Vitamin D Supplementation Among Pregnant Women in Uganda for the Prevention of Hypertensive Disorders in Pregnancy, and Other Adverse Maternal and Foetal Outcomes

Introduction:

Vitamin D deficiency is a global health issue, with an estimated prevalence in Africa of about 34%. Black pregnant and breastfeeding women are among the populations with the highest risk of deficiency, with a prevalence of up to 40% in urban Uganda.

Low Vitamin D status in pregnancy seems to be associated with multiple adverse obstetric outcomes, in particular with hypertensive disorders in pregnancy, gestational diabetes, severe postpartum haemorrhage, preterm birth, and low birth weight; these associations have been studied predominantly in Caucasian populations. Recent studies investigated Vitamin D supplementation in preventing preeclampsia, which is known to be more prevalent and severe in dark-skinned women, but results from Africa are scanty; little data have been published on the supplementation of vitamin D in pregnant women in sub-Saharan countries, including Uganda.

Objective: The objective of this trial is to investigate if vitamin D supplementation among pregnant women in Uganda prevents adverse maternal and foetal outcomes, with special emphasis on preeclampsia.

Methods: This will be a double-blinded randomized trial with parallel groups, where pregnant women attending ANC at St. Mary's Hospital, Lacor (Gulu, Northern Uganda), enrolled at gestational age between 13 and 27 weeks, confirmed by ultrasonography at the first antenatal visit, will be invited to participate. Enrolment is planned to start in the last quarter of 2025 and will last approximately 18 months.

Participants will be randomized in a two-armed randomization, with a 1:1 allocation ratio, into:

* Intervention group - 990 women will receive oral 2.000 IU vitamin D daily; or. * Control group - 990 women will receive an oral placebo daily. A total of 1980 pregnant women will be included; participants will be screened for eligibility at admission and will be required to sign a consent. Questionnaires will be collected upon enrolment, with maternal socio-demographic characteristics and obstetric-medical factors. Study participants will be followed-up throughout the pregnancy, with ANC contacts scheduled at approximately 20, 26, 30, 34, 36, 38, and 40 weeks of gestation, each contact will comprise maternal physical examination, foetal well-being monitoring, the administration of sulfadoxine-pyrimethamine for malaria intermittent preventive treatment in pregnancy, the supplementation of iron and folic acid, and counselling about birth preparedness, nutrition, and danger signs during pregnancy. Upon delivery, information on maternal and foetal outcomes will be extracted from medical records. Participants will be followed up from delivery to 6 weeks postpartum.

The primary analysis will evaluate the effect of assignment to vitamin D supplementation compared with placebo on the incidence of preeclampsia, eclampsia, or HELLP syndrome, following an intention-to-treat principle. Secondary outcomes will include other adverse maternal outcomes, such as GH, GDM, APH, PPH, PROM and preterm birth, and adverse foetal outcomes, such as growth restriction and low APGAR scores.

Expected results: This study will investigate if the supplementation of Vitamin D in pregnant women in Uganda is effective in preventing preeclampsia, and other adverse foetal and maternal outcomes. The obtained results will pave the way for the recommendation of Vitamin D supplementation during ANC in Uganda, with potentially broad health benefits.

• The occurrence of maternal Gestational Hypertension (GH) [Time frame: From enrolment to 6 weeks postpartum]
• Fatal outcome of delivery (live birth or stillbirth), with APGAR score at 1 and 5 minutes [Time frame: At delivery, at 1 minute and 10 minutes after birth]
• Preterm birth, i.e., Gestational Age at delivery < 37 weeks [Time frame: At delivery]
• Mode of delivery [Time frame: At delivery]
• Admission to HDU or ICU [Time frame: From enrolment to 6 weeks postpartum]
• New-born birth weight [Time frame: At delivery]
• Foetal sex and malformations [Time frame: At delivery]
• New-born admission to Nursery or Neonatal Intensive Care Unit (NICU) [Time frame: From delivery to 6 weeks postpartum]
• The occurrence of maternal Gestational Diabetes (GDM) [Time frame: From enrolment to delivery]
• The occurrence of maternal Antepartum Haemorrhage (APH) [Time frame: From 28 weeks of Gestational Age to delivery]
• The occurrence of Primary Postpartum Haemorrhage (1.PPH) [Time frame: From delivery to 24 hours post delivery]
• The occurrence of Prelabour Rupture of Membranes (PROM) [Time frame: From enrolment to delivery]