The Antiretroviral Pregnancy Registry: Three decades of prospective monitoring for birth defects.

PURPOSE: Antiretrovirals (ARVs) are life-saving drugs used for the treatment and prevention of HIV infection and antiviral drugs (AVs) for the treatment of chronic HBV infection. ARVs have proven highly effective in reducing perinatal HIV transmission, however the risk of birth defects from prenatal exposure to ARVs/AVs is an ongoing concern. The Antiretroviral Pregnancy Registry (APR), an international, prospective exposure-registration cohort study, monitors ARV and AV use in pregnancy for early signals of teratogenicity. This communication reports results of 30-years' experience of ARV/AV exposure during pregnancy and lessons learned through continuous quality improvement. METHODS AND RESULTS: Birth defect prevalence is estimated and compared to internal and external groups. Statistical inference is based on exact methods for binomial proportions. Between 2006 and 2023, cumulative enrollment more than tripled from 6893 to 25 960 pregnancies and ARVs/AVs monitored increased from 29 to 222. Through January 2023, there were 21 636 live births and 631 outcomes with birth defects, for overall prevalence of 2.9/100 live births (95% CI 2.7, 3.2). The birth defect prevalence was 3.0% (95% CI 2.7%, 3.3%) among first trimester exposures and 2.8% (95% CI 2.5%, 3.2%) among second/third trimester exposures (prevalence ratio 1.04 [95% CI 0.89, 1.21]). CONCLUSIONS: Birth defect prevalence is not statistically significantly different between first trimester ARV/AV pregnancy exposures compared to second/third trimester exposures and is also not different from two population-based surveillance systems: 2.72/100 live births reported in the Metropolitan Atlanta Congenital Defects Program (MACDP); and 4.17/100 live births from the Texas Birth Defects Registry (TBDR).

Remodeling of the cardiovascular circulation in fetuses of mothers with diabetes: A fetal computational model analysis.

AIMS: Myocardial structural and functional abnormalities are known to occur in fetuses of mothers with diabetes mellitus (FMDM). The main aim of this investigation was to explore the cardiovascular circulatory patterns in FMDM using a validated lumped computational model of the cardiovascular system. METHODS: This was a multi-institutional study involving FMDM compared to fetuses of maternal controls (FC). Fetal echocardiographic Doppler data from left and right ventricular outflow tracts, aortic isthmus, middle cerebral and umbilical arteries were fitted into a validated fetal circulation computational model to estimate patient-specific placental and vascular properties. Non-parametric comparisons were made between resistances, compliances and flows in the brain and placenta in FMDM and FC. RESULTS: Data from 23 FMDM and 31 FC were fitted into the model. In FMDM, compared to FC, placental relative resistance was lower (0.59 ±â€¯0.50 versus 0.91 ±â€¯0.41; p < .05) with higher brain relative resistance (2.36 ±â€¯1.65 versus 1.60 ±â€¯0.85; p < .05). Middle cerebral artery flow was lower in FMDM than FC (0.12 ±â€¯0.14 vs. 0.27 ±â€¯0.21 ml/min; p 0.04) with a lower cerebral-placental flow ratio. Combined stroke volume was lower in FMDM (3.65 ±â€¯2.05 ml) than FC (4.97 ±â€¯2.45 ml) (p 0.04). CONCLUSIONS: Blood flow is redistributed in FMDM to the placenta, away from the brain. This alteration may play a role in the postnatal health of these fetuses.

Obesity May Be Protective against Severe Perineal Lacerations.

Objective. To determine if there is an association between BMI and 3rd- or 4th-degree perineal lacerations in normal spontaneous and operative vaginal deliveries. Study Design. We performed a retrospective case control study using a large obstetric quality improvement database over a six-year period. Cases were identified as singleton gestations with third- and fourth-degree lacerations. Controls were obtained randomly from the database of patients without third- or fourth-degree lacerations in a 1 : 1 ratio. Univariate and multivariate logistic regression analyses were performed. Results. Of 32,607 deliveries, 22,011 (67.5%) charts with BMI documented were identified. Third- or fourth-degree lacerations occurred in 2.74% (n = 605) of patients. 37% (n = 223) were identified in operative vaginal deliveries. In the univariate analysis, obesity, older maternal age, non-Asian race, and birth weight <4000 g were all protective against 3rd- and 4th-degree lacerations. After controlling for age, race, mode of vaginal delivery, and birth weight, obesity remained significant. Conclusion. Being obese may protect against third- and fourth-degree lacerations independent of parity, race, birth weight, and mode of delivery.

Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero.

