Vitamin D metabolism in normal and hypoparathyroid pregnancy and lactation. Case report

Plasma concentrations of vitamin D metabolites in 17 non-pregnant women, 22 pregnant women at delivery, and in eight lactating women 3 and 16 days after delivery, were compared with those in a postpartum hypoparathyroid patient treated with 1 alpha-hydroxyvitamin D (1 alpha-OHD). The mean concentration of 1,25-dihydroxyvitamin D [1,25-(OH)2 D] was 203 (SD 61) pmol/l in the pregnant, and 86 (SD 27) pmol/l in the non-pregnant women (P less than 0.0005). The levels 3 and 16 days after delivery were similar [57 (11) compared with 62 (19) pmol/l], and lower than the non-pregnant value (P less than 0.01). The 25-hydroxyvitamin D (25-OHD) concentration remained unchanged between the 3rd and 16th days after delivery, whereas the 24,25-dihydroxyvitamin D [24,25-(OH)2D] level increased from 2.7 (SD 1.8) to 3.7 (SD 2.3) nmol/l (P less than 0.025). The patient temporarily required an increased supplement of l alpha-OHD during pregnancy, but a dose which was appropriate before pregnancy resulted in marked hypercalcaemia and a rise of 1,25-(OH)2D concentration within 16 days of delivery despite lactation. The results suggest that the metabolic need for the active vitamin D metabolite 1,25-(OH)2D is increased during pregnancy and rapidly reduced during early lactation in healthy and hypoparathyroid women.     

Serum concentrations of vitamin D metabolites in vitamin D supplemented pregnant women. A longitudinal study

The serum concentrations of the vitamin D metabolites 25-OHD, 1,25-(OH)2D, 24,25-(OH)2D and 25,26-(OH)2D, and of vitamin D binding protein (DBP), were determined longitudinally in 22 vitamin D supplemented pregnant women, and in 17 age-matched non-pregnant women studied during the summer. The pregnant women had higher 25-OHD and 1,25-(OH)2D, similar 24,25-(OH)2D, and lower 25,26-(OH)2D concentrations than the non-pregnant group. The relative concentrations of 24,25-(OH)2D and 25,26-(OH)2D (expressed as the molar ratio of these metabolites to 25-OHD) were lower during pregnancy. The DBP levels were increased in pregnancy, but the calculated free fraction (i.e. not bound to DBP) of the hormonal form of vitamin D, 1,25-(OH)2D, was still persistently higher in the pregnant than in the non-pregnant women. The study suggests that a daily vitamin D supplement of 400 IU satisfies the vitamin D requirement of pregnant women living in a cool climate with limited sun exposure. The increased absolute and relative concentration of 1,25-(OH)2D and decreased relative levels of 24,25-(OH)2D and 25,26-(OH)2D further suggest that the increased intestinal calcium and phosphate absorption, which is known to occur during pregnancy, is at least partially mediated by the vitamin D endocrine system.     

Dysregulation of maternal and placental vitamin D metabolism in preeclampsia

IntroductionEpidemiology has linked preeclampsia (PET) to decreased maternal serum 25-hydroxyvitamin D3 (25(OH)D3). However, alterations in systemic and placental/decidual transport and metabolism of 25(OH)D3 during pregnancy suggest that other forms of vitamin D may also contribute to the pathophysiology of PET.MethodsIn a cross sectional analysis of normal pregnant women at 1st (n = 25) and 3rd trimester (n = 21), pregnant women with PET (n = 22), and non-pregnant female controls (n = 20) vitamin D metabolites were quantified in paired maternal serum, placental, and decidual tissue.ResultsSerum 25(OH)D3 was not significantly different in sera across all four groups. In normal 3rd trimester pregnant women serum active 1,25-dihydroxyvitamin D3 (1,25(OH)₂D3) was significantly higher than non-pregnant, normal 1st trimester pregnant, and PET women. Conversely, PET sera showed highest levels of the catabolites 3-epi-25(OH)D3 and 24,25-dihydroxyvitamin D3 (24,25(OH)₂D3). Serum albumin was significantly lower in normal 3rd trimester pregnant women and PET relative to normal 1st trimester pregnant women, but there was no change in free/bioavailable 25(OH)D3. In PET placental tissue, 25(OH)D3 and 3-epi-25(OH)D3 were lower than normal 3rd trimester tissue, whilst placental 24,25(OH)₂D3 was highest in PET. Tissue 1,25(OH)₂D3 was detectable in 1st trimester decidua, which also showed 10-fold higher 25(OH)D3 relative to paired placentae. 3-epi-25(OH)D3 and 24,25(OH)₂D3 were not different for decidua and placenta. In normal 3rd trimester pregnant women, total, free and bioavailable maternal 25(OH)D3 correlated with placental 25(OH)D3, but this was not conserved for PET.DiscussionThese data indicate that PET is associated with decreased activation, increased catabolism, and impaired placental uptake of 25(OH)D3.     

