Mortality Among Children Aged <5 Years Living with HIV Who Are Receiving Antiretroviral Treatment - U.S. President's Emergency Plan for AIDS Relief, 28 Supported Countries and Regions, October 2020-September 2022.

Globally, children aged <5 years, including those living with HIV who are not receiving antiretroviral treatment (ART), experience disproportionately high mortality. Global mortality among children living with HIV aged <5 years receiving ART is not well described. This report compares mortality and related clinical measures among infants aged <1 year and children aged 1-4 years living with HIV with those among older persons aged 5-14, 15-49, and ≥50 years living with HIV receiving ART services at all clinical sites supported by the U.S. President's Emergency Plan for AIDS Relief. During October 2020-September 2022, an average of 11,980 infants aged <1 year and 105,510 children aged 1-4 years were receiving ART each quarter; among these infants and children receiving ART, 586 (4.9%) and 2,684 (2.5%), respectively, were reported to have died annually. These proportions of infants and children who died ranged from four to nine times higher in infants aged <1 year, and two to five times higher in children aged 1-4 years, than the proportions of older persons aged ≥5 years receiving ART. Compared with persons aged ≥5 years living with HIV, the proportions of children aged <5 years living with HIV who experienced interruptions in treatment were also higher, and the proportions who had a documented HIV viral load result or a suppressed viral load were lower. Prioritizing and optimizing HIV and general health services for children aged <5 years living with HIV receiving ART, including those recommended in the WHO STOP AIDS Package, might help address these disproportionately poorer outcomes.

Assessing sex differences in viral load suppression and reported deaths using routinely collected program data from PEPFAR-supported countries in sub-Saharan Africa.

BACKGROUND: In sub-Saharan Africa, more women than men access HIV testing and treatment and may have better viral load suppression (VLS). We utilized routinely reported aggregated HIV program data from 21 sub-Saharan African countries to examine sex differences in VLS and death rates within antiretroviral therapy (ART) programs supported by the United States President's Emergency Plan for AIDS Relief (PEPFAR). METHODS: We included VLS and reported death data for persons aged 15 + years on ART from October-December 2020 disaggregated by sex and age for each subnational unit (SNU). We used linear mixed-model regression to estimate VLS proportion and negative binomial mixed-model regression to estimate the rates of death and death plus interruptions in treatment (IIT). All models were weighted for SNU-level ART population size and adjusted for sex, age, HIV/tuberculosis coinfection, country, and SNU; models for reported deaths and deaths plus IIT were also adjusted for SNU-level VLS. RESULTS: Mean VLS proportion was higher among women than men (93.0% vs. 92.0%, p-value < 0.0001) and 50 + than 15-49 age group (93.7% vs. 91.2%, p-value < 0.0001). The mean rate of reported deaths was higher among men than women (2.37 vs. 1.51 per 1000 persons, p-value < 0.0001) and 50 + than 15-49 age group (2.39 vs. 1.50 per 1000, p-value < 0.0001); the mean rate of reported deaths plus IIT was higher among men (30.1 in men vs. 26.0 in women per 1000, p-value < 0.0001) and higher among 15-49 than 50 + age group (34.7 vs. 22.6 per 1000, p-value < 0.0001). CONCLUSIONS: The mean rate of reported deaths was higher among men in most models despite adjusting for VLS. Further exploration into differences in care-seeking behaviors; coverage of screening, prophylaxis, and/or treatment of opportunistic infections; and more extensive testing options for men to include CD4 is recommended.

Bone and Renal Health in Infants With or Without Breastmilk Exposure to Tenofovir-Based Maternal Antiretroviral Treatment in the PROMISE Randomized Trial.

