|Year : 2019 | Volume
| Issue : 2 | Page : 145-149
Vitamin D supplementation in the first trimester of pregnancy as an intervention to protect against adverse gestational outcomes in the third trimester
Banav Najeeb Muhammed1, Ardawan Fatah Ali2
1 Department of Obstetrics and Gynecology, Medical College, Duhok University, Kurdistan Region, Iraq
2 Department of Medical Lab Technology, Shekhan Technical College of Health, Duhok Polytechnic University, Duhok, Kurdistan Region, Iraq
|Date of Web Publication||17-Jun-2019|
Banav Najeeb Muhammed
Department of Gynecology and Obstetrics, Medical College, Duhok University, Kurdistan Region
Source of Support: None, Conflict of Interest: None
Background: Vitamin D deficiency (VDD) is thought to be common among pregnant women and is a widespread public health problem. Objective: The aim of this study was to know whether the correction of VDD by Vitamin D supplementation given to pregnant women in the first trimester of pregnancy can prevent the development of complications such as preeclampsia (PE), gestational diabetes mellitus (GDM), and small for gestational age (SGA) in the third trimester or not, in a sample of pregnant women. Materials and Methods: The study was an experimental design. It was carried out between December 2016 and October 2018. A total 200 healthy pregnant women were included. They were chosen randomly in the first trimester of pregnancy from the Outpatient Clinic in Duhok Governorate of Kurdistan Region, Iraq. A knowledge questionnaire was used to collect information. Blood samples were taken and analyzed for the determination of 25 hydroxyvitamin D (25[OH] D). We did routine investigations which done for every pregnant woman as a part of antenatal care in the form of complete blood count, general urine examination, random blood sugar, and ultrasound. Results: Mean serum 25[OH] D concentration before supplementation was 8.41 ± 2.48 and after supplementation was 30.96 ± 9.60. There was a reduction in the risk of GDM and SGA but no change in the risk of PE. Conclusion: Supplementation of Vitamin D to pregnant women with VDD in the first trimester may lower the risk of GDM and SGA, but its effects in the prevention of PE need further evaluation. All patients had response to the Vitamin D supplement within 8–10 weeks regardless the outcomes.
Keywords: 25-hydroxyvitamin D , gestational diabetes mellitus, preeclampsia, small for gestational age, Vitamin D deficiency
|How to cite this article:|
Muhammed BN, Ali AF. Vitamin D supplementation in the first trimester of pregnancy as an intervention to protect against adverse gestational outcomes in the third trimester. Med J Babylon 2019;16:145-9
|How to cite this URL:|
Muhammed BN, Ali AF. Vitamin D supplementation in the first trimester of pregnancy as an intervention to protect against adverse gestational outcomes in the third trimester. Med J Babylon [serial online] 2019 [cited 2019 Nov 12];16:145-9. Available from: http://www.medjbabylon.org/text.asp?2019/16/2/145/260469
| Introduction|| |
Vitamin D, a secosteroid that is synthesized in skin and sequentially metabolized in liver and kidneys in humans, has been well known for its function in maintaining calcium and phosphorus homeostasis and promoting bone mineralization. Vitamin D is metabolized first to 25 hydroxyvitamin D (25[OH]D), then to the hormonal form 1, 25-dihydroxyvitamin.
The largest source of Vitamin D in adults is synthesis from solar radiation, ½ h of sunlight exposure delivers 50,000 IU of Vitamin D with white complexioned skin. Dietary intake of Vitamin D makes a relatively small contribution to overall Vitamin D status, as there is little Vitamin D that occurs naturally in the food supply.
We categorized plasma 25-(OH)D concentrations according to previously published criteria for Vitamin D sufficiency (>30 ng/ml), insufficiency (20–29 ng/ml), and deficiency (<20 ng/ml).