Benign obstructive myxometra: report of a case.

Serum concentrations of 25-hydroxyvitamin D (25OHD) and 24,25-dihydroxyvitamin D (24,25(OH)2D) were measured in a cross-sectional study of 94 normal pregnant women at various stages of gestation in order to assess the hormonal regulation of calcium homeostasis during gestation. The 40 week gestational period was divided into four 10 weeks quarters. 25OHD concentration were significantly below control levels (32.2 +/- 3.1 (S.E.) ng/ml) by the second quarter of pregnancy and were even lower at term. Serum levels of 24,25(OH)2D did not decrease until the fourth quarter, when the mean concentration (0.8 +/- 0.1 ng/ml) was approximately one half the control values (1.5 +/- 0.3, p less than 0.025). These data suggest that the metabolic pathways of vitamin D are altered during gestation, perhaps in response to increasing mother-to-fetus transport of calcium. There is decreased 24-hydroxylation and, in view of the lowered 25OHD levels, possibly increased production of 1,25-hydroxyvitamin D (1,25(OH)2D).     

Anticonvulsant drug therapy in human pregnancy: effects on serum concentrations of vitamin D metabolites in maternal and cord blood

Serum concentrations of the main vitamin D metabolites and of calcium, phosphate, and alkaline phosphatase were determined in each of the three trimesters of pregnancy and in simultaneously obtained maternal and cord blood at delivery in 22 epileptic women treated with diphenylhydantoin or carbamazepine alone or with a combination with one other drug. The results were compared with similarly obtained data from 22 normal pregnancies. Women in both groups received supplements of 400 IU vitamin D3 per day. All the women had 25-hydroxyvitamin D levels within the normal range for healthy adults (greater than 12 ng/ml) throughout pregnancy. The epileptic women had, however, significantly (p less than 0.05) lower median 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels and higher median 25,26-dihydroxyvitamin D values than the reference group. The 24,25-dihydroxyvitamin D concentrations did not differ significantly, but the median ratio of 24,25-dihydroxyvitamin D to 25-hydroxyvitamin D was higher in the epileptic women at the end of pregnancy (p = 0.05). The respective differences in cord serum concentrations reflected those of the mothers at delivery. Serum calcium tended to be lower during epileptic pregnancy, but none were hypocalcemic. The alkaline phosphatase and phosphate values did not consistently differ from those of the reference women. The median alkaline phosphatase level of cord serum was slightly higher in the epileptic group, but the calcium and phosphate levels were similar to the reference values. The various biochemical parameters of the carbamazepine-treated women tended to be intermediate between those of the healthy and diphenylhydantoin-treated groups. Antiepileptic drug therapy appears to affect vitamin D metabolism and calcium homeostasis during pregnancy. The derangements may not be of major clinical significance, however, in vitamin D-supplemented and normally functioning women on long-term low-dose therapy.     

Vitamin D and mineral metabolism in intrahepatic cholestasis of pregnancy

Serum concentrations of 25(OH)D, 24,25(OH)2D, 1,25(OH)2D, total protein, calcium, phosphorus, magnesium and alkaline phosphatase were measured in patients with intrahepatic cholestasis of pregnancy and in control subjects at the third trimester of pregnancy and at delivery. 25(OH)D levels of 40.5 +/- 21.5 nmol/l in the patient group were initially significantly (P less than 0.01) higher than the value of 26.3 +/- 9.5 nmol/l in the control group and decreased significantly (P less than 0.01) to 26.0 +/- 16.3 nmol/l at delivery. The levels of active 1,25(OH)2D and inactive 24,25(OH)2D did not alter in either group. Also the concentrations of calcium, phosphorus and magnesium remained unchanged in both groups. No significant differences in fetal vitamin D metabolites were observed between patients and controls, and the other analysed fetal parameters were similar in both groups. Cholestyramine and/or phenobarbital treatment had no influence on vitamin D metabolites. Since levels of 1,25(OH)2D and mineral parameters remained normal and a change in 25(OH)D concentrations was only transient, the clinical role of 25(OH)D variations cannot be substantial.     

