Non-inferiority of low-dose compared to standard high-dose calcium supplementation in pregnancy: study protocol for two randomized, parallel group, non-inferiority trials in India and Tanzania

Background Hypertensive disorders of pregnancy are important causes of maternal morbidity and mortality, as well as preterm birth, the leading cause of death for children under 5 years globally. The World Health Organization currently recommends that pregnant women receive high-dose calcium supplementation (1500–2000 mg elemental calcium) for prevention of preeclampsia in populations with low dietary calcium intake. Trials of low-dose calcium supplementation (< 1000 mg elemental calcium/day) during pregnancy have also shown similar reductions in the risk of preeclampsia; however, no trials to date have directly compared low-dose to the standard high-dose calcium supplementation. Our objective is to assess the non-inferiority of low-dose as compared to standard high-dose calcium supplementation in pregnancy. Methods/design We will conduct two independent trials in Bangalore, India (n = 11,000 pregnancies), and Dar es Salaam, Tanzania (n = 11,000 pregnancies). The trial designs are individually randomized, parallel group, quadruple-blind, non-inferiority trials of low-dose calcium supplementation (500 mg elemental calcium/day) as compared to standard high-dose calcium supplementation (1500 mg elemental calcium/day) among nulliparous pregnant women. Pregnant women will be enrolled in the trial before 20 weeks of gestation and will receive the randomized calcium regimen from randomization until the time of delivery. The co-primary outcomes are (i) preeclampsia and (ii) preterm birth; we will test non-inferiority of the primary outcomes for low-dose as compared to the standard high-dose supplementation regimen in each trial. The trials’ secondary outcomes include gestational hypertension, severe features of preeclampsia, pregnancy-related death, third trimester severe anemia, fetal death, stillbirth, low birthweight, small-for-gestational age birth, and infant death. Discussion The trials will provide causal evidence on the non-inferiority of low-dose as compared to the standard high-dose supplementation in India and Tanzania. A single tablet, low-dose calcium supplementation regimen may improve individual-level adherence, reduce programmatic costs, and ultimately expand implementation of routine calcium supplementation in pregnancy in populations with low dietary calcium intake. Trial registration ClinicalTrials.gov identifier: NCT03350516; registered on 22 November 2018. Clinical Trials Registry—India identifier: CTRI/2018/02/012119; registered on 23 February 2018. Tanzania Medicines and Medical Devices Authority Trials Registry identifier: TFDA0018/CTR/0010/5; registered on 20 December 2018.

Conventional versus Nano Calcium Forms on Peanut Production under Sandy Soil Conditions

Abiotic stresses in sandy soil, which include saline water, saline soil, and lack of nutrients, affect the productivity and quality traits of peanuts (Arachis hypogaea L). Elemental calcium (Ca2+) is necessary for the proper development of peanut pods. This work aimed at comparing conventional Ca and nano-Ca form effects on peanut production and quality traits. Two randomized complete block field experiments were conducted in the 2015 and 2016 seasons. Treatments were control, gypsum plus calcium nitrate Ca(NO3)2, Ca(NO3)2, and chelated calcium, as well as 100, 75, 50, 25, and 12.5% of Ca(NO3)2 doses in a nano form. The results indicated that the treatment of gypsum plus conventional CaNO3 achieved the highest yield and best quality traits, followed by the Ca(NO3)2 and 100% nano Ca(NO3)2 treatments. The treatments of the control, gypsum, and 12.5% nano Ca(NO3)2 had the lowest effect on peanut performance. The conventional treatment of gypsum plus Ca(NO3)2 resulted in the greatest seed yield (1.6 ton ha−1), oil yield (700.3 kg ha−1), and protein yield (380.1 kg ha−1). Peanuts may benefit from Ca2+ better by using gypsum as the soil application and calcium nitrate as the foliar application to prevent disorders of Ca2+ deficiency under sandy soil conditions.

Effect of Oral Calcium Supplementation on Insulin Sensitivity in Patients With Metabolic Syndrome

