2X more preeclampsia when vitamin D less than 30 ng, etc. - meta-analysis March 2013

Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies

British Medical Journal (BMJ) 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f1169 (Published 26 March 2013)
Fariba Aghajafari, assistant professor of family medicine 12,
Tharsiya Nagulesapillai, data analyst 1,
Paul E Ronksley, doctoral candidate 1 3,
Suzanne C Tough, professor of paediatrics 1 4,
Maeve O’Beirne, associate professor of family medicine 2,
Doreen M Rabi, assistant professor of medicine 1 3 5, Rabi at albertahealthservices.ca
1 Department of Community Health Sciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada
2 Department of Family Medicine, University of Calgary, Canada
3 Calgary Institute for Population and Public Health, University of Calgary, Canada
4 Department of Paediatrics, University of Calgary, Canada
5 Department of Medicine, University of Calgary, Canada
Accepted 5 February 2013

Objective To assess the effect of 25-hydroxyvitamin D (25-OHD) levels on pregnancy outcomes and birth variables.

Design Systematic review and meta-analysis.

Data sources Medline (1966 to August 2012), PubMed (2008 to August 2012), Embase (1980 to August 2012), CINAHL (1981 to August 2012), the Cochrane database of systematic reviews, and the Cochrane database of registered clinical trials.

Study selection Studies reporting on the association between serum 25-OHD levels during pregnancy and the outcomes of interest (pre-eclampsia, gestational diabetes, bacterial vaginosis, caesarean section, small for gestational age infants, birth weight, birth length, and head circumference).

Data extraction Two authors independently extracted data from original research articles, including key indicators of study quality. We pooled the most adjusted odds ratios and weighted mean differences. Associations were tested in subgroups representing different patient characteristics and study quality.

Results 3357 studies were identified and reviewed for eligibility. 31 eligible studies were included in the final analysis.
Insufficient serum levels of 25-OHD were associated with

• gestational diabetes (pooled odds ratio 1.49, 95% confidence interval 1.18 to 1.89),
• pre-eclampsia (1.79, 1.25 to 2.58), and
• small for gestational age infants (1.85, 1.52 to 2.26).

Pregnant women with low serum 25-OHD levels had an increased risk of

• bacterial vaginosis and
• low birthweight infants but
• not delivery by caesarean section.

Conclusion Vitamin D insufficiency is associated with an increased risk of gestational diabetes, pre-eclampsia, and small for gestational age infants. Pregnant women with low 25-OHD levels had an increased risk of bacterial vaginosis and lower birth weight infants, but not delivery by caesarean section.

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PDF is attached at the bottom of this page
Forest Plots are also attached - in a separate PDF

Note:

• Used <1 % of the papers published
• Ignores latitude, ethnicity, obesity, vitamin D intake, existing health problems, etc.
• Ignores planned vs emergency C-section
• Insufficient = 30 ng/ml
• They would have had far better results if they considered >40 ng or >50 ng

Wonder just how many clinical trials and meta-analysis will be needed to change the attitudes of doctors
This it the 5th meta-analysis of Pregnancy and Vitamin D in VitaminDWiki as of April 2013
They have many reasons to fear adding vitamin D, one of which is that there will be fewer gynecologists
   It is difficult to get a man to understand something when his salary is dependent upon his not understanding it  Upton Sinclair

See also VitaminDWiki

• Preeclampsia reduced by Vitamin D (50,000 IU bi-weekly) and Calcium – Oct 2015
• Preeclampsia rate cut in half by high level of vitamin D – meta-analysis March 2014
• Almost 3X more likely to get preeclampsia if low vitamin D and high PTH– July 2013
• 2X more likely to have preeclampsia if less than 20 ng of vitamin D – Meta-analysis Jan 2013 Meta-analysis
  Note: The meta-analysis on this page found 2X more when < 30 ng, not just < 20ng
• Pregnancy and vitamin D meta-analysis – July 2012 Meta-analysis
• Low vitamin D increased probability of low birth weight by 60 percent – meta-analysis June 2012 Meta-analysis
• Gestational diabetes 60 percent more likely below 20 ng of vitamin D – meta-analysis Feb 2012 Meta-analysis
• Pregnancy and vitamin D meta-analysis – July 2012 Meta-analysis
• 7X increase in early severe preeclampsia associated with low vitamin D – Aug 2012 preeclampsia links to lots of other studies
• How to reduce preeclampsia - May 2011 preeclampsia
• Low vitamin D results in severe preeclampsia and low birth weight – Mar 2011 preeclampsia
• Women with low vitamin D 4X more likely to have preeclampsia in pregnancy – Nov 2010 preeclampsia
• All preeclampsia items in VitaminDWiki 180 as of Sept 2013
• Pregnancy complications reduced with 4000 IU of vitamin D - 2RCT Jan 2013
• Vitamin D of 32 to 60 ng is needed before, during, and after pregnancy – Dec 2012
• Variety of pregnancy problems with low vitamin D – systematic review Sept 2012
• Prevention of vitamin D deficiency in mothers and infants worldwide - a paradigm shift. – Feb 2012
• Preeclampsia 2.7X more frequent if low vitamin D – meta-analysis Sept 2013
• Overview Pregnancy and vitamin D which 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

