1. Vitamin D insufficiency, preterm delivery and preeclampsia in women with type 1 diabetes – an observational study
MARIANNE VESTGAARD1,2,3 , ANNA L. SECHER1,2 , LENE RINGHOLM1,4 , JENS-ERIK B. JENSEN5 , PETER DAMM1,3,6 & ELISABETH R. MATHIESEN1,2,3
1Center for Pregnant Women with Diabetes, Rigshospitalet, University of Copenhagen, Copenhagen, 2Department of Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, 3Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 4Steno Diabetes Center Copenhagen, Gentofte, 5Department of Endocrinology, Hvidovre Hospital, Hvidovre, and 6Department of Obstetrics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
ACTA Obstetricia et Gynecologica Scandinavica Journal Club
-Obstetrics-
October 2017
Edited by Francesco D’Antonio

2. Introduction
Preterm delivery and preeclampsia are five times more frequent in women with type 1 diabetes compared with healthy women.
Low vitamin D levels have been associated with preterm delivery in healthy women.
It has been reported that vitamin D insufficiency may increase the risk of preeclampsia although not consistently, and vitamin D supplementation seems to reduce preeclampsia risk in healthy pregnancies.
Clinical studies have demonstrated an inverse relationship between vitamin D levels and the blood pressure outside pregnancy, a mechanism that has been linked to the renin–angiotensin–aldosterone system.
Vitamin D seems to play a role in glucose metabolism, thus highlighting the need to of investigate the association between vitamin D levels and adverse pregnancy outcomes in diabetes.

3. Aim of the study
To evaluate whether vitamin D insufficiency is associated with preterm delivery and preeclampsia in women with type 1 diabetes.

4. Material and Methods Study design: Observational cohort study.
Inclusion criteria: Pregnant women with type 1 diabetes referred to the Center for Pregnant Women with Diabetes, Rigshospitalet University Hospital, before 14 completed weeks of gestation with a single living fetus, during the study periods of September 2004 to August 2006 and February 2009 to February Hydroxy-Vitamin D and HbA1c were measured in blood samples in early (median 8 weeks, range 5–14) and late (34 weeks, range 32–36) pregnancy.
Main outcome measures:
Vitamin D levels in women with compared to those who did not deliver preterm. Vitamin D insufficiency and deficiency were defined as 25-hydroxy-vitamin D <50 and <25 nmol/L, respectively.
Prevalence of preeclampsia, preterm delivery, need for antihypertensive treatment, small and large for gestational age infant and median birthweight were compared in women with and in those without Vitamin D insufficiency.

5. Material and Methods
Statistical analysis: Categorical variables were compared by chi-squared or Fisher’s exact test, as appropriate. Continuous variables were analyzed by Mann–Whitney U-test. Univariate and multivariate logistic regression analyses were conducted with preterm delivery (yes/no) or preeclampsia (yes/no) as the dependent variable and given as odds ratio (OR) and 95% CI. In the multivariate logistic regression with preterm delivery as the dependent variable, independent variables were: vitamin D insufficiency in late pregnancy (yes/no), kidney involvement at inclusion (yes/no), HbA1c (%) in late pregnancy (continuous variable) and smoking status at inclusion (yes/no).

6. Results
In women with type 1 diabetes, plasma vitamin D levels were 62 (11–142) nmol/L in early pregnancy and 57 (10141) nmol/L in late pregnancy.
Vitamin D insufficiency was present in 68 (32%) women in early pregnancy and in 73 (37%) women in late pregnancy.
Approximately half (53%) of the women who had vitamin D insufficiency in late pregnancy also had vitamin D insufficiency in early pregnancy.
In late pregnancy vitamin D deficiency (<25 nmol/L) was present in 17 (9%) women whereas a vitamin D level ≥75 nmol/L was present in 55 (28%) women.

7. Results
Preterm delivery occurred more frequently in women with vitamin D insufficiency than in women with vitamin D levels ≥50 nmol/L in late pregnancy (27% vs. 15%, p = 0.04).
Vitamin D insufficiency in early pregnancy was not associated with preterm delivery. The rate of preterm delivery in women with vitamin D insufficiency in early pregnancy compared with the remaining women was 18% vs. 22% (p = 0.59).
Women delivering preterm (n = 39, 20%) were characterized by higher HbA1c and lower vitamin D levels in late pregnancy compared with women delivering at term. Preterm delivery was most often iatrogenic.

8. Results
The prevalence of preterm delivery in women with levels of vitamin D >50 nmol/L, levels between 25 and 49 nmol/L as well as <25 nmol/L in late pregnancy.
The highest prevalence of preterm delivery was seen in the women with vitamin D levels <25 nmol/L.
Univariate logistic regression analysis showed that women with vitamin D insufficiency in late pregnancy delivered preterm twice as often as women with vitamin D levels ≥50 nmol/L (crude OR 2.1; 95% CI 1.0–4.3). After adjustment for kidney involvement at inclusion, HbA1c in late pregnancy and smoking, the adjusted OR for preterm delivery was 1.8 (95% CI 0.8–3.7).HbA1c in late pregnancy was the only independent predictor of preterm delivery (OR 3.2; 95% CI 1.5–6.7).
Neither HbA1c in early nor in late pregnancy was associated with vitamin D levels in late pregnancy. No differences in the development of preeclampsia were seen between the women with vitamin D insufficiency in early and late pregnancy, respectively, and the remaining women (8% vs. 8%, p = 0.93 and 11% vs. 6%, p = 0.25).
Univariate logistic regression analysis showed a crude OR of 1.8 (95% CI 0.9–4.1) for developing preeclampsia in women with vitamin D insufficiency in late pregnancy.

9. Results
Inflammatory markers were comparable between women with and without vitamin D insufficiency in late pregnancy.
However, women with vitamin D insufficiency in early pregnancy were characterized by slightly higher plasma IL-6 levels in comparison with women with vitamin D levels ≥50 nmol/L (1.8 vs. 1.5 ng/L, p = 0.047).
The levels of parathyroid hormone, calcium, albumin, magnesium, high-sensitivity C-reactive protein and IL-6 in the healthy women were all similar to the levels in early pregnancy in the women with type 1 diabetes (data not shown).

10. Limitations
Low power for some of the analsyes performed.
Lack of data on known potential confounders for the vitamin D level such as dietary habits, dietary supplementation, sun exposure and seasonal change.
Most of the preterm birth was iatrogenic and there was a lack of details on the indications. Therefore we were unable to perform subgroup analyses, which would have contributed to further insight on underlying etiologies.
The small number of women developing preeclampsia makes the risk of a type 2 error in the estimation of the association between vitamin D levels and preeclampsia considerable.

11. Low levels of vitamin D were not associated with preeclampsia.
Conclusion
Among women with type 1 diabetes, preterm delivery was twice as frequent in women with vitamin D insufficiency in late pregnancy in crude analysis, but the increase was nonsignificant after adjustments.
Low levels of vitamin D were not associated with preeclampsia.
Larger studies investigating whether low vitamin D levels are a risk factor for preterm delivery in women with diabetes are needed.