Abstract
Objectives:
To determine the incidence of potentially life-threatening complications of hypocalcemia in infants and children in Olmsted County, Minnesota; to determine if vitamin D deficiency contributed to these events and was, at the time of clinical presentation, considered as a possible cause.
Study design:
In this population-based descriptive study, data were abstracted from the Rochester Epidemiology Project, a medical record linkage system covering 95% of patients in Olmsted County, Minnesota. Participants were children aged 0 to 5 years who resided in Olmsted County between January 1, 1996 and June 30, 2017 and who received diagnoses of seizures, cardiomyopathy, cardiac arrest, respiratory arrest, laryngospasm, and/or tetany. The incidence of hypocalcemia plus a potentially life-threatening complication was calculated.
Results:
Among 15,419 patients aged 0 to 5 years in Olmsted County during the study period, 1305 had eligible complications; 460 had serum calcium checked within 14 days of presentation, and 85 had hypocalcemia. Subjects were excluded when causes other than hypocalcemia likely triggered the complication, leaving 16 children whose complication was attributed to hypocalcemia. Three of these 16 patients had a serum 25-hydroxyvitamin D measurement, and two were deficient (≤6 ng/mL [15 nmol/L]). Among children aged 0 to 5 years, the incidence of hypocalcemia plus a potentially life-threatening complication was 6.1 per 100,000 person-years (95% CI 3.5–10.0).
Conclusions:
Vitamin D deficiency is an under-investigated cause of complications of hypocalcemia in children. Serum calcium and 25-hydroxyvitamin D should be measured in children with these complications to identify possibly life-threatening vitamin D deficiency.
Keywords: seizure, cardiomyopathy, cardiac arrest, respiratory arrest, laryngospasm, tetany, 25-hydroxyvitamin D, calcium
Humans obtain vitamin D primarily from solar ultraviolet-B radiation, dietary supplements, and fortified foods and infant formulas (1–3). Inadequate nutrition and negligible sun exposure cause serum 25-hydroxyvitamin D (25(OH)D) values ≤20 ng/mL (50 nmol/L) (4), a concentration associated with increased risk of clinical consequences of vitamin D deficiency (VDD), in one billion people worldwide (1, 2). Sufficient vitamin D enhances dietary calcium absorption by 30 to 40%(1). Vitamin D deficiency, in contrast, can cause hypocalcemia and manifest as rickets, with leg deformities, stunted growth, and swelling of wrists and ankles (1, 5, 6). The frequency of nutritional rickets has risen in ethnic minority populations in Europe and North America in recent years (7). The incidence of nutritional rickets in children younger than 3 years in Olmsted County, Minnesota was relatively steady from 1970 to 2000 but increased substantially after 2000 (8). Ionized calcium is integral to cardiomyocyte contractility, and hypocalcemic-dilated cardiomyopathy and cardiac arrest may occur with sustained hypocalcemia (9–15). Hypocalcemic seizures and tetany can ensue during periods of rapid growth, especially during infancy (9, 11, 16–18). Stridor, laryngospasm, and apnea have been associated with VDD (17, 19, 20). Hence, VDD increases risk of morbidity and mortality, especially among at-risk infants.
Although complications of hypocalcemia are well understood, it is unclear how frequently VDD causes life-threatening hypocalcemia or is routinely considered in patients with these complications. Our primary objective was to determine the population-based incidence of hypocalcemia associated with seizures, cardiomyopathy, cardiac arrest, respiratory arrest, laryngospasm, and/or tetany in children aged 0 to 5 years in Olmsted County, Minnesota. Additional objectives were to determine if VDD contributed to these events and was, at the time of clinical presentation, considered as a possible cause; to assess patterns of race, ethnicity, time of year, breastfeeding status or other risk factors in patients with hypocalcemic complications; and to describe the outcomes of mortality and morbidity of children with hypocalcemic complications.
Methods
We conducted a population-based descriptive study in Olmsted County, Minnesota, using the database of the Rochester Epidemiology Project. The Rochester Epidemiology Project database is a population-based medical record linkage system that includes over fifty years of health care utilization, diagnostic and laboratory data from virtually all medical providers in Olmsted County, Minnesota, covering 98% of all health care services provided for Olmsted County residents (21, 22). The county is served by 2 large integrated health systems, the Mayo Clinic and the Olmsted Medical Center (23). Over 95% of the Olmsted County population has granted authorization for their records to be used for research (24, 25).
