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Three Part Question

In pregnant Asian women in UK [patient] is Vitamin D supplementation [intervention] versus no or any other supplementation [comparison] lead to better clinical, biochemical and radiological outcomes in the mother, foetus, infant and child [outcome]

Clinical Scenario

Both authors work in the North-West region of England which has a relatively high proportion of people of Asian origin. We often encounter pregnant women and children from this ethnicity who are clinically and/or biochemically Vitamin D deficient. One solution to this is to supplement Vitamin D to all pregnant women at risk and this would benefit them and their baby. Currently, in our hospitals Vitamin D is given only to those with proven deficiency and not routinely to those at high risk. We decided to look at the evidence for this.

Search Outcome

SECONDARY DATABASES
Cochrane database of systematic reviews and Cochrane register of controlled trials – "pregnancy OR pregnant" AND "vitamin d" – 52 articles identified
CAT crawler which includes 8 evidence based libraries over the world including BestBETs, CATBank, IMSANZ, NUH, PedsCCM, SORAHSN, UMHS, UNC-CH – "vitamin d" AND pregnan* - 1 article identified
PRIMARY DATABASES
Medline via pubmed – (("vitamin d" AND pregnan*) OR ("Vitamin D"[MeSH] AND "Pregnancy"[MeSH])) AND (England or Scotland or Wales or Ireland or Britain or UK or "United Kingdom"). Limits: English, Humans – 95 articles identified
Embase via dialog datastar - "((pregnancy OR pregnant) AND (vitamin ADJ d) AND (England OR Scotland OR Wales OR Ireland OR Britain OR UK OR United ADJ Kingdom)) AND LG=EN AND HUMAN=YES" – 210 articles identified.
After reading abstracts only 6 relevant articles identified for the review. Of these 3 were part of the same study group and so were counted as one

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Brooke 1980 UK	126 Asian pregnant women in London in 1978-79. Study group – 59 received 1000 IU/day of ergocalciferol during last trimester. Control group – 67 received no supplementation	Double blind randomized controlled trial Level 1b evidence	MATERNAL - CLINICAL
			Maternal weight gain in 3rd trimester	Daily mean weight gain was 46.4 + 29.5 gm in control group and 63.3 + 20.7 gm in study group (p<0.001)
			MATERNAL - BIOCHEMICAL
			Plasma levels of 25 hydroxy Vitamin D	16.2 + 2.7 nmol/l in control group and 168.0 + 12.5 nmol/l in study group (p<0.05)
			Plasma alkaline phosphatase	136.1 + 7.9 IU/l in control group and 114.3 + 6.0 IU/l in study group (p<0.05)
			Levels of albumin as marker of nutritional status	28.3 + 3.1 g/l in control group and 28.8 + 3.2 g/l in study group (p – NS)
			Retinol binding protein as marker of nutritional status	3.7 + 1.0 mg/dl in control group and 4.3 + 1.6 mg/dl in study group (p<0.05)
			Thyroid binding pre-albumin as marker of nutritional status	14.8 + 3.4 mg/dl in control group and 18.5 + 3.5 mg/dl in study group (p<0.01)
			NEONATAL/INFANT - CLINICAL
			Anthropometry at birth, 3, 6, 9 and 12 months	No difference seen in weight, length and head circumference at birth. Infants in study group were significantly heavier at each follow-up visit. Lengths were greater at each visit in the study group but significantly only at the 9 and 12 month age follow-up.
			Fontanelle area at birth	6.1 ¬+ 0.7 sq. cm in control group and 4.1 + 0.4 sq. cm in the study group (p<0.05)
			Symptomatic hypocalcaemia	5 in control group and none in the study group (p<0.01)
			NEONATAL/INFANT – BIOCHEMICAL
			Plasma calcium level on day 3 and 6 of life	Day 3 – 2.18 + 0.04 mmol/l in control group and 2.30 + 0.04 mmol/l in study group (p<0.05).
			Cord albumin, Retinol binding protein (RBP) and Thyroid binding pre-albumin (TBPA) levels	There was small increase in RBP concentration in infants of study group (p<0.05) but no difference in TBPA or albumin
Congdon 1983 UK	76 pregnant women in UK in 3 groups 1. 45 Asian women with no supplementation 2. 19 Asian women who had 1000 U of vitamin D during the last trimester 3. 12 white women	Non-randomised controlled cohort study Level 2b evidence	Mean cord blood concentrations of 25(OH)D	Group 1 - 2.4 +/- 0.4 ng/ml, Group 2 - 6.1 +/- 1.3 ng/ml, Group 3 - 13.4 ng/ml
			Bone mineral content (as assessed by photon absorptiometry)	No significant difference in the bone mineral content (as assessed by photon absorptiometry) of the forearms of babies
Datta 2002 UK	Vitamin D status of 160 pregnant women from non-European ethnic minorities (100 Asian in origin) in South Wales was checked at booking. 80 were deficient and were treated with vitamin D (800 IU/d) which was increased to 1600IU/d if levels were still low on retesting at 36 weeks gestation.	Individual cohort study. Level 2b evidence	Vitamin D status at delivery (as defined by maternal level of 25(OH)D and PTH)	58 of the 80 women supplemented had their vitamin D status rechecked at delivery (73%). Vitamin D levels had returned to normal in 35 of those 58 women (60%) and mean level of vitamin D had increased from 6 mcg/ml at booking to 11 mcg/ml at delivery. Mean parathyroid hormone level remained the same	No control group
Heckmatt 1979 UK	44 pregnant Asian women in Leeds delivering between Sep. 1978 and Jan. 1979 who did not receive any supplementation were compared with 44 Asian women delivering between January and June 1979 who were supplemented with 1000 units of vitamin D for 1 to 3 months before delivery.	Before-After cohort study. Level 2b evidence	Maternal 25- OHD levels at delivery	Concentrations was 36.2 nmol/l in supplemented group vs. 14.2 nmol/l in unsupplemented group (p<0.001)	Control and study groups were not 2 arms of the same trial, rather comparisons were made between unsupplemented pregnant women delivering between Sep 1978 to Jan 1979 and supplemented pregnant women delivering between Jan 1979 to Jun 1979
			Cord 25- OHD levels	Concentrations was 33 nmol/l in supplemented group vs. 21 nmol/l in unsupplemented group (p - NS)

