Mode of delivery and maternal vitamin D deficiency: an optimized intelligent Bayesian network algorithm analysis of a stratified randomized controlled field trial

In the present study, we explored various influential factors related to the association between serum concentrations of 25(OH)D at delivery and mode of delivery using a BN approach. This method has several advantages, including the ability to manage missing data and collinear data effectively^41,42 as well as the capacity to handle complex problems with uncertainties and associations^18,43. Based on our investigation, we report a significant association between vitamin D levels and the mode of delivery. Specifically, our findings indicate that women with moderate and severe vitamin D deficiency had increased odds of undergoing cesarean section compared to those with normal levels of this essential nutrient. Furthermore, our analysis revealed an indirect effect of vitamin D status on pregnancy outcomes, as serum concentrations of 25(OH)D at delivery were positively correlated with the incidence of preeclampsia and gestational age. Importantly, we identified two critical factors that impact 25(OH)D values at delivery: baseline vitamin D concentrations and receiving vitamin D supplementation during pregnancy. Additionally, we found that the type of residence (house vs apartment) was associated with differences in vitamin D levels. Taken together, our results demonstrate the importance of monitoring and maintaining optimal vitamin D levels during pregnancy for optimal maternal and fetal health outcomes.

Previous studies have evaluated the relationship between maternal vitamin D status and mode of delivery using various statistical methods, yielding inconsistent findings^{12,13,14,15,16,17,29,30,31,32}. Many studies have utilized regression models with and/or without adjustment for potential confounding variables, documenting an increased incidence of cesarean section in mothers with vitamin D deficiency^{12,13,14,15,16,17}. For example, after controlling for factors such as race, age, education level, insurance status, and alcohol use, a cross-sectional study on 253 American women revealed that participants with 25(OH)D levels less than 37.5 nmol/liter had almost four times the odds of cesarean delivery compared to those with levels of 25(OH)D 37.5 nmol/liter or greater¹². Another cross-sectional study on 200 Indian pregnant women with singleton pregnancies showed a higher prevalence of hypovitaminosis D among mothers who underwent cesarean delivery compared to those who delivered vaginally (92% of women with vitamin D deficiency and 6% with insufficiency versus 85.6% with deficiency and 10.8% with insufficiency)¹⁴. A case–control study of 60 Danish women demonstrated a significant association between serum 25(OH)D levels and an increased risk of emergency cesarean section due to dystocia, highlighting the importance of vitamin D in the preparation of the uterus muscles and smooth muscle contractility during normal vaginal delivery⁴⁴. Similarly, another study on 2,251 low-income pregnancies demonstrated that after adjusting for energy intake, other nutrients, and other potentially confounding variables, women with vitamin D deficiency had a two-fold increased risk of cesarean delivery due to prolonged labor compared to those with sufficient serum concentrations⁴⁵. Additionally, a cross-sectional study of Iranian women with singleton pregnancies aged 15–45 years suggested that vitamin D deficiency was associated with a higher rate of cesarean delivery and other adverse maternal and neonatal outcomes¹³. Data from a multi-ethnic Asian cohort study of 940 women showed that Chinese and Indian women with 25 (OH) D inadequacy had higher odds ratios of emergency cesarean Sect. (1.9 and 2.41-fold, respectively) than those with sufficient values. Although this study reported an inverse association between maternal 25 (OH)D concentrations and fasting plasma glucose, there was no association between vitamin D insufficiency and risk of GDM in the overall cohort or within any ethnic group¹⁶. A prospective study of 995 singleton pregnancies found that after adjusting for maternal age, BMI, racial origin, smoking, method of conception and season of blood testing, first-trimester maternal serum levels of 25(OH)D were similar between women who delivered vaginally and those required elective or emergency caesarean delivery²⁹. However, it is important to note that although levels of 25(OH)D in the first trimester were similar among all participants, those with declining vitamin levels during pregnancy may have a higher risk of cesarean delivery than those who maintain their vitamin D levels more effectively. Data from a prospective cohort study of 1153 low-income and minority gravidae revealed that after adjustment for age, parity, ethnicity, smoking, BMI, gestation, and season at entry, the cesarean delivery risk was significantly increased for women with vitamin D deficiency, but not for those with vitamin D insufficiency. The authors found that vitamin D deficiency was associated with a two-fold increased risk of cesarean delivery due to prolonged labor¹⁷. However, some investigations report no significant association between 25(OH)D and mode of delivery^29,30,31,32. For example, a study on 461 Nigerian pregnant women found no significant differences between study groups based on 25(OH)D levels (normal, insufficient, and deficient) regarding the rate of cesarean delivery or other pregnancy complications such as preeclampsia, GDM, and preterm delivery³⁰. Similarly, a cross-sectional study of 154 Turkish pregnant women showed no significant difference in the rate of cesarean delivery between women with serum vitamin D levels < 15 ng/ml compared to those with values > 15 ng/ml³¹. Conflicting results among studies could be attributed to limitations such as small sample size, lack of adjustment for potential confounders, and measurement of vitamin D in the first trimester.