The United States Institute of Medicine (IOM) has recently defined levels of serum 25(OH)D >50 nmol/L or 20 ng/mL as adequate for pregnant women; however, other investigators argue that optimal levels should be set higher (>75 nmol/L or 30 ng/mL) (to convert nmol/L to ng/mL divide by 2.496).,
The daily upper safe limit for Vitamin D has been set at 4000 IU by IOM and 10,000 IU by the Endocrine Society.
Vitamin D toxicity generally becomes evident at doses of 20,000 IU/day and can lead to hypercalcemia, hypercalciuria, and elevated (200 nmol/L) levels of serum 25(OH)D.
The Vitamin D deficiency (VDD) epidemic during pregnancy, it appears that the etiology is multifactorial. The factors that affect this include limited sunlight exposure but also reduced dietary Vitamin D and calcium intake, ethnicity, age, socioeconomic status, repeated pregnancies, obesity, and malabsorption. In addition, the oral intakes that are too low to meet the increased demands of pregnancy, even with regular use of prenatal vitamins containing 400 IU Vitamin D3.
VDD has been associated with increased risk of a number of adverse maternal and child health outcomes. These include an increased risk of preeclampsia (PE) and gestational diabetes mellitus (GDM), bacterial vaginosis, and increased production of maternal inflammatory cytokines, insulin resistance, and primary cesarean section. For the offspring, increased risk of preterm birth, small for gestational age (SGA) babies, neonatal hypocalcemia, rickets in infancy, reduced bone density, asthma, and schizophrenia.,
PE is a pregnancy-specific syndrome characterized by high blood pressure and proteinuria after 20 weeks gestation that occurs in up to 8% of pregnant women. Increased production of inflammatory cytokines, such as tumor necrosis factor-α, has been reported in pregnancies complicated by VDD. Furthermore, (1, 25[OH]2D) stimulates the activity of T-regulatory cells, which are vital in supporting placental implantation through immune tolerance. In PE, the metabolism of Vitamin D in placental tissue is altered, and these differences may play a role in the abnormal trophoblastic invasion found in these pregnancies.
GDM is defined as any degree of glucose intolerance with onset or first recognition during pregnancy.
The global prevalence of GDM varies widely, from 1% to 28%, depending on population characteristics (e.g., maternal age, socioeconomic status, race/ethnicity, or body composition), screening methods, and diagnostic criteria, and the amount of GDM varies in direct proportion to the prevalence of type 2DM in a given population or ethnic group. Vitamin D also has a role in insulin homeostasis and resistance. It may improve beta-cell activity and increase insulin sensitivity. Pregnancy is another condition associated with insulin resistance and hyperinsulinemia.
SGA is defined as the estimated weight of the fetus is below the 10th percentile for its gestational age, and abdominal circumference is below the 2.5th percentile. The prevalence of SGA births is approximately 8.6%–9.6% based on the data from several countries. Vitamin D has a key role in fetal growth by its interaction with parathyroid hormone and Ca2+ homeostasis.
| Materials and Methods|| |
We selected pregnant women randomly in their first trimester for this experimental study. The sample size was estimated and 200 participants were included. They attended the clinic at regular interval. Data were collected between December 2016 and October 2018. Verbal consents were obtained from each patient included in this study after explaining the nature of the study.
Ethical approval of this study was obtained from the Scientific Committee of the College of Medicine, University of Duhok, Iraq.
The earliest time of patient's selections following measurement of total circulating 25(OH) D was 7 weeks' gestation, with the target upper limit of gestation of 15 weeks gestation. All participants had singleton viable fetus confirmed by ultrasound at the time of inclusion, and all of them had VDD (<20 ng/ml). Those with preexisting medical diseases (DM and hypertension), metabolic diseases, chronic inflammatory disorders, or receiving long-term therapy for any chronic condition, or had previous history of GDM, PE, and SGA were excluded from the study. Furthermore, those participants who had more than one abortion or who were taking Vitamin D supplementation, multivitamins, aspirin, and metformin also excluded from the study.