BACKGROUND: We assessed bone and kidney outcomes in infants randomized postdelivery as mother-infant pairs within the IMPAACT PROMISE trial to maternal tenofovir disoproxil fumarate-based antiretroviral treatment (mART) or infant nevirapine prophylaxis (iNVP) to prevent breastfeeding HIV transmission. METHODS: Infants were coenrolled in the P1084s substudy on randomization day and followed through Week 74. Lumbar spine bone mineral content (LS-BMC) was assessed at entry (6-21 age days) and Week 26 by dual-energy x-ray absorptiometry. Creatinine clearance (CrCl) was calculated at entry; Weeks 10, 26, and 74. Student t tests compared mean LS-BMC and CrCl at Week 26 and mean change from entry between arms. RESULTS: Of 400 enrolled infants, the mean (SD; n) for entry LS-BMC was 1.68 g (0.35; n = 363) and CrCl was 64.2 mL/min/1.73 m 2 (24.6; n = 357). At Week 26, 98% of infants were breastfeeding and 96% on their assigned HIV prevention strategy. The mean (SD) Week 26 LS-BMC was 2.64 g (0.48) for mART and 2.77 g (0.44) for iNVP; mean difference (95% confidence interval [CI]) -0.13 g (-0.22 to -0.04), P = 0.007, n = 375/398 (94%). Mean absolute (-0.14 g [-0.23 to -0.06]) and percent (-10.88% [-18.53 to -3.23]) increase in LS-BMC from entry was smaller for mART than iNVP. At Week 26, the mean (SD) CrCl was 130.0 mL/min/1.73 m 2 (34.9) for mART vs. 126.1 mL/min/1.73 m 2 (30.0) for iNVP; mean difference (95% CI) 3.8 (-3.0 to 10.7), P = 0.27, n = 349/398 (88%). CONCLUSION: Week 26 mean LS-BMC was lower in infants in the mART group compared with the iNVP group. However, this difference (∼0.23 g) was less than one-half SD, considered potentially clinically relevant. No infant renal safety concerns were observed.

Antiretroviral postnatal prophylaxis to prevent HIV vertical transmission: present and future strategies.

INTRODUCTION: Maternal antiretroviral therapy (ART) with viral suppression prior to conception, during pregnancy and throughout the breastfeeding period accompanied by infant postnatal prophylaxis (PNP) forms the foundation of current approaches to preventing vertical HIV transmission. Unfortunately, infants continue to acquire HIV infections, with half of these infections occurring during breastfeeding. A consultative meeting of stakeholders was held to review the current state of PNP globally, including the implementation of WHO PNP guidelines in different settings and identifying the key factors affecting PNP uptake and impact, with an aim to optimize future innovative strategies. DISCUSSION: WHO PNP guidelines have been widely implemented with adaptations to the programme context. Some programmes with low rates of antenatal care attendance, maternal HIV testing, maternal ART coverage and viral load testing capacity have opted against risk-stratification and provide an enhanced PNP regimen for all infants exposed to HIV, while other programmes provide infant daily nevirapine antiretroviral (ARV) prophylaxis for an extended duration to cover transmission risk throughout the breastfeeding period. A simplified risk stratification approach may be more relevant for high-performing vertical transmission prevention programmes, while a simplified non-risk stratified approach may be more appropriate for sub-optimally performing programmes given implementation challenges. In settings with concentrated epidemics, where the epidemic is often driven by key populations, infants who are found to be exposed to HIV should be considered at high risk for HIV acquisition. All settings could benefit from newer technologies that promote retention during pregnancy and throughout the breastfeeding period. There are several challenges in enhanced and extended PNP implementation, including ARV stockouts, lack of appropriate formulations, lack of guidance on alternative ARV options for prophylaxis, poor adherence, poor documentation, inconsistent infant feeding practices and in inadequate retention throughout the duration of breastfeeding. CONCLUSIONS: Tailoring PNP strategies to a programmatic context may improve access, adherence, retention and HIV-free outcomes of infants exposed to HIV. Newer ARV options and technologies that enable simplification of regimens, non-toxic potent agents and convenient administration, including longer-acting formulations, should be prioritized to optimize the effect of PNP in the prevention of vertical HIV transmission.

The Status of Adolescent Testing and Treatment in PEPFAR-Supported Programs, October 2017 to September 2020.

