PREDIN: Pregnancy and Vitamin D Intervention Study

Study Overview
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Brief Summary
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Vitamin D deficiency is common among certain risk groups in Sweden, and occurs approximately in every tenth pregnant woman.The aim of the randomized double-blind controlled trial Pregnancy vitamin D intervention (PREDIN) is to investigate the dose of vitamin D supplementation required in achieving vitamin D sufficiency (25OHD ≥50 nmol/l) in pregnant women at risk of vitamin D deficiency. In addition, the investigators aim to examine if the overall vitamin D status and vitamin D intake have increased since the expanded vitamin D fortification program was initiated in year 2020.

Detailed Description
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The effect of maternal vitamin D in pregnancy for maternal and offspring health needs to be clarified. In observational studies, the investigators and others show associations between poor maternal vitamin D status in pregnancy and an increased risk of pregnancy complications. Poor maternal vitamin D status is also linked to impaired growth in the first year of life, and potentially also to higher risk of developing obesity in childhood. Risk factors for vitamin D deficiency in Swedish pregnant women are related to lower intake of vitamin D and to less sun exposure. Since the evidence for positive effects of maternal vitamin D status or intake is limited, vitamin D interventions in pregnancy are warranted to clarify the causal effects of vitamin D in pregnancy and the doses required to achieve sufficient vitamin D status in deficient women. In the first trimester, pregnant women will be screened at a routine visit in the antenatal care for the risk of vitamin D deficiency using a validated questionnaire. Women who are classified as having a high risk of vitamin D deficiency will be randomized to one of three study arms: usual antenatal care, 20 µg vitamin D per day or 40 µg vitamin D per day. The participants will be followed up until delivery. Blood will be collected for analysis of vitamin D status (25OHD) at screening and in the third trimester of pregnancy. Information regarding pregnancy, gestational complication and fetal growth will be retrieved from medical records after delivery. About 500 women will be screened and their vitamin D status and vitamin D intake will be compared to a previous population-based cohort study, to investigate if the status or intake of vitamin D has increased since the expanded food fortification program was introduced. The study hypothesis is that vitamin D status and/or vitamin D intake is related to risk of developing complications during pregnancy or delivery and that maternal supplementation with vitamin D during pregnancy will be effective in achieving vitamin D sufficiency in pregnant women at risk of vitamin D deficiency. In addition, the investigators hypothesize that the expanded vitamin D food fortification program has increased the vitamin D status and vitamin D intake of pregnant women in Gothenburg since 2013-2014.

Official Title
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PREDIN: Pregnancy and Vitamin D Intervention Study - A Randomized Controlled Trial

Conditions
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Vitamin D Deficiency, Vitamin D3 Deficiency, Pregnancy Complications

Intervention / Treatment
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* Dietary Supplement: Vitamin D Supplementation 20 µg/day
* Dietary Supplement: Vitamin D Supplementation 40 µg/day
* Other: Usual Antenatal Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: pregnant women in gestational week <15 Exclusion Criteria: multi-fetal pregnancy known disorder to the metabolism of vitamin D, calcium or phosphate (e.g. adrenal gland disorders, kidney disease) ongoing treatment with vitamin D of ≥10/day difficulties understanding the study information