Serum protein pattern in normal pregnancy with special reference to acute-phase reactants

Summary. The concentrations of acute-phase protein reactants, total protein, albumin and globulin fractions were measured throughout normal pregnancy in 27 women. α₁-Antitrypsin and caeruloplasmin concentrations increased gradually to reach their highest levels in the third trimester. Orosomucoid and haptoglobin showed similar patterns: higher levels in the first and third trimester with a decline around 24 weeks gestation. C-Reactive protein showed levels similar to those of non-pregnant healthy individuals (< 5 mg/1) throughout pregnancy. α₁,-, α₂ and β-Globulin concentrations increased from the first trimester towards term. γ-Globulin concentration changed little during gestation. The data obtained provide reference ranges for serum proteins in healthy pregnancy.     

Vitamin D supplementation in pregnancy: a controlled trial of two methods

A randomized study was conducted to evaluate the effects of single-dose and daily vitamin D supplementation in pregnant women during the last trimester of a winter pregnancy in the Northwest of France. The women were divided into three randomized groups: one (N = 21) was given a vitamin D2 supplement of 1000 IU/day during the last three months of pregnancy, one (N = 27) was given a single oral dose of 5 mg at the seventh month of pregnancy, and one (N = 29) acted as a control. Venous plasma samples were obtained at delivery from the women and from cord blood, and levels of calcium, 25-OHD, and 1,25(OH)2D were determined. No significant difference in plasma calcium concentration was found among the three groups, but within each group plasma calcium concentrations were higher in the cord samples than in the respective maternal samples. The levels of the two metabolites measured were consistently lower in the cord samples than in the respective maternal samples. Cord 25-OHD concentrations correlated with those of maternal plasma. No significant modification of maternal calciuria or of the birth weight of term infants was observed. 25-OHD concentrations were greater in maternal and cord plasma from treated mothers, but only a slight difference was observed between the supplemented groups. 1,25(OH)2D concentrations were not significantly different in the three groups. A single 5-mg dose of vitamin D given orally at the seventh month of pregnancy provides effective prophylaxis in the authors' region.     

Blood levels of proteinase inhibitors in pregnancy

Summary. Plasma volume, serum α₂-macroglobulin, α₁-antitrypsin, Cï inactivator and α₂-antiplasmin, and plasma antithrombin III were measured in 10 pregnant women at gestation periods of 12–14 and 37–38 weeks. The proteinase inhibitors were also measured in 10 non-pregnant healthy women. There was a significant increase in the α₁-antitrypsin concentration and significant decreases in α₂-macroglobulin and Cï inactivator, but the total circulating quantity of all the proteinase inhibitors was significantly increased.     

Circulating antithrombins in pregnancy

Summary. In a cross-sectional study circulating levels of antithrombins, antithrombin III¹α-antitrypsin and α₂-macroglobulin were measured in groups of 20 women before pregnancy, during each trimester and post partum . Blood levels of antithrombin III were signicantly lower, α¹ antitrypsin higher and %aL₂-macroglobulin no different when compared with those of the non-pregnant and puerperal states. These findings suggest that there may be not only an increase in total antithrombin production, but also a qualitative change in antithrombin'activity', the principal protein during pregnancy being α¹-antitrypsin.     

Amniotic fluid concentrations of secreted pregnancy-associated endometrial α1 and α2-globulins (α1- and α2-PEG)

Summary. The levels of pregnancy-associated endometrial α₁- and α₂-globulins (α₁- and α₂-PEG), the two major proteins synthesized and secreted by the endometrium in vitro have been assayed in 210 amniotic fluid specimens obtained at termination of pregnancy or by amniocentesis, or at delivery. α₁-PEG was undetectable until week 10 and thereafter rose to peak levels between weeks 20 and 24. Levels fell 15-fold by week 35 but substantial amounts were still present at parturition. α₂-PEG was present at highest levels during early pregnancy, at weeks 6–15, but thereafter levels rapidly fell until during weeks 31–42 α₂-PEG was detectable in only 3 of 25 specimens. During weeks 15–20, when α₂-PEG levels fell and α₁-PEG levels rose, a high correlation was observed between the week of gestation and the log of the ratios of the concentration of these proteins. These observations provide the opportunity to assess the role of endometrial and decidual dysfunction in the aetiology of pregnancy disorders.     