Background: Evidence from epidemiological research suggests that dietary calcium may protect against metabolic abnormality in populations at high risk. Observational studies show the relationship between dietary calcium intake and metabolic syndrome. However evidence for beneficial effect of elemental calcium supplementation on metabolic syndrome is limited. Aims: Present studydetermined whether oral calcium supplementation reduced insulin resistance in patients with metabolic syndrome or not. Methods; Hundred patients who have metabolic syndrome without diabetes mellitus, parathyroid disease, chronic renal failure, pregnancy and lactationwere randomly allocated to the group receiving 1500 mg/ day of elemental calcium as calcium carbonate for 8 weeks and the control group. The primary outcome was change in insulin resistance as measured by homeostasis model assessment of insulin resistance (HOMA-IR). Other outcomes were changes of serum free ionized calcium (FiCa) level with accompanying serum parathyroid hormone (PTH) level. Fasting serum glucose was measured by glucose oxidase method. Serum insulin and PTH level were measured by enzyme linked immunoassay. Total serum ionized calcium was analyzed by Atomic Absorption Spectrophotometry. Serum FiCa(mg/dl) level was calculated by using following formula = [6Ca-(K/3)]/(K+6). Results: Mean age of participants was 47.38±13.2 years in calcium supplement group (n = 50) and 49.46±12.9 years in control group (n=50). Mean body mass index was not significant different between two groups (30.91 ±4.23 vs 30.37 ± 4.62 kg/m2). More female were involved in both group, 72% vs 62% respectively. Baseline biochemical parameters of the participants between two groups were not significantly different. After 8 week intervention period, mean serum FiCa increased significantly from 2.64±1.19 mg/dl to 5.82± 5.59 mg/dl, p&lt;0.0001, serum PTH decreased significantly from 57.88 ±17.05 pg/ml to 35.7±23.12 pg/ml, p&lt;0.0001, HOMA-IR decreased significantly from 5.14 ± 3.71 to 2.94±1.51, p&lt;0.0001. None of these parameters were significantly affected in control group. By comparing biochemical changes of calcium supplement group to control group, Mean (SEM) of paired difference changes were observed in serum FiCa level [3.18(0.81) vs 0.81(0.25)mg/dl, p&lt;0.05], serum PTH level [22.18(3.24) vs 3.58(1.99)pg/ml, p&lt;0.0001] and HOMA-IR [2.19(0.45) vs 0.43(0.21), p&lt;0.05]. It indicated that elemental calcium supplementation not only reduced insulin resistance but also decompensated the higher level of PTH to normal range by replenishing FiCa significantly. Conclusion: Eight-week oral elemental calcium supplementation of 1500mg/day showed beneficial effect on insulin sensitivity in patients with metabolic syndrome.

Ectopic Cushing’s Syndrome and Severe Hypocalcemia Due to Medullary Thyroid Cancer Responsive to Selpercatinib

Introduction: Cushing’s syndrome (CS) due to ectopic ACTH production from medullary thyroid carcinoma (MTC) is characterized by rapid progression of disease, leading to hyperglycemia and hypokalemia. However, hypercortisolemia leading to hypocalcemia is rarely seen. Initiation of selpercatinib greatly improved hypocalcemia and ectopic CS in this case. Clinical Case: A 41-year-old man with a history of MTC (variant RET p.M918T) post thyroidectomy in 2018 developed progressive weight gain, lower extremity edema, weakness, new onset diabetes, severe refractory hypocalcemia and hypokalemia requiring multiple hospitalizations. On initial presentation to our institution, he was lethargic, had multiple ecchymoses, peripheral edema and proximal myopathy. Laboratory evaluation revealed Ca 5.4 mg/dL (NR 8.9 - 10.3), albumin 3 g/dL (NR 3.5 - 5.1), iPTH 1.4 pmol/L (NR 1.6 - 6.9), 25-OH vitamin D 23 pg/mL (NR 25–80) while taking elemental calcium 1500 mg every 6h, calcitriol 0.25 mcg/d and vitamin D3 1000 IU/d. Serum cortisol measured at 9:30 pm was 136 ug/dL (NR 2.5–11.9), ACTH 1,145 pg/mL (NR 7.2–63.3) and 24-h UFC 27,629 ug/d consistent with CS due to ectopic ACTH production. Calcitonin and CEA were 18,687 pg/mL (NR 0–7.5) and 3,766 ng/mL (NR 0–4.7). CT abdomen revealed numerous bilateral liver lesions and bilateral adrenal hyperplasia. In addition to high doses of oral calcium and calcitriol, he required calcium drip up to 1.5mg/kg/hr for about 1 week. He simultaneously began cabozantinib, ketoconazole and metyrapone. Hospital course was complicated by infections and recurrent scrotal bleeding, so he was switched to selpercatinib. Two days after starting selpercatinib, ketoconazole was discontinued, and metyrapone has been gradually reduced. Most recent calcitonin was 149 pg/mL, CEA 97.8 ng/mL and 24-h UFC 10 ug/d on metyrapone 250 mg twice daily. Similarly, refractory hypocalcemia greatly improved, last serum Ca was 8.3 mg/dL on elemental calcium 480 mg/d. He has made significant clinical gains and has returned home from rehab. Clinical Lesson: Hypocalcemia is rarely described as a complication in patients with CS. Our patient had underlying hypoparathyroidism and vitamin D deficiency; however, hypocalcemia was initially refractory to high doses of calcium and calcitriol and only improved with treatment of CS. We suspect hypercortisolemia impaired 25 to 1,25 D activation, thereby reducing calcium absorption, and likely inducing hypercalciuria. These deleterious effects of severe hypercortisolemia combined with underlying hypoparathyroidism led to severe and refractory hypocalcemia requiring repeated admissions, and only improved once his ectopic CS due to MTC was recognized and controlled. The RET kinase inhibitor, selpercatinib, induced a rapid decline in calcitonin, CEA and ACTH levels, and with metyrapone, enabled control of hypercortisolemia and its complications.

