Vitamin D in pregnancy: current perspectives and future directions

As neonatal vitamin D status is determined by circulating maternal 25-hydroxyvitamin D [25(OH)D] concentrations, prevention of maternal vitamin D deficiency during pregnancy is essential for the avoidance of neonatal deficiency. However, a high prevalence of vitamin D deficiency has been extensively reported among gravidae and neonates from ethnic minorities and white populations resident at high latitude. Currently, regulatory authorities recommend vitamin D intakes for pregnant women that are similar to non-pregnant adults of the same age, at 10–15 µg/day (400–600 IU), to meet 25(OH)D thresholds of 25–50 nmol/liter. The lack of pregnancy-specific dietary recommendations is due to inadequate data indicating whether nutritional requirements for vitamin D during pregnancy differ from the non-pregnant state. In addition, there are few dose–response studies to determine the maternal 25(OH)D response to vitamin D intake throughout pregnancy at high latitude. These data are also required to determine vitamin D requirements during pregnancy for prevention of neonatal deficiency, an outcome which is likely to require a higher maternal 25(OH)D concentration than prevention of maternal deficiency only. With regard to the impact of vitamin D on perinatal health outcomes, which could guide pregnancy-specific 25(OH)D thresholds, dietary intervention studies to date have been inconsistent and recent systematic reviews have highlighted issues of low quality and a high risk of bias as drawbacks in the trial evidence to date. Many observational studies have been hampered by a reliance on retrospective data, unclear reporting, suboptimal clinical phenotyping and incomplete subject characterization. Current investigations of vitamin D metabolism during pregnancy have potentially exciting implications for clinical research. This paper provides an update of current dietary recommendations for vitamin D in pregnant women and a synopsis of the evidence relating vitamin D status with maternal and infant health

Exploring the concept of functional vitamin D deficiency in pregnancy: impact of the interaction between 25-hydroxyvitamin D and parathyroid hormone on perinatal outcomes

Background: Associations of vitamin D with perinatal outcomes are inconsistent and few studies have considered the wider calcium metabolic system. Objectives: We aimed to explore functional vitamin D deficiency in pregnancy by investigating associations between vitamin D status, parathyroid hormone (PTH), and perinatal outcomes. Design: SCOPE (Screening for Pregnancy Endpoints) Ireland is a prospective cohort study of low-risk, nulliparous pregnant women. We measured serum 25-hydroxyvitamin D [25(OH)D] and PTH at 15 wk of gestation in 1754 participants. Results: Mean ± SD 25(OH)D was 56.6 ± 25.8 nmol/L (22.7 ± 10.3 ng/mL) and geometric mean (95% CI) PTH was 7.84 pg/mL (7.7, 8.0 pg/mL) [0.86 pmol/L (0.85, 0.88 pmol/L)]. PTH was elevated in 34.3% of women who had 25(OH)D <30 nmol/L and in 13.9% of those with 25(OH)D ≥75 nmol/L. Whereas 17% had 25(OH)D <30 nmol/L, 5.5% had functional vitamin D deficiency, defined as 25(OH)D <30 nmol/L with elevated PTH. Elevated mean arterial pressure (MAP), gestational hypertension, pre-eclampsia, and small-for-gestational-age (SGA) birth were confirmed in 9.2%, 11.9%, 3.8%, and 10.6% of participants, respectively. In fully adjusted regression models, neither low 25(OH)D nor elevated PTH alone increased the risk of any individual outcome. The prevalence of elevated MAP (19.1% compared with 9.7%) and SGA (16.0% compared with 6.7%) were highest (P < 0.05) in those with functional vitamin D deficiency compared with the reference group [25(OH)D ≥75 nmol/L and normal PTH]. The adjusted prevalence ratio (PR) and RR (95% CIs) for elevated MAP and SGA were 1.83 (1.02, 3.27) and 1.53 (0.80, 2.93), respectively. There was no effect of functional vitamin D deficiency on the risk of gestational hypertension (adjusted RR: 1.00; 95% CI: 0.60, 1.67) or pre-eclampsia (adjusted RR: 1.17; 95% CI: 0.32, 4.20). Conclusion: The concept of functional vitamin D deficiency, reflecting calcium metabolic stress, should be considered in studies of vitamin D in pregnancy. The SCOPE pregnancy cohort is registered at http://www.anzctr.org.au as ACTRN12607000551493

