Increased Incidence of Gestational Diabetes in Women Receiving Prophylactic 17α-Hydroxyprogesterone Caproate for Prevention of Recurrent Preterm Delivery

Abstract

A recent study showed that 5% of pregnant white women and 29% of pregnant blacks in the northeastern United States had vitamin D deficiency, defined as a serum level of 25-hydroxyvitamin D [25(OH)D] less than 37.5 nmol/liter. About half of women in both groups had evidence of vitamin D insufficiency, with 25(OH)D levels of 37.5-80 nmol/liter. These findings are ascribed both to a lack of adequate solar exposure and a low oral intake of vitamin D even when a 400-IU supplement is taken. The racial disparity in preeclampsia suggests that vitamin D may be a relevant factor. This nested case-control study enrolled nulliparous pregnant women with singleton pregnancies who were followed from before 16 weeks' gestation to delivery in the years 1997-2001. Of 274 women in the study, 55 developed preeclampsia, defined as had new-onset hypertension and proteinuria developing after 20 weeks' gestation.Women with preeclampsia were older than those without it and likelier to be non-Hispanic white, married, more educated, nonsmokers, and overweight when pregnancy began. Adjusted serum 25(OH)D levels in early pregnancy were 15% lower in women who later developed preeclampsia than in control subjects. Maternal serum levels of 25(OH)D below 37.5 nmol/liter in early pregnancy were associated with a 5-fold increase in the risk of developing preeclampsia, independently of race/ethnicity, season of the year, gestational age at sampling, prepregnancy body mass index, and educational level. Adjusting for calcium intake altered the findings only slightly. After adjusting for several possible confounding factors, a 50-nmol/liter decline in serum 25(OH)D more than doubled the risk of preeclampsia. The adjusted odds ratio was 2.4 with a 95% confidence interval of 1.1-5.4. The disparity in maternal vitamin D levels persisted at the time of delivery. Cord blood serum levels of 25(OH)D were significantly lower in newborn infants whose mothers were preeclamptic. These infants were twice as likely as those whose mothers were not preeclamptic to have a serum 25(OH)D level below 37.5 nmol/liter after adjusting for confounding factors. None of the associations was influenced by maternal race or ethnicity.These findings suggest that maternal vitamin D insufficiency in early pregnancy is an independent risk factor for preeclampsia. If these results are confirmed, vitamin D supplementation in early pregnancy could be an effective and safe means of preventing preeclampsia. EDITORIAL COMMENT(The production and metabolism of vitamin D is complex. It can either be synthesized in the skin as a result of exposure to ultraviolet light or be absorbed through the gut. It is then 25-hydroxylated in the liver. 25-Vitamin D-25(OH)D-is the major form of stored and circulating vitamin D, the latter of which is almost all protein bound, most to vitamin D binding protein, some to albumin, with only 0.03% free. In the kidney, 25(OH)D is hydroxylated again to form 1,25(OH) 2 D, which is the most metabolically active form of vitamin D, promoting calcium absorption from t...

Basal Insulin Requirements after Progesterone Treatment in a Type 1 Diabetic Pregnant Woman

“…Exogenous progesterone decreases insulin sensitivity with the subsequent development of hyperglycemia in rodents (14,20), and the use of 17-OHPC to prevent recurrent preterm delivery is associated with an increased risk of developing glucose intolerance and gestational diabetes mellitus in humans (16,17). In addition, the levels of homeosta-sis model of insulin resistance (HOMA-IR) increase during the luteal phase of the menstrual cycle in association with increases in the serum progesterone levels in humans (23).…”

“…Recent studies have shown a correlation between high progesterone levels and glucose intolerance (14,(16)(17)(18)(19)(20)(21)(22)(23). Exogenous progesterone decreases insulin sensitivity with the subsequent development of hyperglycemia in rodents (14,20), and the use of 17-OHPC to prevent recurrent preterm delivery is associated with an increased risk of developing glucose intolerance and gestational diabetes mellitus in humans (16,17).…”

“…Among these hormones, progesterone has been reported to impair the insulin suppression of hepatic glucose production, insulin sensitivity in muscle and adipose tissue and insulin secretion from the pancreas (10)(11)(12)(13)(14)(15). It has recently been reported that progesterone treatment for the prevention of recurrent preterm delivery increases the incidence of glucose intolerance and gestational diabetes (16,17). However, there have been few reports evaluating the influence of progesterone treatment on glucose tolerance in diabetic pregnant women.…”

The role of progesterone in maternal and fetal medicine

“…Side effects reported in the literature include pain, swelling, pruritis and nodule formation at the injection site, urticaria, nausea and vomiting, mood swings, bloating, abdominal pain, depression, nervousness, sleep disorder and tiredness, dizziness, fever, flu-like symptoms, upper respiratory infection, urinary tract infection, yeast infection, asthma, acne and pain in the joints, back and leg [29,52]. Weekly 17 OHP-C prophylaxis has also been linked with an increased risk of gestational diabetes mellitus in women with a history of spontaneous preterm birth (odds ratio 2.9, 95% CI 2.1-4.1) [53].…”

Increased doses of vaginal progesterone for the prevention of preterm birth in twin pregnancies: a randomised controlled double‐blind multicentre trial

“…Although there were no differences in the treatment compliance rate between the three groups studied, a small percentage of women in each group did not complete the study (P = NS). The side effects of progestogens are poorly reported, except that intramuscular 17P appears to raise the risk for gestational diabetes, 20 and oral natural progesterone, given in very high doses (600-1200 mg/day), may induce liver dysfunction. 21,22 In our trial, no serious systemic adverse effects were encountered, the local tolerance was good in all but one woman and the rate of gestational problems was not higher in progesterone-treated women, except for Results expressed as means ± standard deviations or n (%).…”