Olmsted County, Minnesota is located in the Upper-Midwestern United States (44°N latitude) and has limited sun exposure in winter. The population has increased from 135,897 to 148,700 between 2002 and 2011. In the 2000 and 2010 censuses, the proportions of residents classified as white, black, Asian, and Hispanic were 90% and 85.7%, 2.7% and 4.8%, 4.3% and 5.4%, and 2.4% and 4.2%, respectively. The proportions of individuals under 5 years old were 7.2% and 7.5%, respectively. Compared with the entire U.S. 2010 population, the county is less ethnically diverse (86% versus 72% white), more educated (94% versus 85% high school graduates) and wealthier ($64,090 versus $51,914 median household income). However, characteristics of the population are very similar to the overall population of the upper Midwest (25).
Children aged 0 to 5 years who resided in Olmsted County between January 1, 1996 and June 30, 2017 and who received diagnoses of seizures, cardiomyopathy, cardiac arrest, respiratory arrest, laryngospasm, and/or tetany were eligible for inclusion. We collected data regarding each patient’s date of birth, sex, and self-reported race and ethnicity. The diagnoses of seizure, cardiomyopathy, cardiac arrest, respiratory arrest, laryngospasm, and tetany were based on ICD-9 and ICD-10 codes (Table I; available at www.jpeds.com). We recorded the date of diagnosis, patient age at diagnosis, date of first symptoms, and length/height and weight percentiles nearest to the date the patient presented with the reported complication (index date). The serum total calcium, ionized calcium, and albumin values closest to the index date and the lowest value within 14 days (before/on/after) of the index date were all recorded. We recorded serum 25(OH)D, alkaline phosphatase, and phosphorus measurements closest to the index date within 6 months. We determined the number of days from index date to treatment date for hypocalcemia and VDD and the type of treatment patients received. Radiographs were evaluated for evidence of rickets. Finally, we determined whether the patient had a diet of exclusively breastmilk, formula or a combination of both immediately prior to the index date.
Online Table 1.
ICD-9 and ICD-10 codes
| Code | Description | Type |
|---|---|---|
| I46.2 | Cardiac arrest due to underlying cardiac condition | I10 |
| I46.8 | Cardiac arrest due to other underlying condition | I10 |
| I46.9 | Cardiac arrest, cause unspecified | I10 |
| Z86.74 | Personal history of sudden cardiac arrest | I10 |
| P29.81 | Cardiac arrest of newborn | I10 |
| I97.120 | Postprocedural cardiac arrest following cardiac surgery | I10 |
| I97.121 | Postprocedural cardiac arrest following other surgery | I10 |
| I97.710 | Intraoperative cardiac arrest during cardiac surgery | I10 |
| I97.711 | Intraoperative cardiac arrest during other surgery | I10 |
| O03.36 | Cardiac arrest following incomplete spontaneous abortion | I10 |
| O03.86 | Cardiac arrest following complete or unspecified spontaneous abortion | I10 |
| O04.86 | Cardiac arrest following (induced) termination of pregnancy | I10 |
| O07.36 | Cardiac arrest following failed attempted termination of pregnancy | I10 |
| O08.81 | Cardiac arrest following an ectopic and molar pregnancy | I10 |
| O29.111 | Cardiac arrest due to anesthesia during pregnancy, first trimester | I10 |
| O29.112 | Cardiac arrest due to anesthesia during pregnancy, second trimester | I10 |
| O29.113 | Cardiac arrest due to anesthesia during pregnancy, third trimester | I10 |
| O29.119 | Cardiac arrest due to anesthesia during pregnancy, unspecified trimester | I10 |
| 427.5 | Cardiac arrest | I9 |
| V12.53 | Per hx sudden card arrst | I9 |
| 997.1 | Cardiac complications, not elsewhere classified (includes cardiac arrest as a complication of surgical procedure) | I9 |