Management of hypocalcemia after modified bilateral radical neck dissection followed with total thyroidectomy: a case report

Hypocalcemia is a common complication after total thyroidectomy due to acute hypoparathyroidsm post-surgery. The incident varies from 7%-69% depends on the surgery center. The management is divided based on the onset and symptoms. Carpal-pedal spasm, seizure, bronchospasms are the emergency symptoms of hypocalcemia that require administration of intravenous calcium. However the management of asymptomatic hypocalcemia with oral calcium, vitamin D and hydrochlorothiazide can be difficult due to wide fluctuations of serum calcium and the risks of complication. Hereby we report a 14-year-old girl with hypocalcemia due to hypoparathyroidsm post modified bilateral radical neck dissection and total thyroidectomy. She had papillary thyroid carcinoma and lymph node metastases. After surgery, she developed classic sign of hypocalcemia, numbness in extremities which progressed to cramps. Physical examination revealed chvostek’s sign. Laboratory examination showed critical value of hypocalcemia with normal level of albumin, hypoparathyroidsm and hypovitaminosis D. The initial treatment was started by giving intravenous calcium gluconate 10% and calcitriol. Monitoring level of calcium and phosphate were performed regularly. Calcium level was maintained by giving high dose of elemental calcium, vitamin D3 and hydrochlorothiazide followed.

The Effect of Calcium Supplementation on Body Weight Before and During Pregnancy in Women Enrolled in the WHO Calcium and Preeclampsia Trial

Introduction: Obesity is a major and challenging public health problem. The aim of this substudy is to evaluate the effect of calcium supplementation on body weight in women recruited in the Calcium and Preeclampsia trial. Methods: Women were recruited before pregnancy and randomized to receive a calcium supplement containing 500 mg of elemental calcium or placebo until 20 weeks’ gestation; all women received 1.5 g from 20 weeks until delivery. Results: A total of 630 women conceived during the study, 322 allocated to calcium and 308 to placebo. Among these, 230 allocated to calcium and 227 allocated to placebo had information on body weight at baseline and at 8 weeks' gestation. During the study period, women allocated to calcium had a mean weight increase of 1.1 (SD ±5.5) kg, whereas those allocated to placebo had a mean increase of 1.5 (SD ±6.1) kg, a mean difference of 0.4 kg (95% −0.4 (−1.4 to 0.6); P = .408). Women classified as obese at the start of the trial had a lower body weight gain at 8 weeks’ gestation (1.0 kg; 95% CI: −3.2 to 1.2; P = .330) and at 32 weeks’ gestation (2.1 kg; 95% CI: 5.6-1.3; P = .225) if they received calcium as compared to placebo. However, none of these differences were statistically significant. Conclusion: The smaller increase in body weight found in women supplemented with 500 mg elemental calcium daily is quantitatively consistent with previous studies. However, in this study, the difference was not statistically significant.

Effect of Preoperative Vitamin D Deficiency on Hypocalcemia in Patients with Acute Hypoparathyroidism after Thyroidectomy

Postoperative hypoparathyroidism is a common complication of total or completion thyroidectomy. The association between preoperative vitamin D deficiency (VDD) and the development of more severe postoperative hypocalcemia is still unclear. Objectives. To evaluate the effect of preoperative VDD on severity of hypocalcemia in patients with hypoparathyroidism following thyroidectomy. Methods. Patients who developed acute hypoparathyroidism after total or completion thyroidectomy, defined as postoperative parathyroid hormone (PTH) level <15 pg/mL and albumin-adjusted calcium level <8.6 mg/dL, were prospectively recruited. Patients were divided into two groups according to their preoperative vitamin D status (VDD group: 25-hydroxyvitamin D (25(OH)D) level <20 ng/mL; non-VDD group: 25(OH) level ≥20 ng/mL). The primary outcome was severity of hypocalcemia in postoperative hypoparathyroidism. Significant hypocalcemia was defined as calcium level ≤7.5 mg/dL. Results. Forty-three patients (21 VDD, 22 non-VDD) were enrolled. Serum total albumin-adjusted calcium level was significantly lower in the VDD group (7.71 ± 0.5 vs. 8.16 ± 0.4 mg/dL, p<0.01), and the incidence of symptomatic hypocalcemia was significantly higher in the VDD group (43% vs. 9%, p=0.01). The median maximal daily supplementary dose of elemental calcium was significantly higher in the VDD group (2,400 vs. 1,500 mg/day, p=0.02). Length of hospital stay was nonsignificantly longer in the VDD group (p=0.06). Preoperative vitamin D level <19.6 ng/mL could predict significant and symptomatic hypocalcemia in postoperative hypoparathyroidism with sensitivity of 90% and 82% and specificity of 70% and 69%, respectively. Conclusion. VDD is an independent risk factor for both significant and symptomatic hypocalcemia in hypoparathyroidism patients after thyroid surgery.