Anthropometrics included prepregnancy weight (as recalled by the participant), current weight, and height. Body mass index (BMI) = (weight [kg]/height [m2]) was calculated for each participant according to previously reported by Deore et al. Blood pressure checked in each visit.
Assessment of circulating 25 hydroxyvitamin D and biochemical parameters
In our study, we performed random plasma glucose (RPG), it measured in each visit using the routine laboratory analysis. If the patient's RPG is >139 mg/dl (7.7 mmol/L), then the 75 g oral glucose tolerance test was done. We adopt the WHO 2013 diagnostic criteria, (2-h glucose is 153–199 mg/dl [8.5–11 mmol/L] after overnight fasting with 75 g glucose load are classified as having GDM).
Vitamin D status is assessed by measuring the prohormone 25(OH) D or (calcidiol) in serum, which reflect the Vitamin D produced cutaneously and that obtained from foods or supplements. The first reading of blood sugar was taken in the first visit, the second reading at 8–10 weeks, and the third reading in the third trimester. Urine for albumin was done in cases of newly developed hypertension to confirm PE.
Gestational age was calculated from the date of the last menstrual period and was confirmed using an ultrasound examination during the first visit. All participants answered a generalized questionnaire, which included information on age (18–35 years), parity (0–3), past medical history, medication treatment history, family history, and employment as either homemaker or employed and student.
Intervention study (Vitamin D supplementation) protocol
All participants instructed to take one tablet a day of 5000 IU of Vitamin D. The formula was Vitamin D3(cholecalciferol), (life D3) of Sunlife Company from Germany for 8–10 weeks. A 5 ml of blood was collected in the first visit, and after 10 weeks for determination of serum 25(OH)D.
Patients who completed 8–10 weeks course of Vitamin D supplementation were allowed 2 weeks free of supplementation to be followed by postintervention measurement of serum 25(OH) D values, as 25(OH) D has a half-life of approximately 2–3 weeks. If the level of Vitamin D >20 ng/ml, they maintained on 400–800 IU alone or combined with calcium or multivitamins. Some patients who still had Vitamin D level <20 ng/ml, they continue on the dose 5000 IU for another month until the level increased above 20 ng/L.
The baseline information of the patients was presented in frequency distribution either in frequency and percentage or mean and standard deviation. In addition, the rates of patients' outcome were displayed in frequency and percentage. Paired t-test was performed to compare the Vitamin D level and blood sugars before and after Vitamin D supplementation. The comparison of Vitamin D levels in patients with different outcomes were examined in independent t-test or one-way ANOVA. The null hypothesis was rejected in a P < 0.05. The statistical calculations were performed in Statistical Package for the Social Sciences version 25:00 (SPSS 25:00; IBM, Duhok city, Kurdistan Region, Iraq).
| Results|| |
Total number of study participants was 200 individuals who had satisfied inclusion criteria. The mean maternal age was 27.41 ± 4.28 (range 18–35) years, and BMI mean was 25.58 ± 2.69. Among them, 154 were homemakers and 46 were employed and student. Among participant, 20 patients had previous miscarriages (mean 0.20), 36 had a family history of DM, and 58 had a family history of hypertension. All are shown in [Table 1].
Regarding the outcomes of our patients, 4 patients (2%) only developed GDM, 14 (7%) developed PE, and 5 patients (2.5%) developed SGA as shown in [Table 2].