The mechanisms underlying the association between 25(OH)D deficiency and an increased risk of cesarean section are complex and require further investigation. One potential explanation for this association is the presence of vitamin D receptors in skeletal muscle⁴⁶, which can lead to proximal muscle weakness⁴⁷. and suboptimal muscle function and strength in individuals with vitamin D deficiency^3,47. Additionally, calcium levels, which are regulated by 25(OH)D, play a critical role in smooth muscle performance during labor initiation¹⁸. Adequate levels of serum calcium are necessary for initiating labor, and vitamin D deficiency may negatively impact both skeletal muscle and smooth muscle strength, leading to specific etiologies of cesarean delivery such as CPD or failure to progress¹². Vitamin D may affect myometrial contractility via two pathways: involving the intracellular vitamin D receptor and changes in the calcium metabolism⁴⁴. Invitro studies have demonstrated that vitamin D regulates contractile proteins in myometrial cells⁴⁸. Our analysis predicted that 44.86% of pregnant women will undergo cesarean section due to prolonged labor. Thus, maternal vitamin D deficiency at delivery might increase the probability of cesarean section by reducing the ability to push and more complicated and extended labor.

Moreover, maternal vitamin D deficiency during pregnancy and at delivery has been implicated in the pathogenesis of some maternal medical conditions, including preeclampsia, GDM, and preterm delivery, which can be associated with a higher risk of cesarean Sect.^8,9. A recent systematic review and meta-analysis reported a strong link between maternal vitamin D deficiency and severe preeclampsia, and vitamin D supplementation may be beneficial in preventing this pregnancy complication⁴⁹. Vitamin D deficiency is also associated with many risk factors for endothelial dysfunction and vascular health impairment¹⁹. On the other hand, adequate vitamin D intake can maintain calcium homeostasis, which is inversely correlated with blood pressure⁵⁰ and may directly suppress the proliferation of vascular smooth muscle cells. Vitamin D may also play a critical role in blood pressure control by regulating the renin-angiotensin system⁵¹. Additionally, vitamin D can modulate the synthesis of adipokines related to endothelial and vascular health⁵². Vitamin D concentration can affect glucose homeostasis via various mechanisms, such as improving the insulin sensitivity of target cells (liver, skeletal muscle and adipose tissue), improving and protecting β-cell function, and reducing insulin resistant through immunoregulatory and anti-inflammatory effects^20,21. Women with vitamin D deficiency might be at risk for GDM²². Moreover, vitamin D can influence the pathophysiology of preterm delivery through inflammation and immunomodulation processes; pregnant women with vitamin D deficiency might be susceptible to infection, which is an important predisposing factor for preterm delivery¹⁰. A meta-analysis of 10 studies including 10,098 participants showed that maternal serum concentrations of 25(OH)D levels less than 20 ng/mL were significantly associated with an increased risk of preterm delivery⁵³. Our study based on the structure of BN revealed that moderate and severe vitamin D deficiencies at delivery significantly increase the probability of pregnancy complications like cesarean section, preeclampsia, and preterm delivery, but not GDM. Nevertheless, the absence of a significant relationship between 25(OH)D status and GDM in our study could be due to the conditionally dependent approach of the model. Therefore, no significant relationship between vitamin D concentrations and GDM given the city does not necessarily imply that the relationship does not exist overall. Our findings indicated that fetal distress contributed to approximately 4.3% of cesarean section cases. Fetal distress can partly reflect maternal medical conditions, such as preeclampsia, gestational diabetes, and preterm delivery, which are indirectly associated with cesarean Sect.^23,24,25. Additionally, previous studies have demonstrated that GDM can increase fetal weight and macrosomia, leading to an elevated risk of elective cesarean section and emergency cesarean due to CPD and dystocia²⁸.

We utilized logistic regression models, the most commonly used statistical approach in medical research, to estimate the OR of cesarean section in women with maternal vitamin D deficiency after adjusting confounders. Our results from logistic regression provided similar to those obtained from the BN. In particular, our unadjusted logistic regression model (model 1) showed higher OR for cesarean section in pregnant women with moderate and severe vitamin D deficiency compared with those with normal vitamin D levels. This finding remained significant even after adjusting for other factors such as vitamin D at baseline and city (intervention with vitamin D supplementation) (model 2), vitamin D at baseline, city, and residence type (model 3), and vitamin D at baseline, city, residence type, education, and age at current pregnancy (model 4). Additionally, we found that the AUC of all these models was comparable to that of the BN approach.

To the best of our knowledge, this is the first population-based study globally to illustrate the relationship between the association between 25(OH)D concentrations at delivery and mode of delivery using both BN and logistic regression models. Our study has several strengths, including its population-based design, measurement of 25(OH)D at both baseline and delivery, and the use of appropriate statistical methods for data analysis. These methods have been shown to be superior to traditional regression analysis in various fields of epidemiological studies^18,41,42,43.

However, several limitations should be kept in mind when interpreting our findings. Firstly, we could not apply the liquid chromatography technique as the gold standard method for measuring the circulating levels of 25(OH)D, due to inaccessibility. Nevertheless, the ELISA technique is reliable when performed by expert staff⁵⁴. Secondly, there were variations in vitamin D supplementation intake among the study population. However, our results suggest that vitamin D was the critical determinant of the mode of delivery, regardless of vitamin D at baseline and intervention. Additionally, we had no data on UVB exposure during pregnancy trimesters, calcium intake, sartorial habits, and skin types. Thirdly, our study population was limited to two cities mainly composed of the Persian ethnic group, thus generalizing our results to other ethnicities should be approached with caution. Fourthly, we could not measure myometrial dysfunction by contraction frequency or Montevideo units due to a lack of data. Finally, since the cesarean rate is very high in many countries, including Iran, our findings may not be generalizable to populations with a lower cesarean rate.

In conclusion, our study highlights the adverse effects of maternal vitamin D deficiency on mode of delivery, both directly and indirectly, through maternal complications such as preeclampsia and preterm delivery, leading to a higher probability of cesarean section. Therefore, screening all pregnant women for serum concentrations of 25(OH)D can help identify mothers at risk of adverse pregnancy outcomes.