See also [http://www.vitamindcouncil.org/health-conditions/preeclampsia/| Vitamin D Council on preeclampsia] excellent summary April 2013

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Editorial in same issue: Vitamin D sufficiency in pregnancy

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f1675 (Published 26 March 2013)
Cite this as: BMJ 2013;346:f1675
Robyn Lucas, associate professor 1 robyn.lucas at anu.edu.au, Fan Xiang, research fellow 1, Anne-Louise Ponsonby, professor 2
1 National Centre for Epidemiology and Population Health, Australian National University, Canberra, ACT 0200, Australia
2 Murdoch Childrens Research Institute, Royal Children’s Hospital, Melbourne, Vic, Australia

Better evidence is required to establish optimal levels and need for supplementation
One year ago, the chief medical officers of the United Kingdom recommended that “All pregnant and breastfeeding women should take a daily supplement containing 10 μg (400 IU) of vitamin D,” to counter the high prevalence of vitamin D deficiency in pregnant women. This was aimed at reducing the associated consequences of deficiency, such as rickets in children and osteomalacia in adults.1

In a linked meta-analysis (doi:10.1136/bmj.f1169), Aghajafari and colleagues look beyond bone health to other adverse health outcomes for mother and baby.2 Previous systematic reviews have highlighted challenges in combining data from different studies, including diverse definitions of vitamin D deficiency, variations in vitamin D assays used, use of non-representative samples, and varying study designs and study quality.3 4

A review published in 2011 found insufficient high quality studies to conduct quantitative meta-analysis 3; in the qualitative review the evidence was inconsistent. In a subsequent review, rigorous assessment of study quality resulted in quantitative meta-analyses of only two observational studies and five randomised controlled trials, with additional studies reviewed qualitatively.4 Combined data from trials suggested that bolus high dose vitamin D supplementation (but not daily dosing) was associated with reduced risk of low birth weight (risk ratio 0.40; 95% confidence interval 0.23 to 0.71). Combined trial data found no significant protective effect of vitamin D supplementation on the outcome small for gestational age (0.77, 0.35 to 1.66), although observational studies supported a protective effect. Results for maternal outcomes were inconsistent. In a 2012 Cochrane systematic review, meta-analysis of three trials of daily vitamin D supplementation during pregnancy found a reduced risk of low birth weight (0.48, 0.23 to 1.01), although this was not significant.5

In a recent combined analysis of two randomised controlled trials, higher vitamin D (measured as serum concentration of 25-hydroxyvitamin D; 25-OHD) at delivery was associated with a significantly (P<0.006) decreased risk of “comorbidities of pregnancy.” Comorbidities were gestational diabetes, hypertension, infection, bacterial vaginosis, and preterm birth without pre-eclampsia, but the study did not have enough power to analyse individual outcomes.6

Meta-analysis overcomes the problems of small sample sizes and insufficient power. But challenges arise in combining data from studies of different designs, inclusion and exclusion criteria, and definitions of exposure and outcome. Aghajafari and colleagues’ review contains no primary data from vitamin D intervention studies.2 Only one trial was considered, but was excluded from analysis. The largest effect sizes derive from case-control studies, some with minimal or no adjustment for confounding; comparisons of extreme groups (such as <50 v >75 mmol/L), so that data from most of the sample (the middle group) are omitted 7; and blood sampling after “disease” onset. Serum 25-OHD concentration is labile. It depends on recent intake of vitamin D and sun exposure, both of which may change, and may even be affected by preclinical disease (disease induced vitamin D deficiency).