BACKGROUND: Adolescents have poorer outcomes across the HIV cascade compared with adults. We aimed to assess progress in HIV case finding, antiretroviral treatment (ART), viral load coverage (VLC), and viral load suppression (VLS) among adolescents enrolled in the US President's Emergency Plan for AIDS Relief (PEPFAR)-supported programs over a 3-year period that included the beginning of the COVID-19 pandemic. METHODS: We analyzed PEPFAR program data in 28 countries/regions for adolescents aged 10-19 years between year 1 (October 2017to September 2018), year 2 (October 2018 to September 2019), and year 3 (October 2019 to September 2020). We calculated the number and percent change for HIV tests, HIV-positive tests, and total number on ART. Calculated indicators included positivity, percent of positives newly initiated on ART (ART linkage), VLC (percent of ART patients on ART for ≥6 months with a documented viral load result within the past 12 months), and VLS (percent of viral load tests with <1000 copies/mL). RESULTS: Between years 1 and 3, the number of HIV tests conducted decreased by 44.2%, with a 29.1% decrease in the number of positive tests. Positivity increased from 1.3%-1.6%. The number of adolescents receiving ART increased by 10.4%. In addition, ART linkage increased (77.8%-86.7%) as did VLC (69.4%-79.4%) and VLS (72.8%-81.5%). CONCLUSIONS: Our findings demonstrate PEPFAR's success in increasing the adolescent treatment cohort. We identified ongoing gaps in adolescent case finding, linkage, VLC, and VLS that could be addressed with a strategic mix of testing strategies, optimal ART regimens, and adolescent-focused service delivery models.

Maternal and infant renal safety following tenofovir disoproxil fumarate exposure during pregnancy in a randomized control trial.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) in combination with other antiretroviral (ARV) drugs has been in clinical use for HIV treatment since its approval in 2001. Although the effectiveness of TDF in preventing perinatal HIV infection is well established, information about renal safety during pregnancy is still limited. TRIAL DESIGN: The IMPAACT PROMISE study was an open-label, strategy trial that randomized pregnant women to one of three arms: TDF based antiretroviral therapy (ART), zidovudine (ZDV) based ART, and ZDV alone (standard of care at start of enrollment). The P1084s substudy was a nested, comparative study of renal outcomes in women and their infants. METHODS: PROMISE participants (n = 3543) were assessed for renal dysfunction using calculated creatinine clearance (CrCl) at study entry (> 14 weeks gestation), delivery, and postpartum weeks 6, 26, and 74. Of these women, 479 were enrolled in the P1084s substudy that also assessed maternal calcium and phosphate as well as infant calculated CrCl, calcium, and phosphate at birth. RESULTS: Among the 1338 women who could be randomized to TDF, less than 1% had a baseline calculated CrCl below 80 mL/min. The mean (standard deviation) maternal calculated CrCl at delivery in the TDF-ART arm [147.0 mL/min (51.4)] was lower than the ZDV-ART [155.0 mL/min (43.3); primary comparison] and the ZDV Alone [158.5 mL/min (45.0)] arms; the mean differences (95% confidence interval) were - 8.0 mL/min (- 14.5, - 1.5) and - 11.5 mL/min (- 18.0, - 4.9), respectively. The TDF-ART arm had lower mean maternal phosphate at delivery compared with the ZDV-ART [- 0.14 mg/dL (- 0.28, - 0.01)] and the ZDV Alone [- 0.17 mg/dL (- 0.31, - 0.02)] arms, and a greater percentage of maternal hypophosphatemia at delivery (4.23%) compared with the ZDV-ART (1.38%) and the ZDV Alone (1.46%) arms. Maternal calcium was similar between arms. In infants, mean calculated CrCl, calcium, and phosphate at birth were similar between arms (all CIs included 0). CONCLUSIONS: Although mean maternal calculated CrCl at Delivery was lower in the TDF-ART arm, the difference between arms is unlikely to be clinically significant. During pregnancy, the TDF-ART regimen had no observed safety concerns for maternal or infant renal function. TRIAL REGISTRATION: NCT01061151 on 10/02/2010 for PROMISE (1077BF). NCT01066858 on 10/02/2010 for P1084s.

Approaches to accelerating the study of new antiretrovirals in pregnancy.

