Vitamin D during pregnancy: why observational studies suggest deficiency and interventional studies show no improvement in clinical outcomes? A narrative review
Journal of Endocrinological Investigation, July 2015
S. N. Karras karraspiros at yahoo.gr , P. Anagnostis, D. Naughton, C. Annweiler, A. Petroczi, D. G. Goulis
1. Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
2. School of Life Sciences, Kingston University, Kingston upon Thames, London, UK
3. Robarts Research Institute, The University of Western Ontario, London, ON, Canada
4. Department of Geriatric Medicine, UPRES EA 4638, University Hospital Angers, Angers, France
A considerable number of studies have examined vitamin D status during pregnancy. Although data from observational studies denote vitamin D hypovitaminosis (deficiency or insufficiency) during pregnancy is associated with a plethora of adverse maternal and neonatal outcomes, data from interventional (supplementation) trials fail to reveal a significant impact on maternal and offspring health. The aim of this narrative review was to critically appraise the methodology of the most representative published randomized controlled trials in an attempt to explain the difference between observational and supplementation results.
We found that this difference could be attributed to a variety of factors, namely:
- (i) study design (lack of a specific outcome in conjunction with timing of supplementation, enrolment of participants with heterogeneous vitamin D status);
- (ii) pitfalls in the interpretation of vitamin D equilibrium (lack of determination of plasma half-life);
- (iii) supplementation regimen (administration of a wide range of regimens, in terms of dose, bolus and form);
- (iv) geographical characteristics (vitamin D needs could vary significantly within a country, particularly in areas with a wide range of latitude gradient);
- (v) adaptations of vitamin D metabolism during pregnancy (vitamin D and calcium equilibrium are changed during pregnancy compared with the non-pregnant state) and
- (vi) supplementation of populations with low baseline 25(OH)D values would likely manifest beneficial effects.
All these parameters should be taken into consideration in the design of future vitamin D supplementation trials.
VitaminDWiki
There is been many positive intervention trials and meta-analyses
The articles in Pregnancy AND Intervention are here:
- 3X reduction in preemie Bronchopulmonary Dysplasia if add tiny amount of Vitamin D – meta-analysis June 2024
- 4,000 IU of daily Vitamin D during pregnancy is good (Mongolia this time) – RCT Oct 2023
- Resulting childhood Asthma cut in half if 4,400 IU Vitamin D daily while pregnant - RCT April 2023
- 6,400 IU of Vitamin D is safe and effective during breastfeeding – RCT Dec, 2020
- Vitamin D during pregnancy – single 200,000 IU similar to daily 5,000 IU – April 2020
- Massive improvement in vaginal microbiome during pregnancy with Vitamin D – March 2019
- Autism risk reduced 2X by prenatal vitamins (Vitamin D or Folic) – Feb 2019
- Fetal bones helped a bit by 1,000 IU of vitamin D – RCT Feb 2019
- Adding 1,000 IU vitamin D while pregnant did not help much (no surprise) – RCT Jan 2019
- Pregnancies helped a lot by Vitamin D (injection then 50,000 IU monthly) – RCT May 2018
- 430 genes changed when 3,800 IU Vitamin D added in late second trimester – RCT May 2018
- 300,000 IU of Vitamin D is not enough during pregnancy – RCT May 2018
- Preeclampsia risk reduced 7X by 4,000 IU of Vitamin D daily – RCT March 2018
- Risk of infant Asthma cut in half if mother supplemented Vitamin D to get more than 30 ng – RCT Oct 2017
- Gestational diabetes 30 percent less likely if consumed more than 400 IU of vitamin D daily – Oct 2017
- Monthly 120,000 IU Vitamin D plus daily Calcium was great during pregnancies – RCT Sept 2017
- Preterm birth rate reduced by vitamin D – 78 percent if non-white, 39 percent if white – July 2017
- 1,000 IU of Vitamin D while pregnant helped a little bit (4,000 IU helps a lot) – RCT Dec 2016
- Preeclampsia recurrence reduced 2 X by 50,000 IU of vitamin D every two weeks – RCT July 2017
