Vitamin D Status May Help Explain Maternal Race and Ethnic Factors in Primary Cesarean Section Delivery – April 2020

Am J Perinatol, DOI: 10.1055/s-0040-1709494
Letter to the Editor, William B. Grant 

The paper by Stark et al reported that race or ethnicity had a significant impact on
the risk of primary cesarean delivery.[1] Compared with non-Hispanic Whites (NHWs), non-Hispanic Blacks (NHBs) had a 53% increased risk while Hispanics had a 30% increased risk. The authors identified maternal obesity, advanced maternal age, pregestational diabetes, gestational diabetes, chronic hypertension, and hypertensive disorders of pregnancy as significant factors related to failure to progress. For HNBs, nonreassuring fetal status was a significant factor but failure to progress was not. They also suggested that unmeasured factors might be driving the observed racial and ethnic differences.

A factor not considered by the authors is vitamin D status. In the period 2001 to 2004, based on the U.S. National Health and Nutrition Examination Survey data, the mean serum 25-hydroxyvitamin D [25(OH)D] concentrations for women aged 20 to 39 were: NHBs, 14 ng/mL; Mexican Americans, 20 ng/mL; and NHWs, 28 ng/mL.[2]

Several articles have reported that the risk of primary cesarean delivery was significantly correlated with 25(OH)D concentration. A study from Boston for the period 2005 to 2007, in a multivariable logistic regression analysis controlling for race and other factors, maternal 25(OH)D concentration <15 ng/mL was associated with an increased cesarean delivery rate of 284%.[3] A study in Singapore based on 25(OH)D concentrations measured at 26 to 28 weeks gestation found risk of emergency cesarean delivery for <30 ng/mL versus >30 ng/mL was increased by 90% for Chinese women and by 141% for Indian women.[4] A study in Spain found that maternal 25(OH)D concentration >30 ng/mL was associated with a 40% reduction in cesarean delivery by obstructed delivery compared with <20 ng/mL.[5]

The role of vitamin D in reducing risk of emergency cesarean-section delivery may be due primarily to the reducing risk of low blood flow to the placenta. A recent article noted that an important risk factor for emergency cesarean section births is fetal distress due to hypoxia resulting from reduced uteroplacental blood flow.[6] The authors conducted a trial of sildenafil citrate, a vasodilator also known as Viagra, given to women in early labor or undergoing scheduled induction of labor. Sildenafil citrate reduced the risk of emergency operative birth by 51% (relative risk = 0.51 [95% confidence interval, 0.33–0.73]).[6]

A search for factors linked to the use of cesarean-section delivery found additional support for diagnosis of hypertension, preeclampsia, and overweight/obesity as important risk factors.[7] High-dose vitamin D supplementation has been found to reduce arterial stiffness, a risk factor for hypertension, in overweight African Americans (AAs).[8] An open-label study found that high-dose vitamin D supplementation raising serum 25(OH)D concentrations above 40 ng/mL could reduce blood pressure among hypertensive participants by 12 to 14 mm Hg, which was enough to lower their blood pressure below the cutoffs for hypertension.[9] However, a review of clinical trials of blood pressure lowering medication during pregnancy found a 4-mm Hg reduction but no effect on risk of preeclampsia.[10] Lowering blood pressure to a greater extent might have a beneficial effect on preeclampsia and cesarean section delivery.

Another article reported that for pregnant women with type 2 diabetes mellitus, elevated hemoglobin A1c (HbA1c) was associated with increased risk of preeclampsia and cesarean section delivery.[11] Blacks have higher HbA1c than White Americans, perhaps due to environmental factors such as diet and 25(OH)D concentration as well as to genetics.[12] Vitamin D deficiency is a risk factor for type 2 diabetes mellitus based on secondary results of a vitamin D randomized controlled trial (RCT) involving prediabetics taking 4,000 IU/d vitamin D3.[13]

Preeclampsia reduces blood flow to the uterus.[14] A meta-analysis of observational studies found that 25(OH)D concentrations <20 ng/mL are associated with preeclampsia.[15] An observational study conducted in South Carolina found that pregnant women with early onset preeclampsia had lower 25(OH)D concentrations than those without: the concentrations were 17 versus 22 ng/mL for AAs and 30 versus 42 ng/mL for Whites.[16]

Obesity during pregnancy is associated with gestational diabetes, preeclampsia, induced birth, and cesarean section delivery.[17] An RCT conducted in Iran found that calcium plus vitamin D3 supplementation significantly reduced the cesarean section delivery rate for women who developed gestational diabetes (23 vs. 63%, p = 0.002).[18] A vitamin D supplementation study in Iran found that supplementing vitamin D-deficient women with at least 50,000 IU vitamin D3/month greatly reduced risk of preeclampsia and gestational diabetes.[19]

Of course other factors also increase the risk of requiring primary or emergency cesarean section delivery. Metabolic syndrome is a cluster of different risk factors including abdominal obesity, insulin resistance, high blood pressure, and high cholesterol. AA women (AAW) are prone to metabolic syndrome. A study in the United States found that in a study of 1,918 AAW, prevalence of metabolic syndrome was 47%.[20] “Older age, lower education level, low socioeconomic status, unmarried status, low physical activity level, and smoking were associated with higher prevalence of metabolic syndrome (p < 0.001). The prevalence of borderline hypertension, hypertension, diabetes, stroke, and cardiovascular diseases was significantly higher in AAW with metabolic syndrome (p < 0.001).”[20] Regardless of the cause of metabolic syndrome, vitamin D supplementation may be an efficient way to counter some of the effects of metabolic syndrome.