The Vitamin D level increase from severe deficiency, the mean was 8.41 ± 2.48 to sufficient level of mean 30.96 ± 9.60 after 2 months supplementation of 5000 IU vitamin D3/day, P value was statistically significant. At the same time, the mean blood sugar at the time of deficiency was 97.43 ± 13.84 and after supplementation was 111.18 ± 24.26, this is significant as shown in [Table 3].
|Table 3: Comparison of Vitamin D levels and random blood sugar before and after vitamin D supplementation|
Click here to view
In spite of the reduction of the risk of the SGA and DM as shown in the [Table 2], but the results were insignificant. Furthermore, the development of PE was nonsignificant. All participants with VDD have good response to vitamin D supplimentation as shown in [Table 4].
|Table 4: Comparison of vitamin D level (after supplementation) in patients with different outcomes|
Click here to view
| Discussion|| |
The prevalence of previously undiagnosed DM in Duhok governorate was 10.9% and impaired glucose homeostasis (impaired glucose tolerance and impaired fasting glucose) was 14.3%. The susceptibility of our women to high rates of GDM may be related to increased body weight (69.2%), sedentary lifestyle, and no physical activity. There was no available data on the prevalence of GDM in Duhok.
In the current study, the risk of GDM was 2%, which is compatible to the study done by Zhang et al. who confirmed that the maternal plasma 25(OH) D concentrations in early pregnancy were significantly and inversely associated with GDM risk.
Eighty-seven observational studies and 25 randomized controlled trials involving 55,859, and 2445 women, respectively, were included. These studies concluded that the low blood Vitamin D level during pregnancy was associated with a higher risk of GDM.
In cohort study of 515 pregnant women by Al-Ajlan et al. concluded a significantly higher risk of development of GDM among pregnant women having deficient Vitamin D status.
In a study of Iranian women at high risk for VDD, Hossein Nezhad et al. found that 29% of 741 women had 25(OH) D levels <15 nmol/L and the prevalence of GDM in this subgroup was higher compared to women with 25(OH) D levels ≥35 nmol/L. Another study by Wei et al. included 12 studies with 5615 participants and concluded that among women with 25(OH) D levels <50 nmol/L (20 ng/ml), there is a modest increase in odds of GDM.
A meta-analysis of 20 observational studies that comprised 9209 participants showed that women with VDD experienced a significantly increased risk for developing GDM with a little heterogeneity. A systematic review and meta-analysis to study the link between Vitamin D and gestational diabetes (2012) indicated a significant inverse relationship between serum 25(OH)D and the incidence of GDM and VDD. Furthermore, a systematic review and meta-analysis of 24 observational studies (2013) found that women with circulating 25(OH)D level <50 nmol/L (<20 ng/ml) in pregnancy experienced an increased risk of PE and GDM.
In a large population-based prospective cohort study of 655 pregnant women done by Lacroix et al. found that the low levels of 25OHD at the first trimester are an independent risk factor for developing GDM and associated with insulin resistance at the second trimester.
However, in a prospective cohort study (Spain, 2015) involving 2382 pregnant women, showed no association between maternal 25(OH)D3 concentration and risk of GDM.
Another study by Farrant et al. found Vitamin D insufficiency is common in Indian mothers but is not associated with gestational diabetes or variation in newborn size.
American College of Obstetricians and Gynecologists does not specifically list GDM as being associated with VDD, but the scientific literature suggests that women with GDM are at higher risk than normoglycemic women of low 25(OH)D levels even if the causality of the VDD – GDM association is not yet clear.
Regarding SGA, the risk was 2.5% compared to the data from several countries. In consistent to our results, Aghajafari et al. indicated a significant association between SGA infants (with small fetal growth indices) and mother's Vitamin D insufficiency. Another study done by Gernand et al. concluded that the maternal Vitamin D status in the second trimester is associated with risk of SGA among all women and in the subgroups of White and nonobese women. In observational studies, maternal VDD has been associated with risk of SGA in several general obstetric populations across the US and Europe. Another study by Wang et al. suggested that the maternal Vitamin D insufficiency is independently associated with low birth weight and high risk of SGA in term infants.
A Cochrane review reported that there is limited evidence to assess the impact of Vitamin D supplementation on SGA.
Regarding PE, in our study, there was no reduction in the risk of PE. A similar study from the USA also failed to demonstrate an association between maternal first-trimester Vitamin D levels and the subsequent development of PE after controlling for BMI.