- Only a select group of women will get a modest benefit from 800 IU of vitamin D – Jan 2017
- Reduction of infant asthma may require good vitamin D when lung development starts (4 weeks) – March 2017
- Gestational diabetes treated by Vitamin D plus Omega-3 – RCT Feb 2017
- 3,800 IU Vitamin D during pregnancy did not help much – RCT Jan 2017
- 50,000 IU of vitamin D for 8 weeks of pregnancy raised most above 30 nanograms - RCT Jan 2017
- Gestational Diabetes reduce 3 times by 5,000 IU of Vitamin D – RCT Jan 2016
- Preeclampsia risk reduced by higher levels of vitamin D (VDAART 4,400 IU) - RCT Nov 2016
- Gestational Diabetes treated with 50,000 IU every two weeks – RCT Sept 2016
- Perinatal depression decreased 40 percent with just a few weeks of 2,000 IU of vitamin D – RCT Aug 2016
- Pregnancy – adding 35,000 IU Vitamin D weekly was nice, but not enough – RCT April 2016
- Vitamin D once during pregnancy reduced infant health care costs (300 times ROI) – RCT Dec 2015
- Autism rate in siblings reduced 4X by vitamin D: 5,000 IU during pregnancy, 1,000 IU to infants – Feb 2016
- Preterm birth rate reduced 57 percent by Vitamin D – Nov 2015
- Pregnancy supplemented with 2,000 IU vitamin D got most infants to more than 12 nanograms – Aug 2015
- Preeclampsia reduced by Vitamin D (50,000 IU bi-weekly) and Calcium – Oct 2015
- Clinical trials for pregnancy with Vitamin D intervention – 51 as of Sept 2015
- No multiple sclerosis relapses during pregnancy if 50,000 IU of Vitamin D weekly – RCT April 2015
- Wheezing reduced 35 percent if vitamin D added during pregnancy – April 2015
- 4,000 IU raised vitamin D levels during pregnancy – July 2014
- Pregnant mothers in Quatar needed more than weekly 50,000 IU Vitamin D – Nov 2013
- Gestational diabetes – Vitamin D and Calcium provided huge benefits – RCT March 2015
- Pregnancy helped by single dose of 60,000 IU of Vitamin D – RCT March 2015
- Gestational diabetes reduced by just two 50,000 IU doses of vitamin D – RCT Nov 2014
- Improved births with 2,000 IU vitamin D during pregnancy in India - RCT Feb 2015
- 50,000 IU of Vitamin D every 2 weeks reduced gestational diabetes – RCT Feb 2015
- Infant much healthier if Gestational Diabetic mother got 2 doses of vitamin D – RCT Nov 2014
- 2000 IU vitamin D during pregnancy and 800 IU to infant resulted in less use of antibiotics – RCT April 2014
- Gestational Diabetes reduced with 50,000 IU of vitamin D every 3 weeks and daily Calcium – RCT June 2014
- Gestational Diabetes reduced 40 percent by 5,000 IU of vitamin D – RCT April 2014
- 5,000 IU Vitamin D was not enough to reduce preeclampsia but did help future infant – RCT April 2014
- Breast milk resulted in 20 ng of vitamin D for infant if mother had taken 5,000 IU daily – RCT Dec 2013
The articles in Pregnancy AND Meta-analysis are here:
- Pregnancy and offspring health - umbrella of 250,000 pregnancies - meta-analysis May 2024
- Vitamin D reduces: pre-eclampia 1.6 X, postpartum dep. 3.6 X, autism 1.5X etc. - meta-analysis March 2024
- Vitamin D supplementation decreased the risk of preeclampsia by 39% – meta-analysis Feb 2024
- Yet another reason to take Vitamin D while pregnant – fight COVID - meta-analysis May 2023
- Vitamin D during pregnancy increased child’s bone mineral density – meta-analysis April 2023
- Preeclampsia reduced by 33 percent if high vitamin D – meta-analysis Feb 2023
- Maternal pregnancy problems if Vitamin D is less than 40 ng – meta-analysis Oct 2022
- Worse COVID during 3Q pregnancy if 2.5 ng lower Vitamin D – meta-analysis Sept 2022
- Miscarriage 1.6 X more likely if low vitamin D – meta-analysis May 2022
- Recurrent Miscarriage 4X more likely if low vitamin D – meta-analysis June 2022
- Pregnancy problems (LBW, PTB, SGA) associated with low vitamin D, 42nd meta-analysis – March 2022
- Low Vitamin D associated with preeclampsia - meta-analysis Feb 2022
- Low Vitamin D associated with pre-eclampsia -40th meta-analysis – Feb 2022
- Small vitamin D doses while pregnant do not decrease infant allergies – meta-analysis Feb 2022
- Anemia 1.6 X more likely during pregnancy if low Vitamin D – meta-analysis Dec 2021
- Vitamin D reduces preeclampsia, gestational diabetes and hypertension - 38th meta-analysis Dec 2021