| 779.85 | Cardiac arrest of newborn | I9 |
| V12.59 | Per hx sudden card arrst | I9 |
| 779.89 | Cardiac arrest of newborn | I9 |
| R09.2 | Respiratory arrest | I10 |
| P28.5 | Respiratory failure of newborn | I10 |
| P28.81 | Respiratory arrest of newborn | I10 |
| P28.89 | Other specified respiratory conditions of newborn | I10 |
| P28.9 | Respiratory condition of newborn, unspecified | I10 |
| 770.8 | Other newborn respiratory problems | I9 |
| 770.81 | Primary apnea of newborn | I9 |
| 770.82 | Other apnea of newborn | I9 |
| 770.83 | Cyanotic attacks of newborn | I9 |
| 770.84 | Respiratory failure of newborn | I9 |
| 770.87 | Respiratory arrest of newborn | I9 |
| 770.88 | Hypoxemia of newborn | I9 |
| 770.89 | Other respiratory problems after birth | I9 |
| 799.1 | Respiratory arrest | I9 |
| 770.8 | Other newborn respiratory problems | I9 |
| 770.89 | Other respiratory problems after birth | I9 |
| 768.9 | Hypoxemia of newborn | I9 |
| A36.81 | Diphtheritic cardiomyopathy | I10 |
| B33.24 | Viral cardiomyopathy | I10 |
| E85.4 | Organ-limited amyloidosis | I10 |
| I25.5 | Ischemic cardiomyopathy | I10 |
| I42.0 | Dilated cardiomyopathy | I10 |
| I42.1 | Obstructive hypertrophic cardiomyopathy | I10 |
| I42.2 | Other hypertrophic cardiomyopathy | I10 |
| I42.3 | Endomyocardial (eosinophilic) disease | I10 |
| I42.4 | Endocardial fibroelastosis | I10 |
| I42.5 | Other restrictive cardiomyopathy | I10 |
| I42.6 | Alcoholic cardiomyopathy | I10 |
| I42.7 | Cardiomyopathy due to drug and external agent | I10 |
| I42.8 | Other cardiomyopathies | I10 |
| I42.9 | Cardiomyopathy, unspecified | I10 |
| I43 | Cardiomyopathy in diseases classified elsewhere | I10 |
| O90.3 | Peripartum cardiomyopathy | I10 |
| 425 | Cardiomyopathy | I9 |
| 425.0 | Endomyocardial fibrosis | I9 |
| 425.1 | Hypertrophic (obstructive) cardiomyopathy | I9 |
| 425.11 | Hypertrophic obstructive cardiomyopathy | I9 |
| 425.18 | Other hypertrophic cardiomyopathy | I9 |
| 425.2 | Obscure cardiomyopathy of africa | I9 |
| 425.3 | Endocardial fibroelastosis | I9 |
| 425.4 | Other primary cardiomyopathies | I9 |
| 425.5 | Alcoholic cardiomyopathy | I9 |
| 425.7 | Nutritional and metabolic cardiomyopathy | I9 |
| 425.8 | Cardiomyopathy in other diseases classified elsewhere | I9 |
| 425.9 | Secondary cardiomyopathy, unspecified | I9 |
| 674.5 | Peripartum cardiomyopathy | I9 |
| 674.50 | Peripartum cardiomyopathy, unspec as to episode of care or not applicable | I9 |
| 674.51 | Peripartum cardiomyopathy, delivered, w or wo mention of antepartum condition | I9 |
| 674.52 | Peripartum cardiomyopathy, delivered, with mention of postpartum condition | I9 |
| 674.53 | Peripartum cardiomyopathy, antepartum condition or complication | I9 |
| 674.54 | Peripartum cardiomyopathy, postpartum condition or complication | I9 |
| 277.39 | Other amyloidosis (includes cardiomyopathy) | I9 |
| 425.1 | Hypertrophic obstructive cardiomyopathy | I9 |
| 425.4 | Other hypertrophic cardiomyopathy | I9 |
| 674.8 | Peripartum cardiomyopathy, unspec as to episode of care or not applicable | I9 |
| 674.82 | Peripartum cardiomyopathy, unspec as to episode of care or not applicable | I9 |
| 674.84 | Peripartum cardiomyopathy, unspec as to episode of care or not applicable | I9 |
| 277.3 | Other amyloidosis (includes cardiomyopathy) | I9 |
| J38.5 | Laryngeal spasm | I10 |
| 478.75 | Laryngeal spasm | I9 |
| G40.001 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, not intractable, with status epilepticus |
I10 |
| G40.009 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, not intractable, without status epilepticus | I10 |
| G40.011 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, intractable, with status epilepticus | I10 |
| G40.019 | Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset, intractable, without status epilepticus | I10 |