Another study by Shand et al. found no difference in the rates of PE, gestational hypertension, preterm birth, or composite adverse pregnancy outcomes by 25OHD concentration.
Our study was incompatible with the study done by Behjat Sasan et al. who suggests that the Vitamin D supplementation therapy in pregnancy could help in reducing the incidence of gestational hypertension/PE.
Two meta-analyses including 8 and 31 studies found significantly higher risks PE in women with VDD.,
A nested case–control study conducted by Bodnar et al. found maternal VDD may be an independent risk factor for PE.
| Conclusion|| |
The findings of our study highlight the need for Vitamin D supplementation among women during pregnancy. In this study, we found the supplementation of 5000 IU of Vitamin D/day for 8–10 weeks continuously is enough to elevate the serum level of 25(OH)D >20 ng/L. The response to Vitamin D supplementation was not affected by PE and GDM. There was a decrease in the risk of GDM and SGA but no change in the risk of PE. However, VDD is a correctable state, if proven effective; Vitamin D supplementation would be substantial and likely to impact the health of both mother and offspring.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
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 One 2008;3:e3753.
Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol 2014;21:319-29.
Royal College of Obstetricians and Gynaecologists. Vitamin D in Pregnancy (Scientific Impact Paper No.43); June 2014.
Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-81.
World Health Organization Guideline. Vitamin D Supplementation in Pregnant Women. World Health Organization Guideline; 2012.
Ginde AA, Sullivan AF, Mansbach JM, Camargo CA Jr. Vitamin D insufficiency in pregnant and nonpregnant women of childbearing age in the United States. Am J Obstet Gynecol 2010;202:436.e1-8.
Mithal A, Kalra S. Vitamin D supplementation in pregnancy. Indian J Endocrinol Metab 2014;18:593-6.
Al-Musharaf S, Fouda MA, Turkestani IZ, Al-Ajlan A, Sabico S, Alnaami AM, et al.
Vitamin D deficiency prevalence and predictors in early pregnancy among Arab women. Nutrients 2018;10. pii: E489.
Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM, et al.
Maternal Vitamin D deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab 2007;92:3517-22.
van der Pligt P, Willcox J, Szymlek-Gay EA, Murray E, Worsley A, Daly RM, et al.
Associations of maternal Vitamin D deficiency with pregnancy and neonatal complications in developing countries: A systematic review. Nutrients 2018;10. pii: E640.
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 Nutr 2010;140:999-1006.
Baker AM, Haeri S, Camargo CA Jr., Espinola JA, Stuebe AM. A nested case-control study of midgestation Vitamin D deficiency and risk of severe preeclampsia. J Clin Endocrinol Metab 2010;95:5105-9.
American Diabetes Association. Gestational diabetes mellitus. Diabetes Care 2004;27(suppl 1):S88-90.
Nguyen CL, Pham NM, Binns CW, Duong DV, Lee AH. Prevalence of gestational diabetes mellitus in Eastern and Southeastern Asia: A systematic review and meta-analysis. J Diabetes Res 2018;2018:6536974.
Al-Ajlan A, Al-Musharaf S, Fouda MA, Krishnaswamy S, Wani K, Aljohani NJ, et al.
Lower Vitamin D levels in Saudi pregnant women are associated with higher risk of developing GDM. BMC Pregnancy Childbirth 2018;18:86.
Mutlu N, Esra H, Begum A, Fatma D, Arzu Y, Yalcin H, et al.
Relation of maternal Vitamin D status with gestational diabetes mellitus and perinatal outcome. Afr Health Sci 2015;15:523-31.
Saleem T, Sajjad N, Fatima S, Habib N, Ali SR, Qadir M, et al.
Intrauterine growth retardation – Small events, big consequences. Ital J Pediatr 2011;37:41.
Nam HK, Lee KH. Small for gestational age and obesity: Epidemiology and general risks. Ann Pediatr Endocrinol Metab 2018;23:9-13.