Comment(s)

Vitamin D refers to group of closely related sterols produced by the action of ultraviolet light on certain provitamins. It can be obtained either through photosynthesis in the skin or through dietary sources. The major biological functions of vitamin D are to increase the efficiency of intestinal calcium absorption, decrease renal calcium excretion, and, in conjunction with parathyroid hormone (PTH), mobilize calcium from bone. It is metabolized by successive hydroxylation to 25-hydroxyvitamin D and then to 1, 25-dihydroxyvitamin D, which is the active metabolite of the vitamin. Significant changes in maternal vitamin D and calcium metabolism occur during pregnancy, to provide the calcium needed for foetal bone mineral accretion. Approximately 25-30 g of calcium are transferred to the foetal skeleton by the end of pregnancy, most of which is transferred during the last trimester. Deficiency in vitamin D during pregnancy is most likely to occur in women whose diet is relatively low in the vitamin, such as vegetarians, and those who either remain indoors or whose clothing leaves little exposed skin, particularly in relatively sunless climates. There has been longstanding evidence of Vitamin D deficiency among pregnant Asian women and their newborn babies in UK [Alfaham, Brooke, Okonofua]. Effect of low maternal vitamin D not only includes problems of maternal osteomalacia, neonatal hypocalcaemic seizures, dental enamel hypoplasia and infantile rickets but has recently been shown to reduce bone mass in children up to the age of 9 years [Javaid]. Current UK Department of Health recommendations based on Committee on Medical Aspects of Food Policy (COMA) recommend that all pregnant and breast feeding women should receive 10 micrograms (400 IU) of vitamin D daily [Department of Health]. However recommendations by NICE [National Collaborating Centre for Women's and Children's Health] based on a Cochrane review [Mahomed] state that there is insufficient evidence to evaluate the effectiveness of vitamin D in pregnancy and in the absence of evidence of benefit, vitamin D supplementation should not be offered routinely to pregnant women. The same Cochrane study however recommended that Vitamin D supplementation in the later part of pregnancy should be considered in vulnerable groups, such as Asian women living in Northern Europe, and possibly others in climates with long winters. The contradictory statements from DOH and NICE have led to confusion and in a recent survey of GP practices in the Thames Valley area and Lambeth (where 67.9% practices had Asian or African–Caribbean population constituting more than 8% of total population), no practice was supplementing pregnant women and only two (3.4%) of the practices stated that they supplemented infants [Metson]. The same lack of supplementation in high-risk groups was also noted in Leicester [Shenoy]. In fact the origin of our review was as a result of a GP based in Blackburn requesting a district wide policy for use of calcium and Vitamin D in pregnant women. Our review clearly shows that there is an improvement in maternal Vitamin D status as a result of supplementation [Brooke, Maxwell, Datta, Heckmatt]. There is also some affect on maternal nutritional status as measured by maternal weight gain and levels of retinol binding protein and thyroid binding pre-albumin [Brooke, Maxwell]. The cord blood 25 OH cholecalciferol levels showed improvement as a result of supplementation [Congdon, Heckmatt]. After birth there was significantly less incidence of asymptomatic and symptomatic hypocalcaemia in the supplemented group and there was evidence of significant improvements in weight and length of the infant up to 1 year of age [Brooke]. It is however worth noting that in all these studies mothers were getting at least 800 IU of Vitamin D which is double the recommendation by the UK department of health. In a recent review the evidence behind the recommended daily intake of Vitamin D of 400 IU has been questioned and the authors strongly argue for the need to give pregnant women at least 1000 IU/day of Vitamin D [Hollis]. There is need for a randomised double blind trail to answer questions about the most appropriate dose and duration of Vitamin D supplementation in pregnant women. In the meantime, on the basis of our review, we recommend that Vitamin D supplementation of 400 IU/day should be routinely offered to pregnant women of Asian origin living in UK and add our voice to the concern raised by other authors about the conflicting advice received from NICE and COMA [Moy, Callaghan, Bishop]. OTHER REFERENCES Alfaham M, Woodhead S, Pask G, Davies D. Vitamin D deficiency: a concern in pregnant Asian women. Br J Nutr 1995; 73:881–7. Brooke OG, Brown IR, Cleeve HJ, Sood A. Observations on the vitamin D state of pregnant Asian women in London. Br J Obstet Gynaecol. 1981 Jan; 88(1):18-26. Okonofua F, Menon RK, Houlder S, et al. Calcium, vitamin D and parathyroid hormone relationships in pregnant Caucasian and Asian women and their neonates. Ann Clin Biochem 1987; 24:22–8. Javaid MK, Crozier SR, Harvey NC, Gale CR, Dennison EM, Boucher BJ, Arden NK, Godfrey KM, Cooper C; Princess Anne Hospital Study Group. Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study. Lancet. 2006 Jan 7; 367(9504):36-43. Erratum in: Lancet. 2006 May 6; 367(9521):1486. Department of Health. Nutrition and bone health: with particular reference to calcium and vitamin D. Report on health and social subjects 49. London: HMSO, 1998. National Collaborating Centre for Women's and Children's Health, NHS. Antenatal care: routine care for the healthy pregnant woman. London: NICE, 2003. Mahomed K, Gulmezoglu AM. Vitamin D supplementation in pregnancy. The Cochrane Database of Systematic Reviews 1999, Issue 1. Metson D. Should GPs be prescribing more vitamin D? Br J Gen Pract. 2005 Dec; 55(521):966. Shenoy SD, Swift P, Cody D, Iqbal J. Maternal vitamin D deficiency, refractory neonatal hypocalcaemia, and nutritional rickets. Arch Dis Child. 2005 Apr; 90(4):437-8. Hollis BW, Wagner CL. Assessment of dietary vitamin D requirements during pregnancy and lactation. Am J Clin Nutr. 2004 May; 79(5):717-26. Review. Moy R, Shaw N, Mather I. Vitamin D supplementation in pregnancy. Lancet. 2004 Feb 14; 363(9408):574. Callaghan AL, Moy RJ, Booth IW, Debelle G, Shaw NJ. Incidence of symptomatic vitamin D deficiency. Arch Dis Child. 2006 Jul; 91(7):606-7. Bishop N. Don't ignore vitamin D. Arch Dis Child. 2006 Jul; 91(7):549-50.