Vitamin D supplementation studies in South Carolina have found that supplementing pregnant women of all races/ethnicities with 4,000 IU/d vitamin D3 can raise serum 25(OH)D concentrations to >40 ng/mL with no adverse effects[21] and can significantly reduce risk of preterm delivery.[22]

Thus, there is a strong evidence that vitamin D supplementation during pregnancy sufficient to raise 25(OH)D concentrations above 30 to 40 ng/mL would have significant benefits in reducing adverse pregnancy outcomes. While some of the studies were conducted on AAs, additional studies with AAs should be conducted. Meanwhile, since there are multiple benefits of vitamin D supplementation during pregnancy and few, if any, adverse effects, all women should be advised to take vitamin D3 during pregnancy as well as before and after. Taking vitamin D while nursing helps ensure that the infant gets vitamin D.[23]

References

• 1 Stark EL, Grobman WA, Miller ES. The association between maternal race and ethnicity and risk factors for primary cesarean delivery in nulliparous women. Am J Perinatol 2019 (e-pub ahead of print). Doi: 10.1055/s-0039-1697587
• 2 Ginde AA, Liu MC, Camargo Jr CA. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med 2009; 169 (06) 626-632
• 3 Merewood A, Mehta SD, Chen TC, Bauchner H, Holick MF. Association between vitamin D deficiency and primary cesarean section. J Clin Endocrinol Metab 2009; 94 (03) 940-945
• 4 Loy SL, Lek N, Yap F. , et al; Growing Up in Singapore Towards Healthy Outcomes (GUSTO) study group. Association of maternal vitamin D status with glucose tolerance and caesarean section in a multi-ethnic Asian cohort: the growing up in Singapore towards healthy outcomes study. PLoS One 2015; 10 (11) e0142239
• 5 Rodriguez A, García-Esteban R, Basterretxea M. , et al. Associations of maternal circulating 25-hydroxyvitamin D3 concentration with pregnancy and birth outcomes. BJOG 2015; 122 (12) 1695-1704
• 6 Turner J, Dunn L, Tarnow-Mordi W, Flatley C, Flenady V, Kumar S. Safety and efficacy of sildenafil citrate to reduce operative birth for intrapartum fetal compromise at term: a phase 2 randomized controlled trial. Am J Obstet Gynecol 2020 (e-pub ahead of print). Doi: 10.1016/j.ajog.2020.01.025
• 7 Gondwe T, Betha K, Kusneniwar GN. , et al. Maternal factors associated with mode of delivery in a population with a high cesarean section rate. J Epidemiol Glob Health 2019; 9 (04) 252-258
• 8 Raed A, Bhagatwala J, Zhu H. , et al. Dose responses of vitamin D3 supplementation on arterial stiffness in overweight African Americans with vitamin D deficiency: a placebo controlled randomized trial. PLoS One 2017; 12 (12) e0188424
• 9 Mirhosseini N, Vatanparast H, Kimball SM. The association between serum 25(OH)D status and blood pressure in participants of a community-based program taking vitamin D supplements. Nutrients 2017; 9 (11) E1244
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• 11 Bashir M, Dabbous Z, Baagar K. , et al. Type 2 diabetes mellitus in pregnancy: the impact of maternal weight and early glycaemic control on outcomes. Eur J Obstet Gynecol Reprod Biol 2019; 233: 53-57
• 12 Hivert MF, Christophi CA, Jablonski KA. , et al. Genetic ancestry markers and difference in A1c between African American and White in the Diabetes Prevention Program. J Clin Endocrinol Metab 2019; 104 (02) 328-336
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• 16 Robinson CJ, Alanis MC, Wagner CL, Hollis BW, Johnson DD. Plasma 25-hydroxyvitamin D levels in early-onset severe preeclampsia. Am J Obstet Gynecol 2010; 203 (04) 366.e1-366.e6
• 17 Rodríguez-Mesa N, Robles-Benayas P, Rodríguez-López Y, Pérez-Fernández EM, Cobo-Cuenca AI. Influence of body mass index on gestation and delivery in nulliparous women: a cohort study. Int J Environ Res Public Health 2019; 16 (11) E2015
• 18 Karamali M, Asemi Z, Ahmadi-Dastjerdi M, Esmaillzadeh A. Calcium plus vitamin D supplementation affects pregnancy outcomes in gestational diabetes: randomized, double-blind, placebo-controlled trial. Public Health Nutr 2016; 19 (01) 156-163
• 19 Rostami M, Tehrani FR, Simbar M. , et al. Effectiveness of prenatal vitamin D deficiency screening and treatment program: a stratified randomized field trial. J Clin Endocrinol Metab 2018; 103 (08) 2936-2948
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• 22 McDonnell SL, Baggerly KA, Baggerly CA. , et al. Maternal 25(OH)D concentrations ≥40 ng/mL associated with 60% lower preterm birth risk among general obstetrical patients at an urban medical center. PLoS One 2017; 12 (07) e0180483
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