Interactions between vitamin D status, calcium intake and parathyroid hormone concentrations in healthy pregnant women

Emerging evidence highlights the potential of the vitamin D and calcium metabolic system to impact pregnancy outcomes and adverse effects of vitamin D-parathyroid hormone (PTH) interactions on perinatal health have been reported(1,2). PTH concentrations reflect homeostasis in the calcium metabolic system, and can be impacted by calcium intake as well as circulating 25-hydroxyvitamin D [25(OH)D] concentrations, reflecting vitamin D status. Little explored in pregnancy, we aimed to examine the relative importance of vitamin D status and calcium intake on PTH concentrations among healthy pregnant women. This was a cross-sectional analysis of 142 white-skinned participants of mean (SD) 14 (2) weeks’ gestation at baseline of a dose-response randomised controlled trial of vitamin D [NCT02506439](3). Serum 25(OH)D was measured by a CDC-accredited LC-MS/MS method and calcium intakes were estimated using a validated quantitative food frequency questionnaire(4). Serum albumin-corrected calcium and intact PTH were measured by colorimetric assay (Randox Laboratories Ltd.) and ELISA (MD Biosciences Inc.), respectively. Serum 25(OH)D was stratified at 50 nmol/L and calcium intakes by < 800, 800–1000 and ≥ 1000 mg/day according to the Institute of Medicine(5). After log transformation of PTH, we used Pearson’s correlations and two-way ANOVA to explore effects of calcium intakes and 25(OH)D on PTH. Geometric mean (95% CI) PTH concentration was 9·24 (8·37, 10·19) pg/mL. Mean (SD) 25(OH)D and calcium intake were 54·9 (22·6) nmol/L and 1182·5 (485·8) mg/day, respectively. 44% of participants had a 25(OH)D < 50 nmol/L and calcium intake was < 800 and ≥ 1000 mg/day in 22% and 63%, respectively. PTH was inversely correlated with vitamin D status (r = −0·311, P < 0·01), but not calcium intake (r = −0·087) or serum calcium (r = 0·057). There was no evidence of an interaction between calcium intake and 25(OH)D on PTH concentration (P = 0·941). There was a statistically significant main effect of serum 25(OH)D (P = 0·025) but not calcium intake (P = 0·822) on PTH. To conclude, in this group of healthy pregnant women with largely sufficient calcium intake, vitamin D status, but not calcium intake was important for maintaining calcium homeostasis

Adherence to the infant vitamin D supplementation policy in Ireland

Purpose: From September 2010 until November 2019, Ireland’s infant vitamin D supplementation policy recommended administration of 5 μg/day of vitamin D3 from birth to 12 months to all infants, regardless of feeding method. This study aims to examine policy adherence. Methods: In the prospective COMBINE birth cohort study (recruited 2015–2017), detailed longitudinal supplement data were examined in 364 infants across the first year of life, according to product type, dose, frequency, and duration. Vitamin D supplement use at 2, 6, and 12 months in COMBINE was compared with the BASELINE cohort (recruited 2008–2011, n = 1949). Results: In COMBINE, 92% of infants initiated supplementation at birth. The median supplementation duration was 51 (40, 52) weeks, with a range of 3–52 weeks. While supplementing, most parents (92%) used an exclusive vitamin D supplement as recommended and 88% gave 5 µg/day. Half (51%) gave vitamin D daily and a further 33% supplemented at least 3–6 times/week. Overall, 30% adhered fully to the policy, providing 5 µg vitamin D3 daily from birth to 12 months. A further 16% were broadly compliant, giving 5 µg frequently for the full 12 months. Vitamin D supplement use at 2, 6, and 12 months in COMBINE was 93%, 89%, and 72%, considerably higher than our earlier BASELINE cohort at 49%, 64%, and 44% at the same time points (all P < 0.001). Conclusions: We report a high level of vitamin D supplementation initiation at birth, with full to broad policy adherence among more than half of infants. There is scope to improve overall compliance by focusing on supplementation frequency

Tirzepatide for the treatment of adults with type 2 diabetes: an endocrine perspective