| G40.101 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, not intractable, with status epilepticus | I10 |
| G40.109 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, not intractable, without status epilepticus | I10 |
| G40.111 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, intractable, with status epilepticus | I10 |
| G40.119 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures, intractable, without status epilepticus | I10 |
| G40.201 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, not intractable, with status epilepticus | I10 |
| G40.209 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, not intractable, without status epilepticus | I10 |
| G40.211 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, intractable, with status epilepticus | I10 |
| G40.219 | Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures, intractable, without status epilepticus | I10 |
| G40.301 | Generalized idiopathic epilepsy and epileptic syndromes, not intractable, with status epilepticus | I10 |
| G40.309 | Generalized idiopathic epilepsy and epileptic syndromes, not intractable, without status epilepticus | I10 |
| G40.311 | Generalized idiopathic epilepsy and epileptic syndromes, intractable, with status epilepticus | I10 |
| G40.319 | Generalized idiopathic epilepsy and epileptic syndromes, intractable, without status epilepticus | I10 |
| G40.A01 | Absence epileptic syndrome, not intractable, with status epilepticus | I10 |
| G40.A09 | Absence epileptic syndrome, not intractable, without status epilepticus | I10 |
| G40.A11 | Absence epileptic syndrome, intractable, with status epilepticus | I10 |
| G40.A19 | Absence epileptic syndrome, intractable, without status epilepticus | I10 |
| G40.B01 | Juvenile myoclonic epilepsy, not intractable, with status epilepticus | I10 |
| G40.B09 | Juvenile myoclonic epilepsy, not intractable, without status epilepticus | I10 |
| G40.B11 | Juvenile myoclonic epilepsy, intractable, with status epilepticus | I10 |
| G40.B19 | Juvenile myoclonic epilepsy, intractable, without status epilepticus | I10 |
| G40.401 | Other generalized epilepsy and epileptic syndromes, not intractable, with status epilepticus | I10 |
| G40.409 | Other generalized epilepsy and epileptic syndromes, not intractable, without status epilepticus | I10 |
| G40.411 | Other generalized epilepsy and epileptic syndromes, intractable, with status epilepticus | I10 |
| G40.419 | Other generalized epilepsy and epileptic syndromes, intractable, without status epilepticus | I10 |
| G40.501 | Epileptic seizures related to external causes, not intractable, with status epilepticus | I10 |
| G40.509 | Epileptic seizures related to external causes, not intractable, without status epilepticus | I10 |
| G40.801 | Other epilepsy, not intractable, with status epilepticus | I10 |
| G40.802 | Other epilepsy, not intractable, without status epilepticus | I10 |
| G40.803 | Other epilepsy, intractable, with status epilepticus | I10 |
| G40.804 | Other epilepsy, intractable, without status epilepticus | I10 |
| G40.811 | Lennox-gastaut syndrome, not intractable, with status epilepticus | I10 |
| G40.812 | Lennox-gastaut syndrome, not intractable, without status epilepticus | I10 |
| G40.813 | Lennox-gastaut syndrome, intractable, with status epilepticus | I10 |
| G40.814 | Lennox-gastaut syndrome, intractable, without status epilepticus | I10 |
| G40.821 | Epileptic spasms, not intractable, with status epilepticus | I10 |
| G40.822 | Epileptic spasms, not intractable, without status epilepticus | I10 |
| G40.823 | Epileptic spasms, intractable, with status epilepticus | I10 |
| G40.824 | Epileptic spasms, intractable, without status epilepticus | I10 |
| G40.89 | Other seizures | I10 |
| G40.901 | Epilepsy, unspecified, not intractable, with status epilepticus | I10 |