- Need at least 6,000 IU daily while breastfeeding to eliminate Vitamin D deficiency – meta-analysis Oct 2021
- Gestational diabetes risk reduced 1.5X by Vitamin D – meta-analysis March 2021
- Gestational Diabetes – increased risk if poor Vitamin D Receptor – 2 Meta-Analyses 2021
- Small vitamin D doses given during pregnancy do not reduce childhood asthma – meta-analysis Dec 2020
- Multiple Sclerosis 40 percent more likely if mother had low vitamin D – meta-analysis Jan 2020
- Pregnancies helped by Vitamin D (insulin and birth weight in this case) – meta-analysis Oct 2019
- Preeclampsia 2.7 X less likely if 50,000 IU of Vitamin D every 2 weeks – meta-analysis Sept 2019
- Autism risk increased 30 percent by Cesareans (both low vitamin D) – meta-analysis Sept 2019
- Vitamin D treats Gestational Diabetes, decreases hospitalization and newborn complications – meta-analysis March 2019
- Birth size and weight increased by Vitamin D – meta-analysis Feb 2019
- Pregnancies helped by Vitamin D in many ways – 27th meta-analysis Jan 2019
- Vitamin D supplementation reduced SGA, fetal mortality, infant mortality – JAMA Meta – May 2018
- Gestational Diabetes 39 percent more likely if insufficient Vitamin D – Meta-analysis March 2018
- Preeclampsia reduced 2X by Vitamin D, by 5X if also add Calcium – meta-analysis Oct 2017
- Preeclampsia risk reduced 60 percent if supplement with Vitamin D (they ignored dose size) – meta-analysis Sept 2017
- Small for gestational age is 1.6 X more likely if mother was vitamin D deficient – meta-analysis Aug 2017
- Miscarriage 2 times more likely if low vitamin D – meta-analysis May 2017
- Fewer than half of pregnancies will get even 20 ng of vitamin D with 800 IU daily dose – meta-analysis May 2017
- Low Vitamin D results in adverse pregnancy and birth outcomes – Wagner meta-analysis March 2017
- Bacterial vaginosis in pregnancy increased prematurity risk by 60 percent - meta-analysis 1999
- Preterm birth rate reduced by 43 percent with adequate Vitamin D supplementation – meta-analysis Feb 2017
- Vitamin D during pregnancy reduces risk of childhood asthma by 13 percent – meta-analysis Dec 2016
- Vitamin D helps during pregnancy – meta-analysis Feb 2016
- Preterm birth 30 percent more likely if low vitamin D – meta-analysis May 2016
- Preterm birth extended by 2 weeks with Omega-3 – Meta-analysis Nov 2015
- Gestational Diabetes Mellitus 1.5X more likely if low vitamin D – meta-analysis Oct 2015
- Infant wheezing 40 percent less likely if mother supplemented with vitamin D, vitamin E, or Zinc – meta-analysis Aug 2015
- Birth weight and length increased with high levels of vitamin D – meta-analysis March 2015
- Pregnancy and Vitamin D – meta-analysis April 2015
- More vitamin D needed during pregnancy – meta-analysis Oct 2014
- Preeclampsia rate cut in half by high level of vitamin D – meta-analysis March 2014
- Preeclampsia 2.7X more frequent if low vitamin D – meta-analysis Sept 2013
- 2X more preeclampsia when vitamin D less than 30 ng, etc. - meta-analysis March 2013
- 2X more likely to have preeclampsia if less than 20 ng of vitamin D – Meta-analysis Jan 2013
Overview Pregnancy and vitamin D has the following summary
| IU | Cumulative Benefit | Blood level | Cofactors | Calcium | $*/month |
| 200 | Better bones for mom with 600 mg of Calcium | 6 ng/ml increase | Not needed | No effect | $0.10 |
| 400 | Less Rickets (but not zero with 400 IU) 3X less adolescent Schizophrenia Fewer child seizures | 20-30 ng/ml | Not needed | No effect | $0.20 |
| 2000 | 2X More likely to get pregnant naturally/IVF 2X Fewer dental problems with pregnancy 8X less diabetes 4X fewer C-sections (>37 ng) 4X less preeclampsia (40 ng vs 10 ng) 5X less child asthma 2X fewer language problems age 5 | 42 ng/ml | Desirable | < 750 mg | $1 |
| 4000 | 2X fewer pregnancy complications 2X fewer pre-term births | 49 ng/ml | Should have cofactors | < 750 mg | $3 |
| 6000 | Probable: larger benefits for above items Just enough D for breastfed infant More maternal and infant weight | Should have cofactors | < 750 mg | $4 |
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