Prevention of Adverse Pregnancy Outcome With Vitamin D Supplementation During Pregnancy
Condition: Pregnancy
Study type: Interventional

Summary: 
      We hypothesized that vitamin D supplementation during pregnancy can prevent adverse pregnancy
      outcome.
    

Detailed description: 
      Vitamin D deficiency has been associated with many chronic diseases. These include
      cardiovascular diseases, diabetes mellitus, multiple sclerosis, breast and prostate cancers.
      Recently, its role in pregnancy has been explored. Vitamin D deficiency has been found to be
      associated with adverse pregnancy outcome. These include pre eclampsia, gestational diabetes
      mellitus, preterm labor and low birth weight.

      Bodnar et al, evaluated role of vitamin D deficiency during pregnancy in PE in a nested case
      control study. The investigators looked at the role of vitamin D at gestational age of < 22
      weeks. Women who developed PE were found to have low levels of vitamin D. These women had
      serum levels of vitamin D < 15 ng/ml, were supplemented during pregnancy with prenatal
      vitamins, were still found to have 5 fold greater chances of developing PE (adjusted odds
      ratio, 5.0; 95% confidence interval, 1.7-14.1).Children of above group of women were also
      found to have low levels of vitamin D. The authors concluded that vitamin D deficiency may be
      an independent factor for the development of PE.(1)

      In an epidemiological study from Norway, involving 23,423 primigravidae, the rsik of PE was
      found to be 27% greater in women who did not receive D supplements, compared to women who
      received 10-15µg/day of vitamin D(2).

      Circulating levels of 1-25(OH) have been found to be low in women with PE.(3) This has been
      attributed to reduced expression and activity of 1α-hydroxylase in human placenta from
      preeclamptic pregnancies.(4) This association with PE has also been found to be influenced by
      VEGF (Vascular endothelial growth factor). Active forms of vitamin D have been found to
      increase the expression of VEGF , and its release in vascular smooth cells, in in-vitro
      studies.(5)

      Vitamin D deficiency has also been associated with small for gestational age (SGA) (6) The
      difference has been found to be more subtle for Caucasians as compared to African-Americans
      in West. The investigators showed a U shaped association between D levels and SGA. After
      confounder adjustment, compared with serum 25(OH)D 37.5-75 nmol/L, SGA odds ratios (95% CI)
      for levels <37.5 and >75 nmol/L were 7.5 (1.8, 31.9) and 2.1 (1.2, 3.8), respectively. In a
      similar study by Brooke, among Asian women resident in UK, vitamin D supplementation with
      1000IU in third trimester, compared with placebo, was associated with decreased incidence of
      small for gestational age (15% versus 29%). Investigators suggested supplementation with
      vitamin D among Asians living in UK.(7)

      Vitamin D deficiency has been related to gestational diabetes mellitus (GDM) in pregnant
      women. Zhang et al, found that vitamin D deficiency in early pregnancy is linked with
      increased risk for GDM. Vitamin D deficiency was associated with a 2.66-fold (OR (95% CI):
      2.66 (1.01-7.02)) increased GDM risk. Moreover, each 5 ng/ml decrease in 25-[OH] D
      concentrations was related to a 1.29-fold increase in GDM risk (OR (95% CI): 1.29
      (1.05-1.60)).(8) Similarly, in an Iranian study, women who were found to have GDM, were found
      to have lower levels of serum 1,25 (OH), as compared to normoglycemic women. (9) Serum levels
      of <12 nmol/L were found associated with GDM. This may be linked to the fact that 1,25(OH)
      stimulates insulin secretion.

      Vitamin D deficiency has also been linked to increased risk for cesarean section. In a study
      of 253 women, who underwent cesarean section, multivariable logistic regression analysis
      controlling for race, age, education level, insurance status, and alcohol use, women with
      25(OH)D less than 37.5 nmol/liter were almost 4 times as likely to have a cesarean than women
      with 25(OH)D 37.5 nmol/liter or greater (adjusted odds ratio 3.84; 95% confidence interval
      1.71 to 8.62).(10) Poor muscular performance due to vitamin D deficiency may be the reason
      for the increased cesarean section rate.

      Preterm labor, is the other adverse pregnancy outcome, which is thought to be affected by
      maternal serum levels of 1,25(OH). In a recently concluded RCT, a comparison was made between
      400IU, 2000IU and 4000IU of daily supplementation with vitamin D. Women who were prescribed
      highest doses had significant less chances of spontaneous preterm birth at < 37 and at < 32
      weeks.(11) Inflammation plays a key role in the etiology of preterm labor. And vitamin D is
      known to influence the production of inflammatory mediators like interleukin 1, interleukin
      -6 and tumor necrosis factor by macrophages.(12) This may be a reason for decreased incidence
      of preterm birth in women who received vitamin D supplementation.

      Birth weight of newborn is also affected by maternal serum D levels. In a study from
      neighboring Iran, of 449 women, birth weight, length and apgar score were significantly
      better in women who took diet adequate in calcium and vitamin D.(13) Vitamin D
      supplementation during pregnancy leads to increased calcium stores in infants and improved
      weight gain as well. Levels < 25ng/ml are associated with rickets and osteomalacia. There is
      positive correlation between maternal and neonatal cord levels of vitamin D. This
      relationship has also been shown in studies from other part of world. (14-16)This indicates
      that these newborns are entering the world, with deficiency of vitamin D, which starts in
      utero. Apart from affecting skeletal development, it also affects the innate immune system of
      newborn. In a case-control study, children who were deficient in vitamin D were found to be
      more prone to acute respiratory tract infections. The mean serum 25(OH)D concentrations in
      the study group newborns were lower than those of the control group (9.12+/-8.88 ng/ml and
      16.33+/-13.42 ng/ml, respectively) (P=0.011). (17) It has been observed that infants born to
      D replete mothers will become D deficient, 8 weeks after birth, unless they are supplemented
      with vitamin D. In an earlier cross sectional study, from Karachi city Atiq M, had found low
      levels of vitamin D in newborns who were breastfed. The age group was from 6 weeks to 11
      months. Thirty-four (48%) mothers and 37 (52%) infants had levels less than 25 nmol/ L (i.e.
      <10ng/ml). The investigators found a significant correlation between serum 25(OH)D levels of
      infants under three months of age and their mothers (p<0.01).(18) Though this study was
      carried out in a private university hospital, where majority of mothers belonged to upper
      socio economic class.

      Content of vitamin D in breast milk is dependant upon the serum levels in mothers.
      Supplementation of lactating mothers has been recommended to avoid deficiency in newborn, but
      is not a norm in our practice. There is also increased motivation for exclusive breast
      feeding for the first 4-6 months in our society. Hence with prevalence of vitamin D
      deficiency as high as 90% in our population (data submitted for publication), our newborns
      are more at risk for vitamin D deficient rickets
    

Intervention name(s): D Max drops
Intervention type(s): Dietary Supplement
Intervention description(s): Women in study arm will be cases, and will recieve ferrous sulphate and calcium lactate, along with 4000IU D Max drops
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: vitamin D; adverse pregnancy outcome; Pakistan