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. BMJ 2013;346:f1169.
Deore DN, Surwase SP, Masroor S, Khan ST, Kathore V. A cross sectional study on the relationship between the body mass index (BMI) and the audiovisual reaction time (ART). J Clin Diagn Res 2012;6:1466-8.
Meek CL, Murphy HR, Simmons D. Random plasma glucose in early pregnancy is a better predictor of gestational diabetes diagnosis than maternal obesity. Diabetologia 2016;59:445-52.
Rani PR, Begum J. Screening and diagnosis of gestational diabetes mellitus, where do we stand. J Clin Diagn Res 2016;10:QE01-4.
Aloia JF, Patel M, Dimaano R, Li-Ng M, Talwar SA, Mikhail M, et al.
Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. Am J Clin Nutr 2008;87:1952-8.
Gonzalez C. Vitamin D supplementation: An update.US Pharm 2010;35:58-76.
Holick MF. Vitamin D status: Measurement, interpretation, and clinical application. Ann Epidemiol 2009;19:73-8.
Al-Timimi DJ, Saleh SF. Prevalence and related factors of asymptomatic hyperglycaemia among Kurd in Duhok, Iraq. Duhok Med J 2009;3:73-83.
Zhang Y, Gong Y, Xue H, Xiong J, Cheng G. Vitamin D and gestational diabetes mellitus: A systematic review based on data free of Hawthorne effect. BJOG 2018;125:784-93.
Wei SQ, Qi HP, Luo ZC, Fraser WD. Maternal vitamin D status and adverse pregnancy outcomes: A systematic review and meta-analysis. J Matern Fetal Neonatal Med 2013;26:889-99.
Zhang MX, Pan GT, Guo JF, Li BY, Qin LQ, Zhang ZL, et al.
Vitamin D deficiency increases the risk of gestational diabetes mellitus: A meta-analysis of observational studies. Nutrients 2015;7:8366-75.
Lacroix M, Battista MC, Doyon M, Houde G, Ménard J, Ardilouze JL, et al.
Lower Vitamin D levels at first trimester are associated with higher risk of developing gestational diabetes mellitus. Acta Diabetol 2014;51:609-16.
Farrant HJ, Krishnaveni GV, Hill JC, Boucher BJ, Fisher DJ, Noonan K, et al.
Vitamin D insufficiency is common in Indian mothers but is not associated with gestational diabetes or variation in newborn size. Eur J Clin Nutr 2009;63:646-52.
Gernand AD, Simhan HN, Caritis S, Bodnar LM. Maternal Vitamin D status and small-for-gestational-age offspring in women at high risk for preeclampsia. Obstet Gynecol 2014;123:40-8.
Wang H, Xiao Y, Zhang L, Gao Q. Maternal early pregnancy Vitamin D status in relation to low birth weight and small-for-gestational-age offspring. J Steroid Biochem Mol Biol 2018;175:146-50.
De-Regil LM, Palacios C, Ansary A, Kulier R, Peña-Rosas JP. Vitamin D supplementation for women during pregnancy. Cochrane Database Syst Rev 2016;1:CD008873.
Shand AW, Nassar N, Von Dadelszen P, Innis SM, Green TJ. Maternal Vitamin D status in pregnancy and adverse pregnancy outcomes in a group at high risk for pre-eclampsia. BJOG 2010;117:1593-8.
Behjat Sasan S, Zandvakili F, Soufizadeh N, Baybordi E. The effects of Vitamin D supplement on prevention of recurrence of preeclampsia in pregnant women with a history of preeclampsia. Obstet Gynecol Int 2017;2017:8249264.
Palacios C, De-Regil LM, Lombardo LK, Peña-Rosas JP. Vitamin D supplementation during pregnancy: Updated meta-analysis on maternal outcomes. J Steroid Biochem Mol Biol 2016;164:148-55.
[Table 1], [Table 2], [Table 3], [Table 4]