Total effect of gestational hypertension on neonatal iron deficiency in very-preterm infants.

Abstract Background: Gestational hypertension (GH) is a major risk factor for adverse maternal and perinatal morbidity and outcomes, including placental dysfunction, preterm birth, and fetal growth restriction. Maternal GH is thought to disrupt placental perfusion, potentially reducing placental blood flow and nutrient transfer to the fetus. Moreover, elevated maternal hepcidin reported in pre-eclampsia and some hypertensive pregnancies could impair placental iron transfer in hypertensive pregnancies leading to neonatal iron deficiency and heightened risks of anemia-related developmental impairment. Prior research has highlighted the role of maternal anemia and iron status in neonatal health, but limited studies have explored the specific impact of GH on neonatal iron metabolism. Given the robust pool of evidence highlighting the long-term negative consequences of iron deficiency (ID) during development, it is imperative to identify and address potential sources of ID where possible. This study aims to evaluate whether maternal GH is independently associated with lower neonatal iron status (assessed by serum ferritin) at NICU discharge in very preterm infants. Methods: Guided by a directed acyclic graph, we estimated the total effect of GH on ID using multivariable logistic regression. Covariates entered a priori consisted of maternal anemia, body-mass index, age, smoking during pregnancy, twin gestation, and infant sex. These variables were chosen for their potential to influence both maternal blood pressure and neonatal iron status. Gestational age and birthweight were intentionally omitted to avoid adjustment for post-exposure mediators. Missing data were addressed with 20-fold multiple imputation. Results are reported as adjusted odds ratios (aOR) with 95 % confidence intervals (CI). This analysis drew from a retrospective population-based cohort of very preterm infants (< 32 weeks gestation) born at the IWK Health Centre between 2005 and 2018 to mothers residing in Nova Scotia. Infants with major congenital malformations, chromosomal anomalies, or death before discharge were excluded. Unit protocol provided elemental iron prophylaxis at 2–4 mg/kg/day beginning at 2–4 weeks of age, with dose increases (up to 6 mg/kg/day) guided by serum ferritin (SF) checks every 2–4 weeks. ID at discharge was defined as SF < 50 µg/L. Antenatal and neonatal variables were abstracted from electronic and paper records. Results:Of 262 very-preterm infants, 82 (31.3 %) were iron-deficient at NICU discharge despite supplementation. GH affected 45 (17.2%) of mothers. Iron-deficiency occurred in 48.9% (n = 22/45) of GH-exposed vs 27.6% (n = 60/217) of non-exposed infants (crude OR = 2.50; 95% CI 1.30 – 4.84; p < 0.05). After multiple imputation and adjustment for maternal anemia, body-mass index, age, cigarette use during pregnancy, twin gestation, and neonatal sex, GH remained the only independent predictor of discharge iron-deficiency (aOR = 2.28; 95 % CI 1.13 – 4.62; p < 0.05). No other covariate reached statistical significance. Model diagnostics indicated good fit and no serious collinearity (Hosmer–Lemeshow p = 0.68; all variance-inflation factors < 2). Conclusion: Gestational hypertension markedly increases the risk of iron deficiency in very-preterm infants at NICU discharge, even under standardized iron-supplementation protocols. These findings support the hypothesis that in utero factors linked to GH can diminish the efficacy of standardized post-natal iron therapy. Furthermore, these results could justify closer monitoring or tailored iron dosing for GH-exposed infants, pending prospective studies. Moreover, the present findings underscore the importance of optimizing maternal cardiovascular and hematologic health during pregnancy.