Clinical Bottom Line

1. All pregnant women of Asian origin in UK should be given 400 IU of Vitamin D supplementation. 2. There is a need to clarify the confusion created by the guidance issued by NICE. 3. There is also a need to do further research to identify the most appropriate dose of Vitamin D supplementation in pregnant women.

References

1. Brooke OG, Brown IR, Bone CD, Carter ND, Cleeve HJ, Maxwell JD, Robinson VP, Winder SM Vitamin D supplements in pregnant Asian women: effects on calcium status and fetal growth Br Med J 1980;280:751–4
2. Maxwell JD, Ang L, Brooke OG, Brown IR Vitamin D supplements enhance weight gain and nutritional status in pregnant Asians Br J Obstet Gynaecol 1981 Oct; 88(10):987-91
3. Brooke OG, Butters F, Wood C Intrauterine vitamin D nutrition and postnatal growth in Asian infants Br Med J (Clin Res Ed) 1981 Oct 17; 283(6298):1024
4. Congdon P, Horsman A, Kirby PA, Dibble J, Bashir T Mineral content of the forearms of babies born to Asian and white mothers BMJ 1983; 286:1233–5
5. Datta S, Alfaham M, Davies DP, Dunstan F, Woodhead S, Evans J, Richards B Vitamin D deficiency in pregnant women from a non-European ethnic minority population: an interventional study Br J Obstetr Gynaecol 2002; 109:905–8
6. Heckmatt JZ, Peacock M, Davies AE, McMurray J, Isherwood DM Plasma 25-hydroxyvitamin D in pregnant Asian women and their babies Lancet 1979 Sep 15;2(8142):546-8