INTRODUCTION: Women who are pregnant or who could become pregnant experience delayed access to or underinformed use of important new antiretroviral (ARV) drugs because of traditional drug development processes that ostensibly aim to reduce potential harm but effectively fail to ensure that timely information about safe and effective use in pregnancy is available. DISCUSSION: The World Health Organization and International Maternal, Pediatric, Adolescent Antiretroviral Clinical Trials Network convened a year-long workshop on "Approaches to Enhance and Accelerate Study of New Drugs for HIV and Associated Infections in Pregnant Women." Workshop participants were tasked with defining key principles and optimal approaches to including pregnant women in pre- and post-licensure trials in order to accelerate the availability of pharmacokinetic and safety data for new ARV agents in pregnancy. ARV efficacy in pregnancy and ARV efficacy for prevention of vertical transmission can be extrapolated from proof of efficacy in non-pregnant adults, provided that drug levels in pregnancy are similar. However, short-term safety and pharmacokinetics must be studied directly in pregnant women and should be conducted and included in initial licensure for all new ARVs. Accelerating the timeline for completion of pre-clinical studies is essential for pregnancy short-term safety and pharmacokinetic studies to be safely completed by the time a drug is licensed. Composite key pregnancy, birth and neonatal outcomes are critical for drugs expected to have broad use, and studies should be initiated at or soon after drug licensure. Teratogenicity risk cannot be feasibly assessed before drug licensure and will depend on robust post-marketing surveillance systems. With some modifications, these principles will apply to ARVs used for prevention, two-drug regimens, long-acting ARVs and ARVs administered through novel delivery systems. CONCLUSIONS: Implementation of the proposed principles and framework will enhance and accelerate the study of new ARVs in pregnancy, resulting in more timely, equitable and informed access to new ARVs for pregnant women.

Cost-effectiveness of Routine Provider-Initiated Testing and Counseling for Children With Undiagnosed HIV in South Africa.

BACKGROUND: We compared the cost-effectiveness of pediatric provider-initiated HIV testing and counseling (PITC) vs no PITC in a range of clinical care settings in South Africa. METHODS: We used the Cost-Effectiveness of Preventing AIDS Complications Pediatric model to simulate a cohort of children, aged 2-10 years, presenting for care in 4 settings (outpatient, malnutrition, inpatient, tuberculosis clinic) with varying prevalence of undiagnosed HIV (1.0%, 15.0%, 17.5%, 50.0%, respectively). We compared "PITC" (routine testing offered to all patients; 97% acceptance and 71% linkage to care after HIV diagnosis) with no PITC. Model outcomes included life expectancy, lifetime costs, and incremental cost-effectiveness ratios (ICERs) from the health care system perspective and the proportion of children with HIV (CWH) diagnosed, on antiretroviral therapy (ART), and virally suppressed. We assumed a threshold of $3200/year of life saved (YLS) to determine cost-effectiveness. Sensitivity analyses varied the age distribution of children seeking care and costs for PITC, HIV care, and ART. RESULTS: PITC improved the proportion of CWH diagnosed (45.2% to 83.2%), on ART (40.8% to 80.4%), and virally suppressed (32.6% to 63.7%) at 1 year in all settings. PITC increased life expectancy by 0.1-0.7 years for children seeking care (including those with and without HIV). In all settings, the ICER of PITC vs no PITC was very similar, ranging from $710 to $1240/YLS. PITC remained cost-effective unless undiagnosed HIV prevalence was <0.2%. CONCLUSIONS: Routine testing improves HIV clinical outcomes and is cost-effective in South Africa if the prevalence of undiagnosed HIV among children exceeds 0.2%. These findings support current recommendations for PITC in outpatient, inpatient, tuberculosis, and malnutrition clinical settings.

PEPFAR's Role in Protecting and Leveraging HIV Services in the COVID-19 Response in Africa.

PURPOSE OF REVIEW: We describe the impact of COVID-19 on PEPFAR programs in Africa and how PEPFAR adapted and leveraged its interventions to the changing landscape of the COVID-19 pandemic. RECENT FINDINGS: To mitigate the potential impact of COVID-19 on the HIV response and protect the gains, continuity of treatment was the guiding principle regarding the provision of services in PEPFAR-supported countries. As the COVID-19 pandemic matured, PEPFAR's approach evolved from a strictly "protect and salvage" approach to a "restore and accelerate" approach that embraced innovative adaptations in service and "person-centered" care. The impact of service delivery interruptions caused by COVID-19 on progress towards HIV epidemic control in PEPFAR-supported African countries remains undetermined. With COVID vaccine coverage many months away and more transmissible variants being reported, Africa may experience more pandemic surges. HIV programs will depend on nimble and innovative adaptations in prevention and treatment services in order to advance epidemic control objectives.

The impact of COVID-19 on multi-month dispensing (MMD) policies for antiretroviral therapy (ART) and MMD uptake in 21 PEPFAR-supported countries: a multi-country analysis.