Gestational age at sampling is also relevant to causal interpretations if low vitamin D status at late sampling is linked to outcomes that are usually associated with earlier gestational onset. Aghajafari and colleagues found that “vitamin D deficiency”—variously defined and measured at different gestational ages—is adverse for maternal and infant health. If lower vitamin D status causes these outcomes in a linear way, more severe deficiency (<50 nmol/L) would be expected to have a stronger effect than less severe deficiency (<75 nmol/L). The opposite effect seems to occur for pre-eclampsia.2

Despite these challenges to interpreting the evidence, these studies have clear clinical implications. In 2010 the US Institute of Medicine recommended that a serum concentration of 25-OHD of 50 nmol/L or more should be considered sufficient for bone health.8 Although optimal maternal 25-OHD levels at different gestational times are not known, levels below 50 nmol/L are common during pregnancy, particularly in populations at high latitudes and in specific subpopulations. Evidence of a causal association between vitamin D deficiency and some maternal and neonatal outcomes is insufficient, but the evidence for bone health is clear cut. The findings of this meta-analysis support a goal of vitamin D sufficiency for all pregnant women.2 Supplements, diet, and sunlight exposure all influence 25-OHD levels and should be used together, with care, because U shaped dose-response curves are reported for a range of health outcomes, including small for gestational age,9 with disease risk increasing at both low and high 25-OHD levels.

Most studies are undertaken in developed countries. Yet Asian and African countries have higher infant mortality and represent half of the global population. Where it has been measured, vitamin D deficiency is common in these countries, under the combined influences of darker skin, cultural practices that limit sun exposure, and, in some locations, urban air pollution blocking ultraviolet radiation. For example, median 25-OHD levels of pregnant women living in Beijing were only 26 nmol/L.10 If there is a causal association between vitamin D deficiency and adverse maternal and neonatal outcomes, gains from ensuring sufficiency may be great in these countries.

Current evidence on vitamin D status and neonatal and pregnancy health derives largely from observational studies, small trials, low doses of vitamin D supplementation, unclear study processes of randomisation and blinding, or low adherence. In their editorial, Harvey and Cooper called for large well designed randomised controlled trials to clarify the causal association between vitamin D supplementation and health.11 This is particularly needed to delineate the importance of vitamin D in pregnancy, with its potentially lifelong effects on the health of offspring.12

References for editorial

1. Department of Health. Vitamin D—advice on supplements for at risk groups. 2012. www.dh.gov.uk/health/2012/02/advice-vitamin-d/.
2. Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O’Beirne M, Rabi DM. Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies. BMJ2013;346:f1169. FREE Full Text
3. Nassar N, Halligan GH, Roberts CL, Morris JM, Ashton AW. Systematic review of first-trimester vitamin D normative levels and outcomes of pregnancy. Am J Obstet Gynecol2011;205:208.e1-7. Medline
4. Thorne-Lyman A, Fawzi WW. Vitamin D during pregnancy and maternal, neonatal and infant health outcomes: a systematic review and meta-analysis. Paediatr Perinat Epidemiol2012;26(suppl 1):75-90. CrossRefMedline
5. De-Regil L, Palacios C, Ansary A, Kulier R, Pena-Rosas J. Vitamin D supplementation for women during pregnancy. Cochrane Database Syst Rev2012;2:CD008873. Medline
6. Wagner CL, McNeil RB, Johnson DD, Hulsey TC, Ebeling M, Robinson C, et al. Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis. J Steroid Biochem Mol Biol 2013; published online 10 Jan.
7. Zhang C, Qiu C, Hu FB, David RM, van Dam RM, Bralley A, et al. Maternal plasma 25-hydroxyvitamin D concentrations and the risk for gestational diabetes mellitus. PloS One2008;3:e3753. CrossRefMedline
8. Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Ross A, Taylor CL, Yaktine AL, Del Valle HB, eds. Institute of Medicine of the National Academies, 2010.
9. Bodnar LM, Catov JM, Zmuda JM, Cooper ME, Parrott MS, Roberts JM, et al. Maternal serum 25-hydroxyvitamin D concentrations are associated with small-for-gestational age births in white women. J Nutr2010;140:999-1006. FREE Full Text
10. Wang O, Nie M, Hu YY, Zhang K, Li W, Ping F, et al. Association between vitamin D insufficiency and the risk for gestational diabetes mellitus in pregnant Chinese women. Biomed Environ Sci2012;25:399-406. Medline
11. Harvey NC, Cooper C. Vitamin D: some perspective please. BMJ2012;345:e4695. FREE Full Text
12. Lucas RM, Ponsonby AL, Pasco JA, Morley R. Future health implications of prenatal and early-life vitamin D status. Nutr Rev2008;66:710-20. Cross Ref Medline Web of Science

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Low Doses Of Vitamin D Linked With Harmful Outcomes During Pregnancy
(Medical News Today title for this study makes vitamin D look bad)