birth outcomes (livebirth, stillbirth, prematurity), the timing and frequency of adverse events across visits, congenital anomalies, and growth through 12 months. Maternal and infant HIV incidence were monitored throughout follow‑up.
Key findings
Overall, 545 infants were included in the analysis: 147 in cohort 1, 154 in cohort 2, and 244 in cohort 3. Mean duration of intrauterine exposure to study product was 23.3 days in cohort 1, 59.7 days in cohort 2, and 113.8 days in cohort 3. Of 550 pregnancy outcomes, 545 (99%) were livebirths.
Safety endpoints for infants to 12 months:
- Serious adverse events occurred in 66 of 398 infants (17%) exposed to the DVR and 15 of 147 infants (10%) exposed to oral PrEP.
- Grade 3 or higher adverse events occurred in 95 of 398 infants (24%) in the DVR group and 29 of 147 infants (20%) in the oral PrEP group.
- Investigators reported that none of the SAEs or grade 3+ events were related to exposure to study product.
- Timing: 41 (51%) of 81 new‑onset SAEs occurred by age 6 weeks, and 10 (91%) of 11 congenital anomalies were diagnosed by age 6 months.
- No maternal or infant HIV acquisitions occurred during the trial.
Collectively, these data indicate that both the DVR and oral TDF/FTC PrEP regimens were generally well tolerated in infants with in‑utero exposure and showed no signals of product‑related harm over the first year of life.
Safety interpretation and contextual analysis
At first glance, the numerically higher proportions of SAEs (17% vs 10%) and grade 3+ events (24% vs 20%) in infants with DVR exposure deserve attention. The trial investigators explicitly reported that none of these events were considered related to product exposure, which is an important qualifier. Several contextual factors must be considered when interpreting these numerical differences:
- Sample size and randomization ratios: The DVR arm included more infants (398) than the oral PrEP arm (147) because of the 2:1 and 4:1 randomization ratios; absolute counts and proportions can be influenced by this design and by chance.
- Heterogeneity of adverse event causes: In infant studies, SAEs are commonly driven by infections (e.g., sepsis, pneumonia), hospitalizations for neonatal conditions, and other non‑drug‑related events. The distribution of event types matters more than aggregate counts when assessing product causality.
- Timing of events: The fact that approximately half of new SAEs occurred within the neonatal period (≤6 weeks) and most congenital anomalies were detected by 6 months is consistent with expected timing for perinatal complications and congenital diagnoses rather than a delayed effect of low systemic exposure from the DVR.
- Biological plausibility: The DVR provides low systemic dapivirine exposure compared with oral dosing; transplacental transfer is expected to be limited. TDF/FTC crosses the placenta more readily, yet long‑term experience with TDF/FTC in pregnant people (as treatment or PrEP) has not identified major teratogenic signals in large observational cohorts.
Strengths
MTN‑042/DELIVER has several methodological strengths. It used randomized allocation to compare two real‑world PrEP options for pregnant women and included multiple gestational cohorts to capture varying durations of fetal exposure. The multi‑country African setting enhances relevance to regions with high maternal HIV incidence. Systematic infant follow‑up to 12 months and inclusion of all infants born to maternal participants in the primary analysis reduce selection bias.
Limitations
Important limitations temper the findings. The trial was open‑label, which could affect clinical management decisions and reporting of events. Imbalanced randomization ratios resulted in a smaller comparator group, limiting statistical precision for between‑group comparisons. The study was not powered to detect rare congenital anomalies or small differences in uncommon outcomes. Follow‑up to 12 months captures early growth and major morbidities but does not address longer‑term neurodevelopmental outcomes or childhood growth trajectories that could be relevant for subtle drug effects. Finally, the trial period overlapped the COVID‑19 pandemic, which could have influenced healthcare access and hospitalization rates in ways that are challenging to disentangle from treatment effects.
Expert commentary and implications for practice
From a clinical and public‑health perspective, the key message is pragmatic: both DVR and oral TDF/FTC PrEP were not associated with product‑related infant harm through 12 months of age in this randomized phase 3b trial. That finding complements existing maternal safety data and supports offering these woman‑controlled HIV prevention options during pregnancy, particularly in settings with ongoing high HIV transmission.
Clinicians should continue to counsel pregnant women about the benefits of preventing maternal HIV acquisition versus the remaining uncertainties. Given the large body of evidence supporting the safety of oral TDF/FTC in pregnancy from treatment cohorts and observational PrEP studies, and the biological expectation of low fetal dapivirine exposure from the DVR, these data reduce but do not eliminate residual uncertainty. Shared decision‑making should incorporate patient preference, adherence considerations, access to product options, and local HIV epidemiology. Routine clinical monitoring of infants should follow standard neonatal and pediatric protocols; no additional product‑specific surveillance is indicated based on current evidence, although continued pharmacovigilance and longer‑term developmental follow‑up are advisable.
Research priorities
Remaining knowledge gaps include the following: (1) larger pooled datasets or longer follow‑up to detect rare congenital anomalies or late‑emerging developmental effects; (2) mechanistic studies characterizing placental transfer and infant pharmacokinetics for dapivirine when used in pregnancy; (3) prospective neurodevelopmental assessments beyond 12 months; and (4) implementation research to optimize uptake, adherence, and choice of PrEP modality for pregnant and postpartum women in diverse health systems.
Conclusion
MTN‑042/DELIVER provides robust randomized evidence that in‑utero exposure to the dapivirine vaginal ring or daily oral TDF/FTC for HIV prevention was generally safe through 12 months of infant follow‑up, without product‑related serious adverse events and with no HIV transmissions. These results strengthen the evidence base for offering both PrEP options to pregnant women at substantial risk of HIV and support integrating women‑centered choices into antenatal prevention strategies. Ongoing surveillance and longer‑term follow‑up remain important to confirm these reassuring early findings.
Funding and trial registration
Funding: US National Institutes of Health.
ClinicalTrials.gov: 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. PMID: 41173578.
2. ClinicalTrials.gov. MTN‑042: Dapivirine Vaginal Ring and Oral PrEP in Pregnant Women (DELIVER). NCT03965923. Available at: https://clinicaltrials.gov/ct2/show/NCT03965923 (accessed 2025).