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vitamin D Supplementation 20 µg/day<br>Dietary supplements containing 20 µg of vitamin D per day will be provided to study subjects. | Dietary Supplement: Vitamin D Supplementation 20 µg/day<br>* At a routine visit at the antenatal care in early pregnancy (gestational week <15) women will be provided with with vitamin D3 (cholecalciferol) supplements. Two tablets, with a total content of 20 µg (800 IE), are taken daily throughout pregnancy.<br>|
| Experimental: Vitamin D Supplementation 40 µg/day<br>Dietary supplements containing 40 µg of vitamin D per day will be provided to study subjects. | Dietary Supplement: Vitamin D Supplementation 40 µg/day<br>* At a routine visit at the antenatal care in early pregnancy (gestational week <15) women will be provided with with vitamin D3 (cholecalciferol) supplements. Two tablets, with a total content of 40 µg (1600 IE), are taken daily throughout pregnancy.<br>|
| Active Comparator: Usual Antenatal Care<br>Women randomized to usual antenatal care will receive advise about vitamin D supplementation according to usual antenatal care routines. | Other: Usual Antenatal Care<br>* In early pregnancy (gestational week <15) women are advised by the regular midwife to take a daily supplement of Vitamin D throughout pregnancy, according to usual antenatal care routines.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in maternal vitamin D status (25OHD) between intake of vitamin D supplements containing either 40 µg per day or 20 µg per day during pregnancy | Analyses of 25OHD (25OHD3 and 25OHD2) from blood samples drawn in first- and third trimester of pregnancy | From inclusion in first trimester to follow-up in third trimester, up to 9 months | 
| Difference in maternal vitamin D status (25OHD) between intake of vitamin D supplements (both 40 µg per day or 20 µg per day) during pregnancy and usual antenatal care routines | Analyses of 25OHD (25OHD3 and 25OHD2) from blood samples drawn in first- and third trimester of pregnancy | From inclusion in first trimester to follow-up in third trimester, up to 9 months | 
| Difference in maternal 3-epi-25-Hydroxyvitamin D between the three groups; intakes of vitamin D supplements 40 µg/day or 20 µg/day or usual antenatal care routines | Analyses of vitamin D metabolites 3-epi-25-Hydroxyvitamin D3 from blood samples drawn in first- and third trimester of pregnancy | From inclusion in first trimester to follow-up in third trimester, up to 9 months | 
| Difference in maternal 1,25-dihydroxyvitamin D between the three groups; intakes of vitamin D supplements 40 µg/day or 20 µg/day or usual antenatal care routines | Analyses of 1,25-dihydroxyvitamin D from blood samples drawn in first- and third trimester of pregnancy | From inclusion in first trimester to follow-up in third trimester, up to 9 months | 
| Difference in maternal vitamin D binding proteins between the three groups; intakes of vitamin D supplements 40 µg/day or 20 µg/day or usual antenatal care routines | Analyses of vitamin D binding proteins from blood samples drawn in first- and third trimester of pregnancy | From inclusion in first trimester to follow-up in third trimester, up to 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gene variant related to vitamin D metabolism | Analyses of gene variants in blood sample drawn at inclusion in first trimester of pregnancy | At inclusion in first trimester of pregnancy | 
| Ferritin | Analyses of ferritin | From inclusion in first trimester to follow-up in third trimester, up to 9 months | 
| Hemoglobin | Analyses of hemoglobin | From inclusion in first trimester to follow-up in third trimester, up to 9 months | 
| Metabolomics | Analyses of metabolomics in blood | From inclusion in first trimester to follow-up in third trimester, up to 9 months | 
| C-reactive protein | Analyses of inflammation e.g. c-reactive protein | From inclusion in first trimester to follow-up in third trimester, up to 9 months | 
| Interleukines | Analyses of inflammation e.g. interleukines | From inclusion in first trimester to follow-up in third trimester, up to 9 months | 
| Cytokines | Analyses of inflammation e.g. cytokines | From inclusion in first trimester to follow-up in third trimester, up to 9 months | 
| Cortisol | Analyses of cortisol | From inclusion in first trimester to follow-up in third trimester, up to 9 months | 
| Parathyroid hormone | Analysis of parathyroid hormone in sampled blood at the routine laboratory | From inclusion in first trimester to follow-up in third trimester, up to 9 months | 
| Estrogen | Analyses of estrogen, in sampled blood, at the routine laboratory | From inclusion in first trimester to follow-up in third trimester, up to 9 months | 
| Progesterone | Analyses of progesterone, in sampled blood, at the routine laboratory | From inclusion in first trimester to follow-up in third trimester, up to 9 months | 
| Dietary intake | Dietary intake of mother during pregnancy assessed by dietary record at two time points | At inclusion in first trimester and at follow-up in third trimester, up to 9 months | 
| Body weight development | Self-reported weight (in kilograms) during pregnancy until delivery. | From inclusion in first trimester to follow-up in third trimester, up to 9 months | 
| Incidence of pregnancy-induced hypertension | Diagnosis of pregnancy-induced hypertension, and gestational diabetes | Up to delivery | 
| Incidence of pre-eclampsia | Diagnosis of pre-eclampsia and gestational diabetes | Up to delivery | 
| Incidence of gestational diabetes | Diagnosis of gestational diabetes | Up to delivery (up to 9 months) | 
| Incidence of preterm delivery | Delivery before 37 weeks completed weeks of gestation | Up to 37 completed weeks | 
| Incidence of small for gestational age (SGA) | SGA born infant | At delivery | 
| Incidence of large for gestational age (LGA) | LGA born infant | At delivery | 
| Incidence of Intrauterine growth restriction (IUGR) | IUGR | At delivery | 
| Apgar scores | Vitality signs are estimated as Apgar scores at 1, 5 and 10 minutes after birth of the newborn. Apgar stands for Appearance, pulse, grimace, activity and respiration. The maximium score at each time point is 10 scores and a high score indicates high vitality, where as a low score indicates very low vitality. | At 1, 5 and 10 minutes after delivery | 
| Incidence of Caesarean sections | Delivery by caesarean sections | At delivery | 
| Incidence of miscarriage | Miscarriage | During the first 21+6 weeks of pregnancy | 
| Incidence of Intrauterine fetal demise (IUFD) | IUFD | Any time during pregnancy after pregnancy week 22+0 (up to 9 months) |