Tirzepatide is a novel glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 (GLP-1) receptor agonist approved in the United States as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes and under investigation for use in chronic weight management, major adverse cardiovascular events and the management of other conditions, including heart failure with preserved ejection fraction and obesity and non-cirrhotic non-alcoholic steatohepatitis. The Phase 3 SURPASS 1-5 clinical trial programme was designed to assess efficacy and safety of once-weekly subcutaneously injected tirzepatide (5, 10 and 15 mg), as monotherapy or combination therapy, across a broad spectrum of people with type 2 diabetes. Use of tirzepatide in clinical studies was associated with marked reductions of glycated haemoglobin (−1.87 to −2.59%, −20 to −28 mmol/mol) and body weight (−6.2 to −12.9 kg), as well as reductions in parameters commonly associated with heightened cardiometabolic risk such as blood pressure, visceral adiposity and circulating triglycerides. In SUPRASS-2, these reductions were greater than with the GLP-1 receptor agonist semaglutide 1 mg. Tirzepatide was well tolerated, with a low risk of hypoglycaemia when used without insulin or insulin secretagogues and showed a generally similar safety profile to the GLP-1 receptor agonist class. Accordingly, evidence from these clinical trials suggests that tirzepatide offers a new opportunity for the effective lowering of glycated haemoglobin and body weight in adults with type 2 diabetes

A detailed exploration of early infant milk feeding in a prospective birth cohort study in Ireland: combination feeding of breast milk and infant formula and early breast-feeding cessation

Breast-feeding initiation and continuation rates in the UK and Ireland are low relative to many European countries. As a core outcome of the prospective Cork Nutrition and Development Maternal-Infant Cohort (COMBINE) study (Cork, Ireland), we aimed to describe infant milk feeding practices in detail and examine the prevalence and impact of combination feeding of breast milk and infant formula on breast-feeding duration. COMBINE recruited 456 nulliparous mothers (2015â 2017) for maternalâ infant follow-up via interview at hospital discharge (median 3 (interquartile range (IQR) 2, 4) d (n 453)), 1 (n 418), 2 (n 392), 4 (n 366), 6 (n 362) and 9 (n 345) months of age. Median maternal age was 32 (IQR 29, 34) years, 97 % of mothers were of white ethnicity, 79 % were Irish-born and 75 % were college-educated. Overall, 75 % breastfed to any extent at discharge and 44 % breastfed solely. At 1, 2, 4, 6 and 9 months, respectively, 40, 36, 33, 24 and 19 % breastfed solely. Combination feeding of breast milk and infant formula was common at discharge (31 %) and 1 month (20 %). Reasons for combination feeding at 1 month included perceived/actual hunger (30 %), healthcare professional advice (31 %) and breast-feeding difficulties (13 %). Of mothers who breastfed to any extent at discharge, 45 % stopped within 4 months. Mothers who combination fed were more likely to cease breast-feeding than those who breastfed solely (relative risk 2·3 by 1 month and 12·0 by 2 months). These granular data provide valuable insight to early milk feeding practices and indicate that supporting early breast-feeding without formula use may be key to the successful continuation of breast-feeding

An exploration of the calcium metabolic system in pregnancy and public health programmes to improve early nutrition in maternal-infant cohorts