| G40.909 | Epilepsy, unspecified, not intractable, without status epilepticus | I10 |
| G40.911 | Epilepsy, unspecified, intractable, with status epilepticus | I10 |
| G40.919 | Epilepsy, unspecified, intractable, without status epilepticus | I10 |
| R56.00 | Simple febrile convulsions | I10 |
| R56.01 | Complex febrile convulsions | I10 |
| R56.1 | Post traumatic seizures | I10 |
| R56.9 | Unspecified convulsions | I10 |
| P90 | Convulsions of newborn | I10 |
| F44.5 | Conversion disorder with seizures or convulsions | I10 |
| 123.1 | Cysticercosis | I9 |
| 291.0 | Alcohol withdrawal delirium | I9 |
| 300.11 | Conversion disorder | I9 |
| 333.2 | Myoclonus | I9 |
| 344.8 | Other specified paralytic syndromes | I9 |
| 344.81 | Other specified paralytic syndromes, locked-in state | I9 |
| 344.89 | Other specified paralytic syndromes, other specified paralytic syndrome | I9 |
| 345 | Epilepsy | I9 |
| 345.0 | Generalized nonconvulsive epilepsy | I9 |
| 345.00 | Generalized nonconvulsive epilepsy-without mention of intractable epilepsy | I9 |
| 345.01 | Generalized nonconvulsive epilepsy-with intractable epilepsy | I9 |
| 345.1 | Generalized convulsive epilepsy | I9 |
| 345.10 | Generalized convulsive epilepsy-without mention of intractable epilepsy | I9 |
| 345.11 | Generalized convulsive epilepsy-with intractable epilepsy | I9 |
| 345.2 | Petit mal status, epileptic | I9 |
| 345.3 | Grand mal status, epileptic | I9 |
| 345.4 | Partial epilepsy, with impairment of consciousness | I9 |
| 345.40 | Localization-related (focal) (partial) epilepsy and epileptic syndromes with complex partial seizures, without mention of intractable epilepsy | I9 |
| 345.41 | Localization-related (focal) (partial) epilepsy and epileptic syndromes with complex partial seizures, with intractable epilepsy | I9 |
| 345.5 | Partial epilepsy, without mention of impairment of consciousness | I9 |
| 345.50 | Localization-related (focal) (partial) epilepsy and epileptic syndromes with simple partial seizures, without mention of intractable epilepsy | I9 |
| 345.51 | Localization-related (focal) (partial) epilepsy and epileptic syndromes with simple partial seizures, with intractable epilepsy | I9 |
| 345.6 | Infantile spasms | I9 |
| 345.60 | Infantile spasms-without mention of intractable epilepsy | I9 |
| 345.61 | Infantile spasms-with intractable epilepsy | I9 |
| 345.7 | Epilepsia partialis continua | I9 |
| 345.70 | Epilepsia partialis continua-without mention of intractable epilepsy | I9 |
| 345.71 | Epilepsia partialis continua-with intractable epilepsy | I9 |
| 345.8 | Other forms of epilepsy | I9 |
| 345.80 | Other forms of epilepsy and recurrent seizures, without mention of intractable epilepsy | I9 |
| 345.81 | Other forms of epilepsy and recurrent seizures, with intractable epilepsy | I9 |
| 345.9 | Epilepsy, unspecified | I9 |
| 345.90 | Epilepsy, unspecified-without mention of intractable epilepsy | I9 |
| 345.91 | Epilepsy, unspecified-with intractable epilepsy | I9 |
| 780.3 | Convulsions | I9 |
| 780.31 | Febrile convulsions | I9 |
| 780.32 | Complex febrile convulsions | I9 |
| 780.33 | Post traumatic seizures | I9 |
| 780.39 | Other convulsions | I9 |
| 779.0 | Convulsions in newborn | I9 |
| 344.8 | Other specified paralytic syndromes, other specified paralytic syndrome | I9 |
| 345.0 | Generalized nonconvulsive epilepsy-without mention of intractable epilepsy | I9 |
| 345.1 | Generalized convulsive epilepsy-without mention of intractable epilepsy | I9 |
| 345.4 | Localization-related (focal) (partial) epilepsy and epileptic syndromes with complex partial seizures | I9 |
| 345.5 | Localization-related (focal) (partial) epilepsy and epileptic syndromes with simple partial seizures | I9 |
| 345.7 | Epilepsia partialis continua-without mention of intractable epilepsy | I9 |