INTRODUCTION: Increasing access to multi-month dispensing (MMD) of antiretroviral therapy (ART) supports treatment continuity and viral load suppression for people living with HIV (PLHIV) and reduces burden on health facilities. During the COVID-19 response, PEPFAR worked with ministries of health to scale up MMD and expand eligibility to new groups of PLHIV, including children and pregnant/breastfeeding women. We analysed PEPFAR program data to understand the impact of the policy changes on actual practice. METHODS: We conducted a desk review in 21 PEPFAR-supported countries to identify and collect official documentation released between March and June 2020 addressing changes to MMD guidance during the COVID-19 response. MMD coverage, the proportion of all ART clients on MMD, was assessed in the calendar quarters preceding the COVID-19 response (Q4 2019, October-December 2019; and Q1, January-March 2020) and the quarters following the start of the response (Q2 2020, April-June 2020; Q3 2020, July-September, 2020; Q4 2020, October-December 2020). We used the two-proportion Z-test to test for differences in MMD coverage pre-COVID-19 (Q4 2019) and during implementation of COVID-19 policy adaptations (Q2 2020). RESULTS AND DISCUSSION: As of June 2020, 16 of the 21 PEPFAR-supported countries analysed adapted MMD policy or promoted intensified scale-up of MMD in response to COVID-19. MMD coverage for all clients on ART grew from 49% in Q4 2019 pre-COVID-19 to 72% in Q2 2020 during COVID-19; among paediatric clients (< 15), MMD coverage increased from 27% to 51% in the same period. Adaptations to MMD policy were associated with a significantly accelerated growth in the proportion of clients on MMD (p < 0.001) for all populations, irrespective of age and dispensing interval. CONCLUSIONS: Access to MMD markedly expanded during the COVID-19 pandemic, supporting treatment continuity while mitigating exposure to COVID-19 at health facilities. This model is beneficial in public health emergencies and during disruptions to the healthcare system. Outside emergency contexts, expanded MMD eligibility extends client-centred care to previously excluded populations. The success in expanding MMD access during COVID-19 should motivate countries to recommend broader MMD access as a new standard of care.

Effect on growth of exposure to maternal antiretroviral therapy in breastmilk versus extended infant nevirapine prophylaxis among HIV-exposed perinatally uninfected infants in the PROMISE randomized trial.

BACKGROUND: Malnutrition is highly prevalent in HIV-exposed perinatally uninfected infants (HEUs) increasing the risk of morbidity and mortality throughout the life course. We set out to compare the effect of postnatal exposure to maternal antiretroviral therapy (mART) in breastmilk versus infant Nevirapine prophylaxis (iNVP) on somatic growth of HEUs in the randomized PROMISE trial. METHODS AND FINDINGS: We randomized 2431 mothers with HIV and their 2444 HEUs from six African countries and India 6-14 days after delivery to mART or iNVP for prevention of breastmilk HIV transmission. The mART regimen contained tenofovir/emtricitabine (99%) plus lopinavir/ritonavir. Infant growth parameters were compared at postnatal week 10, 26, 74 and 104 using World Health Organization (WHO) z-scores for length-for-age (LAZ), weight-for-age (WAZ), and head circumference-for-age (HCAZ). Week 26 LAZ was the primary endpoint measure. Student T-tests compared mean LAZ, WAZ, and HCAZ; estimated mean and 95% confidence interval (CI) are presented. Maternal and infant baseline characteristics were comparable between study arms. The estimated median breastfeeding duration was 70 weeks. After a mean follow-up of 88 weeks, mean LAZ and WAZ were below the WHO reference population mean at all timepoints, whereas mean HCAZ was not. The mART and iNVP arms did not differ for the primary outcome measure of LAZ at week 26 (p-value = 0.39; estimated mean difference (95%CI) of -0.05 (-0.18, 0.07)) or any of the other secondary growth outcome measures or timepoints (all p-values≥0.16). Secondary analyses of the primary outcome measure adjusting for week 0 LAZ and other covariates did not change these results (all p-values≥0.09). However, infants assigned to mART were more likely to have stunting compared to iNVP infants at week 26 (odds ratio (95% CI): 1.28 (1.05, 1.57)). CONCLUSIONS: In HEUs, growth effects from postnatal exposure to mART compared to iNVP were comparable for measures on length, weight and head circumference with no clinically relevant differences between the groups. Despite breastfeeding into the second year of life, length and weight were below reference population means at all ages in both arms. Further investment is needed to optimize postnatal growth of infants born to women with HIV. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number NCT01061151.