Alterations in vitamin D metabolites and minerals in diabetic pregnancy

Vitamin D metabolites and minerals involved in bone metabolism were studied in 68 control mothers, 14 gestational diabetics and 68 insulin-dependent diabetics during pregnancy and at delivery. 25(OH)D and 1,25(OH)2D concentrations were significantly (p less than 0.001) lower in insulin-dependent diabetics than in the control or gestational diabetic groups. A similar difference was also observed between infants. 24,25(OH)2D, phosphorus and magnesium values were similar in all groups. Corrected calcium values were significantly lower in both mothers (p less than 0.001) and infants (p less than 0.05) in the insulin-dependent group than in the other two groups. Postpartum, 10% of infants of diabetic mothers received calcium therapy. Our results show alterations in vitamin D and mineral metabolism in pregnant insulin-dependent diabetics and their newborn infants and indicate observation during pregnancy and after delivery.     

Immunohistological localization of pregnancyassociated endometrial α2-globulin (α2-PEG) in endometrial adenocarcinoma and effect of medroxyprogesterone acetate

Summary. Endometrium from postmenopausal women with endometrial adenocarcinoma was examined immunohistochemically using a monoclonal antibody to pregnancy-associated endometrial α₂-globulin (α₂-PEG), the major secretory protein of the glandular epithelium during the late luteal phase of the menstrual cycle and early pregnancy. Specimens were obtained at initial diagnostic curettage and at hysterectomy after medroxyprogesterone acetate (MPA) therapy. α₂-PEG was not detected in any malignant tissue irrespective of histological differentiation. Non-malignant endometrium obtained in association with malignant tissue was negative for α₂-PEG before treatment although after MPA therapy all specimens obtained exhibited marked α₂-PEG localization in glands. In four specimens endogenous alkaline phosphatase was observed consistently only in the malignant endometrium. Malignant endometrium does not appear to synthesize α₂-PEG nor is its synthesis induced by an oral progestogen, so that it does not represent a useful marker for endometrial carcinoma. Non-malignant endometrium in postmenopausal women appears to be fully capable of α₂-PEG production after stimulation with an oral progestogen.     

Amerlex free triiodothyronine and free thyroxine levels in normal pregnancy

Summary. Free triiodothyronine (FT₃) and free thyroxine (FT₄) were measured in 159 women during normal pregnancy and compared with non-pregnancy reference ranges for these hormones. FT₃ values fell from the reference level of 6·34 (SD 1·06) pmol/l to 3·87 (SD 0·54) pmol/l in the 3rd trimester; corresponding figures for FT₄ were: reference 16·92 (SD 2·97) pmol/l, 3rd trimester 11·29 (SD 2·01) pmol/l. There were no significant changes in the 1st trimester; 4% and 69% of FT₃ results in the 2nd and 3rd trimesters respectively fell below the reference range of mean ±2 SD. The corresponding findings for FT₄ were 4% and 42%. FT₃ correlated reasonably well with total T₃ ( r =0·90) and was acceptably precise (within-batch CV 2·1% at 5·6 pmol/l, between-batch CV between 3·1% and 4·7% at six levels).     

Can the fetus regulate its calcium uptake?

Summary. To investigate the role of the fetus in vitamin D metabolism concentrations of vitamin D metabolites, 25(OH)D, 24,25(OH)2D and 1,25(OH)2D, were measured in human umbilical artery and vein. There were no differences between artery and vein in 25(OH)D and 24,25(OH)2D levels. 1,25(OH)2D concentrations were statistically significantly higher in the artery than in the vein. It has been shown in animal experiments that 1,25(OH)2D is an important factor in the maintenance of the placental calcium gradient. We suggest that the fetus actively produces 1,25(OH)2D and hence has the capacity to control its calcium influx.     

Can the fetus regulate its calcium uptake?

To investigate the role of the fetus in vitamin D metabolism concentrations of vitamin D metabolites, 25(OH)D, 24,25(OH)2D and 1,25(OH)2D, were measured in human umbilical artery and vein. There were no differences between artery and vein in 25(OH)D and 24,25(OH)2D levels. 1,25(OH)2D concentrations were statistically significantly higher in the artery than in the vein. It has been shown in animal experiments that 1,25(OH)2D is an important factor in the maintenance of the placental calcium gradient. We suggest that the fetus actively produces 1,25(OH)2D and hence has the capacity to control its calcium influx.     