| 345.8 | Other forms of epilepsy and recurrent seizures, without mention of intractable epilepsy | I9 |
| 345.9 | Epilepsy, unspecified-without mention of intractable epilepsy | I9 |
| 780.3 | Febrile convulsions | I9 |
| 780.39 | Complex febrile convulsions | I9 |
| 780.3 | Other convulsions | I9 |
| P71.3 | Neonatal tetany without calcium or magnesium deficiency | I10 |
| R29.0 | Tetany | I10 |
| 781.7 | Tetany | I9 |
| E55.0 | Rickets, active | I10 |
| E55.9 | Vitamin d deficiency, unspecified | I10 |
| E83.51 | Hypocalcemia | I10 |
| E58 | Dietary calcium deficiency | I10 |
| P71.0 | Cow’s milk hypocalcemia in newborn | I10 |
| P71.1 | Other neonatal hypocalcemia | I10 |
| P71.9 | Transitory neonatal disorder of calcium and magnesium metabolism, unspecified | I10 |
| 268 | Vitamin d deficiency | I9 |
| 268.0 | Rickets, active | I9 |
| 269.1 | Deficiency of other vitamins | I9 |
| 268.2 | Osteomalacia, unspecified | I9 |
| 268.9 | Unspecified vitamin d deficiency | I9 |
| 275.4 | Disorders of calcium metabolism | I9 |
| 275.40 | Unspecified disorder of calcium metabolism | I9 |
| 275.41 | Hypocalcemia | I9 |
| 275.5 | Hungry bone syndrome | I9 |
| 775.4 | Hypocalcemia and hypomagnesemia of newborn | I9 |
The clinical data were adjudicated by three clinicians, and patients were excluded from the study cohort if causes other than hypocalcemia were more likely to have triggered the complication. Other reasons for exclusion included subjects who had not given prior authorization to retrospective chart review for research purposes, being born at ≤37 weeks and the index date was the date of birth, the diagnosis code pulled was not applicable to the study, surgical complications, index date ≤ 3 days after birth, congenital anomalies, infection, and trauma.
The study was approved by the Mayo Clinic Institutional Review Board, and all included records had research authorization for retrospective chart review.
Statistical analyses
Continuous variables were summarized using means and standard deviations, and categorical variables were summarized using frequencies and percentages. Age- and sex-adjusted incidence rates per 100,000 persons in Olmsted County were calculated using the number of persons with a complication fitting inclusion criteria as the numerator and age- and sex-specific person-years of the population of Olmsted County aged 0 to 5 for 1996 through 2017 as the denominator (population count obtained from the decennial United States census for Olmsted County with linear interpolation between census years, each person was counted as contributing an entire person-year of observation). 95% confidence intervals were calculated assuming a Poisson error distribution. Race-specific incidence calculations use the race-specific information from the United States census from Olmsted County for the denominator counts and person-year calculations. Comparison of incidence was done using generalized linear regression modeling with a Poisson error. All analyses were performed using SAS version 9.4 (SAS Institute Inc; Cary, NC).
Results
Between January 1, 1996 and June 30, 2017, 1305 of 15,419 patients aged 0 to 5 years in Olmsted County had eligible life-threatening complications. Specifically, 930 patients had seizures, 338 had cardiac arrest, 105 had respiratory arrest, 75 had laryngospasm, 66 had cardiomyopathy, and 2 had tetany. Among these, 460 (35%) had a serum calcium level measurement and 85 (18.5% of patients with a serum calcium level measured) had a serum calcium below the laboratory reference range for pediatric patients (total calcium <8.8 mg/dL [2.2 mmol/L] or ionized calcium <3.7 mg/dL [0.93 mmol/L]) (26) (Figure 1 and Table 2).
Figure 1.
Study flow chart showing inclusion and exclusion criteria. Numbers of subjects are shown in parentheses.
Table 2.