Impact of postpartum tenofovir-based antiretroviral therapy on bone mineral density in breastfeeding women with HIV enrolled in a randomized clinical trial.

OBJECTIVES: We set out to evaluate the effect of postnatal exposure to tenofovir-containing antiretroviral therapy on bone mineral density among breastfeeding women living with HIV. DESIGN: IMPAACT P1084s is a sub-study of the PROMISE randomized trial conducted in four African countries (ClinicalTrials.gov number NCT01066858). METHODS: IMPAACT P1084s enrolled eligible mother-infant pairs previously randomised in the PROMISE trial at one week after delivery to receive either maternal antiretroviral therapy (Tenofovir disoproxil fumarate / Emtricitabine + Lopinavir/ritonavir-maternal TDF-ART) or administer infant nevirapine, with no maternal antiretroviral therapy, to prevent breastmilk HIV transmission. Maternal lumbar spine and hip bone mineral density were measured using dual-energy x-ray absorptiometry (DXA) at postpartum weeks 1 and 74. We studied the effect of the postpartum randomization on percent change in maternal bone mineral density in an intention-to-treat analysis with a t-test; mean and 95% confidence interval (95%CI) are presented. RESULTS: Among 398/400 women included in this analysis, baseline age, body-mass index, CD4 count, mean bone mineral density and alcohol use were comparable between study arms. On average, maternal lumbar spine bone mineral density declined significantly through week 74 in the maternal TDF-ART compared to the infant nevirapine arm; mean difference (95%CI) -2.86 (-4.03, -1.70) percentage points (p-value <0.001). Similarly, maternal hip bone mineral density declined significantly more through week 74 in the maternal TDF-ART compared to the infant nevirapine arm; mean difference -2.29% (-3.20, -1.39) (p-value <0.001). Adjusting for covariates did not change the treatment effect. CONCLUSIONS: Bone mineral density decline through week 74 postpartum was greater among breastfeeding HIV-infected women randomized to receive maternal TDF-ART during breastfeeding compared to those mothers whose infants received nevirapine prophylaxis.

Safety and Efficacy of 48 and 96 Weeks of Alendronate in Children and Adolescents With Perinatal Human Immunodeficiency Virus Infection and Low Bone Mineral Density for Age.

No safety concerns were identified in a randomized, crossover study of alendronate/placebo in youth with perinatal HIV infection and low bone mineral density (BMD). BMD improved with 48 weeks of alendronate and continued to improve with an additional 48 weeks of therapy. Gains were largely maintained 48 weeks after stopping alendronate.

Enhanced and Timely Investigation of ARVs for Use in Pregnant Women.

BACKGROUND: Concerns have been voiced that the exclusion of pregnant women from clinical trials results in a lack of safety and pharmacokinetic data for antiretroviral drugs (ARVs) in pregnancy, creating clear risks to pregnant women living with HIV (PWLHIV), and their infants. SETTING: The World Health Organization convened a Paediatric Antiretroviral Drug Optimization group meeting, December 10-12, 2018, in Geneva, Switzerland. METHODS: The group, comprised of clinicians, scientists, HIV program managers, regulators, and community representatives, were tasked to consider how ARVs are studied in PWLHIV, define alternative approaches to studying ARVs in PWLHIV, identify ways to shorten the timeline to determine safe use of new agents during pregnancy, and define strategies to collaborate with regulators and industry to change longstanding practices. RESULTS: Most new ARVs are not studied in pregnant populations until after drug licensure, primarily opportunistically among women who become pregnant while taking the ARV of interest. Acceleration of the timeline will require earlier completion of preclinical studies and a new paradigm, namely-under certain conditions-allow women who become pregnant while participating in phase III ARV studies the option of remaining on study and enroll pregnant women into phase III trials of new agents to obtain preliminary safety and dosing and efficacy data. CONCLUSION: A revision of the current approach to the study of antiretrovirals in pregnant women is urgently needed to improve timely access and safe use of new agents during pregnancy.