Blood levels of proteinase inhibitors in pre-eclampsia

Summary. The blood levels of α₂-macroglobulin, α₁-antitrypsin, CT inactivator, antithrombin III and α₂-antiplasmin were measured in 18 primigravidae with moderate or severe pre-eclampsia and in 18 gestation-matched primigravidae with uncomplicated pregnancy. The mean levels of the proteinase inhibitors did not differ between the pre-eclampsia and uncomplicated pregnancy groups.     

Follicular fluid α1-antitrypsin—correlation with fertilizing capacity of oocytes

Summary. Follicular fluid and serum concentrations of α-antitrypsin (α₁-AT) were determined by radial immunodiffusion in 72 samples obtained from 33 infertile women undergoing in-vitro fertilization and embryo transfer. A statistically significantly lower concentration of α₁-AT was found in follicular fluids from which mature oocytes were recovered (mean 1.52, SE 0.06 g/l) than in those yielding immature oocytes (mean 2·96, SE 0·22 g/l). There was also a significantly higher rate of fertilization (85%) for oocytes from follicular fluids with α₁-AT concentrations of ≤2·0 g/l than for those obtained when the α₁-AT concentration was >2·0 g/l (only 25%). The mean follicular fluid α₁-AT concentration (1 ·52, SE 0·06 g/l) of follicles yielding mature oocytes was significantly lower than the relevant mean serum concentration (3·17, SE 0·10 g/l). There was, however, no significant difference between follicular and serum concentration of α₁-AT in the group yielding immature oocytes or in the serum concentrations between the different oocyte maturity groups. The measurement of follicular α₁-AT may be a useful adjunct in predicting which oocytes are mature and likely to be fertilized.     

Higher prevalence of vitamin D deficiency in German pregnant women compared to non-pregnant women

Purpose

Adequate vitamin D status is crucial for normal development of the fetus and for maternal health. As data on vitamin D status (25-hydroxyvitamin D, 25(OH)D) in German women of different states of pregnancy were not available, this study compared the vitamin D status of German women in all trimesters of pregnancy with that of non-pregnant women.

Methods

The study sample of 858 women (18–45 years) was recruited from April 2013 to March 2015 as a part of the cross-sectional Germany-wide VitaMinFemin study. Serum 25(OH)D levels were determined using chemiluminescence immunoassay.

Results

A total of 78.1% of the pregnant women and 53.9% of the non-pregnant women had a vitamin D status <50.0 nmol/L (p < 0.001). In pregnant women, the multivariate binary analysis showed that winter [odds ratio (OR) 13.5], longitude of residence between 6.3°E and 8.9°E (OR 2.0) or 9.0°E and 10.9°E (OR 2.3) and third trimester (OR 2.3) were associated with a higher risk of vitamin D status <25.0 nmol/L, whereas increasing age per one year (OR 0.9) with a lower risk. Compared with non-pregnant women, pregnant women were 3.7 times more likely to have a vitamin D status <25.0 nmol/L.

Conclusion

A low vitamin D status is prevalent among German pregnant women and should be improved to supply mother and fetus adequately.

     

Association of Vitamin D with outcome after intra cytoplasmic sperm injection

Objective: To observe effects of vitamin D levels on pregnancy outcome after intra cytoplasmic sperm injection (ICSI).

Method: It was a cross-sectional study conducted in Australian Concept Infertility Medical Center from July 2011 to August 2014. Estimation of 25-hydroxy cholecalciferol (25-OHD) of consented females (252) was done before treatment protocol for ICSI. Results of β hCG performed 14 days after embryo transfer categorized groups; Pregnant with ß hCG more than 25?IU/mL and rest included in non-pregnant group. Both groups were compared by independent sample t-test and Pearson’s Chi Square test. Binary Logistic Regression Analysis was used to estimate odds ratio of pregnancy outcome with its predictors including Vitamin D.

Results: The mean value of 25-OHD, number of oocytes, fertilized oocytes and endometrial thickness was significantly higher in pregnant women. A significant positive association of 25-OHD with clinical pregnancy and thickness of endometrium was observed. After adjustment with female age and BMI, positive association of vitamin D with endometrial thickness was observed.

Conclusion: Deficiency of 25-OHD in females hinders the accomplishment of optimal endometrial thickness required for implantation of embryo after ICSI. The improvement in vitamin D status can thus improve success results in assisted reproductive clinics.