Although pregnancy and infancy represent periods of particular nutritional vulnerability, many gaps in the evidence base remain during these life-stages. The research in this thesis was conducted in two phases across three studies in pregnant women and infants. The aim of the first phase was to examine the vitamin D-calcium metabolic system in pregnancy. In the largest clinical study to date, serum 25- hydroxyvitamin D [25(OH)D] and parathyroid hormone [PTH] were analysed in 1754 women in the SCOPE pregnancy cohort. While 25% of participants had a 25(OH)D concentration > 75 nmol/L, 17% were 80th percentile), occurred in 5.5% of participants. The prevalence of elevated mean arterial pressure (19.1 vs. 9.7%) and small-for-gestational-age (16.0 vs. 6.7%) were highest in those with functional vitamin D deficiency (P < 0.05), compared with the reference group [25(OH)D ≥ 75 nmol/L and normal PTH]. The adjusted prevalence ratio and risk ratio (95% CIs) were 1.83 (1.02, 3.27) and 1.53 (0.80, 2.93) for elevated mean arterial pressure and small-for-gestational-age, respectively. These data indicate the need to consider the broader calcium metabolic system in future studies of vitamin D and perinatal health. Following this, the relative impact of serum 25(OH)D and calcium intake on PTH was explored using baseline data from a vitamin D dose-response trial (n = 142). PTH was inversely correlated with 25(OH)D (r = -0.311, P < 0.001), but not calcium intake (r = -0.087, P = 0.306). In categorical analyses, there was no 25(OH)D-calcium interaction effect on PTH (P = 0.941) and 25(OH)D < 50 nmol/L, but not stratified calcium intake, significantly affected PTH concentration (P = 0.025 and 0.822, respectively). In this group of white-skinned pregnant women, who generally had sufficient calcium intakes, serum 25(OH)D was important for maintaining PTH concentration. The background nutritional status and participant population appear to be critical factors. The second research phase explored early life nutrition in the COMBINE birth cohort. COMBINE, a prospective, nutrition-led study, recruited 456 participants between 2015 and 2017 and has 9 study visits over the first 2 years of life. Examination of infant feeding practices indicated that 44% gave breastmilk as the main milk source at hospital discharge, 36% at 2 months, 24% at 6 months and 19% at 9 months. The rate of infant formula only feeding increased from 25% at discharge to 49% at 2 months and 74% at 9 months of age. Combination feeding of breastmilk and infant formula was common at discharge (31%) and 1 month (20%); these mothers were more likely to stop breastfeeding altogether than those who breastfed (all P< 0.05). The median (IQR) age of introduction to solid foods was 21 (18, 24) weeks; 9% introduced solids before 17 weeks of age. While these data provide evidence of some progress towards longer breastfeeding durations, there remains much scope to improve infant feeding practices in Ireland. Adherence to the national infant vitamin D supplementation policy, implemented in 2010, is not monitored nationally and the policy has not been formally evaluated; policy adherence was examined in the COMBINE cohort (n = 365). Most parents initiated supplementation at birth (92%), used a vitamin D3 only product (94%), and gave the recommended 5 µg dose (88%). Half (51%) administered vitamin D daily and a further 33% supplemented at least 3-6 times/week. Overall, 30% adhered fully to the policy, providing 5 µg vitamin D3 daily from birth to 12 months. Given high levels of maternal and infant deficiency and the current lack of a maternal supplementation policy in Ireland, the infant vitamin D supplementation policy should remain a public health priority. With two research foci, the data generated in this thesis provides much-needed advancement of knowledge regarding the vitamin D-calcium metabolic system in pregnancy and public health nutrition in the first year of life

Vitamin D in pregnancy: current perspectives and future directions

As neonatal vitamin D status is determined by circulating maternal 25-hydroxyvitamin D [25(OH)D] concentrations, prevention of maternal vitamin D deficiency during pregnancy is essential for the avoidance of neonatal deficiency. However, a high prevalence of vitamin D deficiency has been extensively reported among gravidae and neonates from ethnic minorities and white populations resident at high latitude. Currently, regulatory authorities recommend vitamin D intakes for pregnant women that are similar to non-pregnant adults of the same age, at 10–15 µg/day (400–600 IU), to meet 25(OH)D thresholds of 25–50 nmol/liter. The lack of pregnancy-specific dietary recommendations is due to inadequate data indicating whether nutritional requirements for vitamin D during pregnancy differ from the non-pregnant state. In addition, there are few dose–response studies to determine the maternal 25(OH)D response to vitamin D intake throughout pregnancy at high latitude. These data are also required to determine vitamin D requirements during pregnancy for prevention of neonatal deficiency, an outcome which is likely to require a higher maternal 25(OH)D concentration than prevention of maternal deficiency only. With regard to the impact of vitamin D on perinatal health outcomes, which could guide pregnancy-specific 25(OH)D thresholds, dietary intervention studies to date have been inconsistent and recent systematic reviews have highlighted issues of low quality and a high risk of bias as drawbacks in the trial evidence to date. Many observational studies have been hampered by a reliance on retrospective data, unclear reporting, suboptimal clinical phenotyping and incomplete subject characterization. Current investigations of vitamin D metabolism during pregnancy have potentially exciting implications for clinical research. This paper provides an update of current dietary recommendations for vitamin D in pregnant women and a synopsis of the evidence relating vitamin D status with maternal and infant health