As the immune system develops, T cells are selected or regulated to become tolerant of self antigens and reactive against foreign antigens. In mice, the induction of such tolerance is thought to be attributable to the deletion of self-reactive cells. Here, we show that the human fetal immune system takes advantage of an additional mechanism: the generation of regulatory T cells (Tregs) that suppress fetal immune responses. We find that substantial numbers of maternal cells cross the placenta to reside in fetal lymph nodes, inducing the development of CD4+CD25highFoxP3+ Tregs that suppress fetal antimaternal immunity and persist at least until early adulthood. These findings reveal a form of antigen-specific tolerance in humans, induced in utero and probably active in regulating immune responses after birth.

Reproductive options for HIV-serodiscordant couples.

The foundation of a family is a personal enterprise with deep biological and emotional motivations. Family life is a no lesser priority for individuals living with HIV than for others. Moreover, the dramatic reduction in HIV-related morbidity and mortality as a consequence of the widespread use of HAART has led to a growing number of HIV-infected individuals and their partners requiring education and counseling regarding HIV disease and reproduction. After careful evaluation of health status and fertility in both partners, two main alternatives may be considered--natural conception or assisted reproduction techniques. This review discusses the pros and cons of reproductive options in HIV-infected persons and proposes a protocol for their counseling.

Assessing the risk of birth defects associated with antiretroviral exposure during pregnancy.

OBJECTIVE: The purpose of this study was to examine teratogenic risk of antiretroviral (ARV) drugs. STUDY DESIGN: The Antiretroviral Pregnancy Registry (APR) monitors prenatal exposures to ARV drugs and pregnancy outcome through a prospective exposure-registration cohort. Statistical inference uses exact methods for binomial proportions. RESULTS: Through July 2003, APR has monitored 3583 live births exposed to ARV. Among 1391 first trimester exposures, there were 38 birth defects, prevalence of 2.7% (95% CI 1.9-3.7), not significantly higher than the CDC's population surveillance rate, 3.1 per 100 live births (95% CI 3.1-3.2). For lamivudine, nelfinavir, nevirapine, stavudine, and zidovudine, sufficient numbers of live births (>200) following first-trimester exposures have been monitored to allow detection of a 2-fold increase in risk of birth defects overall; no increases have been detected. CONCLUSION: APR data demonstrate no increase in prevalence of birth defects overall or among women exposed to lamivudine, nelfinavir, nevirapine, stavudine, and zidovudine.

Pharmacokinetics of nelfinavir and indinavir in HIV-1-infected pregnant women.

BACKGROUND: Protease inhibitor (PI)-based combination antiretroviral therapy is often indicated for treatment of maternal HIV disease, but little is known about PI pharmacokinetics during pregnancy. Increased cytochrome P450 activity may affect the disposition of PI and decrease drug exposure. METHODS: Steady-state PI pharmacokinetics, measured by the area under the plasma concentration versus time curve (AUC(tau)), were evaluated in women on stable antiretroviral regimens containing nelfinavir (n = 9) or indinavir (n = 4) with or without ritonavir (n = 2) during the second and third trimesters of pregnancy and postpartum. Cytochrome P450 activity was assessed by measuring the urine 6 beta-hydroxycortisol to cortisol ratio (6 beta-OHF/F). RESULTS: AUC(tau) in women on indinavir alone decreased and 6 beta-OHF/F ratios increased during pregnancy compared with postpartum control values (n = 2). Nelfinavir results demonstrated no clear change and were highly variable. CONCLUSIONS: The results for indinavir suggest that metabolic induction occurs during pregnancy, which apparently resolves spontaneously postpartum. This may warrant dosage adjustment during pregnancy. This induction is offset by concomitant use of ritonavir. Nelfinavir results were variable and, therefore, the impact of pregnancy on nelfinavir disposition was not fully determined.

CD7 is a differentiation marker that identifies multiple CD8 T cell effector subsets.

The adaptive immune response of human CD8 T cells to invading pathogens involves the differentiation of naive cells into memory and effector cells. However, the lineage relationship between memory and effector cells and the differentiation of CD8 T cells into distinct subsets of effector cell subpopulations are subjects of considerable debate. CD7 identifies three populations of CD8 T cells: CD7 high (CD7(high)), low (CD7(low)), and negative (CD7(neg)) that translate into subsets with distinct functional properties. The CD7(high) subset contains naive and memory cells and the CD7(low) and CD7(neg) subsets contain effector cells. The effector cells can functionally be divided into cytokine-secreting effector CD8 T cells and lytic effector CD8 T cells. These data provide a model of human CD8 T cell differentiation in which specialized distinct subpopulations can be identified by expression of CD7.