Effect of pregnancy versus postpartum maternal isoniazid preventive therapy on infant growth in HIV-exposed uninfected infants: a post-hoc analysis of the TB APPRISE trial

**Background:** Isoniazid preventive therapy (IPT) is recommended by the WHO for women living with HIV (WLWH) to prevent tuberculosis, including during pregnancy. The TB APPRISE trial previously found that IPT initiated during pregnancy was associated with an increased incidence of composite adverse pregnancy outcomes compared to IPT initiated postpartum. However, the effects of in utero IPT exposure on long-term infant growth were unknown. This post-hoc analysis aimed to examine the effects of maternal pregnancy-IPT versus postpartum-IPT on growth outcomes among HIV-exposed uninfected (HEU) infants in the first year of life, and to assess whether infant sex modified these effects.

**Methods:** This analysis used data from the P1078 TB APPRISE trial, a randomised, double-blind, placebo-controlled, multicentre non-inferiority study conducted at 13 sites across 8 countries (Botswana, Haiti, India, South Africa, Tanzania, Thailand, Uganda, Zimbabwe) with high TB prevalence (>60 cases per 100,000). Pregnant WLWH (14–34 weeks gestation) were randomised to receive a 28-week course of IPT (300 mg daily) either during pregnancy (pregnancy-IPT arm) or starting at postpartum week 12 (postpartum-IPT arm). The analysis included 898 HEU infants (448 pregnancy-IPT, 450 postpartum-IPT) who had at least one follow-up after birth. Exclusion criteria included lack of infant information, HIV infection in the infant, and twin births. Growth outcomes (weight and length) were measured at birth and at weeks 4, 8, 12, 24, 36, 44, and 48 postpartum. Growth faltering was defined as z-scores < -2 using WHO child growth standards: underweight (WAZ < -2), stunting (LAZ < -2), and wasting (WLZ < -2). Time to growth faltering was compared using multivariable Cox proportional hazards regression, with data censored at 12 weeks and 48 weeks postpartum. Models were adjusted for infant sex, maternal BMI, age, ART regimen, viral load, CD4 count, education, and household food insecurity. Sex-stratified analyses were pre-specified.

**Key Results:** Among 898 HEU infants, 447 (49.8%) were female. Baseline maternal and infant characteristics were similar between arms. Overall, 10.7% of infants were premature, 11.5% had low birth weight (LBW), and 19.2% were small for gestational age (SGA). Infants in the pregnancy-IPT arm had a 1.60-fold higher risk of LBW (aRR 1.60 [95% CI: 1.07, 2.41], p=0.022) compared to the postpartum-IPT arm. There was no significant difference in preterm birth (aRR 1.31 [95% CI: 0.87, 1.97], p=0.20) or SGA (aRR 0.96 [95% CI: 0.71, 1.31], p=0.82) overall. For growth faltering, infants in the pregnancy-IPT arm had a 1.47-fold higher risk of becoming underweight by 12 weeks (aHR 1.47 [95% CI: 1.06, 2.03], p=0.021) and a 1.34-fold higher risk by 48 weeks (aHR 1.34 [95% CI: 1.01, 1.78], p=0.042). Maternal IPT timing was not associated with stunting (aHR by 48 weeks 1.08 [95% CI: 0.89, 1.30]) or wasting (aHR by 48 weeks 1.02 [95% CI: 0.79, 1.32]). Infant sex significantly modified the effect of pregnancy-IPT on underweight (p=0.037 at 12 weeks; p=0.022 at 48 weeks). Male infants in the pregnancy-IPT arm experienced a 2.02-fold increased risk of becoming underweight by 12 weeks (aHR 2.02 [95% CI: 1.29, 3.18], p=0.0022) and a 1.82-fold increased risk by 48 weeks (aHR 1.82 [95% CI: 1.23, 2.69], p=0.0027). Male infants also had increased risk of LBW (aRR 2.04 [95% CI: 1.16, 3.68], p=0.015), preterm birth (aRR 1.81 [95% CI: 1.04, 3.21], p=0.038), and wasting by 12 weeks (aHR 1.61 [95% CI: 1.04, 2.49], p=0.031). Among female infants, pregnancy-IPT was not associated with any growth faltering outcomes. Cofactor analysis showed that for every 1 kg/m² increase in maternal BMI, infant risk of underweight decreased by 7% (aHR 0.93 [95% CI: 0.90, 0.96]) and wasting by 8% (aHR 0.92 [95% CI: 0.89, 0.94]).

**Clinical Implications:** This post-hoc analysis demonstrates that maternal IPT during pregnancy is associated with an increased risk of LBW and underweight among HEU infants, with effects persisting through the first year of life and being particularly pronounced in male infants. These findings add to prior evidence from the TB APPRISE trial regarding adverse pregnancy outcomes associated with pregnancy IPT. The sex-specific effects suggest biological mechanisms related to differential in utero growth trajectories and placental responses between male and female fetuses. The results provide important data for policymakers and clinicians weighing the risks and benefits of IPT timing in pregnant WLWH. The authors note that breastfeeding and maternal smoking/drinking variables were not included in models due to methodological concerns about mediation and bias. Limitations include the post-hoc design, lack of a no-IPT comparator after 12 weeks postpartum, and absence of in utero growth data. The findings warrant further investigation into mechanisms and support careful monitoring of infant growth when IPT is initiated during pregnancy.