Distribution of complications in 1305 children
| Cardiac Arrest | Cardiomyopathy | Laryngospasm | Respiratory Arrest | Seizure | Tetany | Overall # Children | # with Calcium Checked | # with low Calcium |
|---|---|---|---|---|---|---|---|---|
| X | 1 | 0 | 0 | |||||
| X | 770 | 221 | 23 | |||||
| X | 60 | 31 | 13 | |||||
| X | X | 1 | 1 | 1 | ||||
| X | X | 12 | 10 | 3 | ||||
| X | 66 | 1 | 0 | |||||
| X | X | 2 | 1 | 0 | ||||
| X | X | 2 | 0 | 0 | ||||
| X | 42 | 7 | 0 | |||||
| X | X | 11 | 8 | 0 | ||||
| X | 169 | 82 | 29 | |||||
| X | X | 123 | 71 | 8 | ||||
| X | X | 24 | 12 | 2 | ||||
| X | X | X | 4 | 4 | ||||
| X | X | 3 | 2 | 1 | ||||
| X | X | X | 2 | 1 | 0 | |||
| X | X | 6 | 4 | 0 | ||||
| X | X | X | 5 | 3 | 3 | |||
| X | X | X | X | 2 | 1 | 1 | ||
| Total | 1305 | 460 | 85 |
One hundred eighty-four patients had two complications (14.1%), 11 had three complications (0.8%), and two had four complications (0.2%). Seizures were the most frequent life-threatening complication (61%), followed by cardiac arrest (22%). Of the 105 patients who experienced respiratory arrest, 21 (20%) had hypocalcemia, the highest proportion of any complication (Figure 2 and Table 2).
Figure 2.
Relative proportions of 1305 children with complications who had calcium measured and who had hypocalcemia. Numbers of subjects are shown in parentheses and the relative sizes of the circles are approximate. One hundred ninety-seven children (15.1%) had more than one complication, resulting in the sums of categories exceeding the total number of subjects.
From the group of 85 patients who had hypocalcemia, we excluded 69 patients who were judged to more likely have had causes other than hypocalcemia trigger the complication (Figure 1), leaving 16 patients in our study group (Table 3). Children were excluded most commonly because they were born at less than 37 weeks, and the date of their complication was their birth date. Ten of the 16 subjects (63%) were males, and 7 (44%) were black. The mean (±SD) age at the index date was 13.5 ± 13.6 months; the median age was 10.3 months. The mean age at the time of complication was 8.0 months old in white children and 17.5 months old in black children. Mean total calcium was 7.52 ± 1.11 mg/dL and mean ionized calcium was 2.8 ± 0.68 mg/dL. The median (range) alkaline phosphatase was 452 U/L (134 to 2122 U/L). Mean length/height percentile was 22.8 ± 24.5 and mean weight percentile was 34.7 ± 34.8.
Table 3.
Characteristics of 16 children with hypocalcemic complications
| Patient | Age at index date (mo) | Year of complication (before or after 1/1/2000) | Diagnoses | Total calcium (8.8–10.8 mg/dL) | Ionized calcium (3.7–5.5 mg/dL) | 25(OH)D(20–50 ng/mL) |
|---|---|---|---|---|---|---|
| 1 | 0–3 | after | seizures | 2.0 | ||
| 2 | 0–3 | after | seizures | 8.0 | ||
| 3 | 0–3 | after | seizures | 6.9 | ||
| 4 | 0–3 | after | seizures, cardiac arrest | 1.61 | ||
| 5 | 0–3 | before | cardiac arrest | 3.48 | ||
| 6 | 3–6 | after | seizures, cardiomyopathy, cardiac arrest | 3.3 | ||
| 7 | 3–6 | after | respiratory arrest, tetany | 6.8 | 2.0 | 4.0 |
| 8 | 6–9 | after | seizures, cardiac arrest, respiratory arrest | 4.8 | 2.7 | 6.0 |
| 9 | 12–15 | after | cardiac arrest, respiratory arrest | 2.6 | ||
| 10 | 12–15 | after | cardiac arrest | 3.4 | ||
| 11 | 15–18 | after | seizures | 7.8 | 3.69 | 51.0 |
| 12 | 18–21 | after | seizures | 8.4 | ||
| 13 | 24–27 | before | seizures | 8.7 | ||
| 14 | 24–27 | after | seizures | 8.4 | ||
| 15 | 27–30 | after | seizures | 8.3 | ||
| 16 | 48–51 | after | seizures, cardiac arrest | 7.1 | 3.0 |
| Patient | Alkaline phosphatase (83–248 U/L at 0–14 d, 122–469 U/L at 15 d-<1 yr, 142–335 U/L at 1–10 yr) | Rickets present on x-ray | Length/height percentile | Weight percentile | Diet during infancy before index date |
|---|---|---|---|---|---|
| 1 | 0–5 | 0–5 | breast milk and formula | ||
| 2 | 75–80 | 60–65 | breast milk | ||
| 3 | 0–5 | 15–20 | breast milk and formula | ||
| 4 | 134 | 0–5 | 0–5 | breast milk and formula | |
| 5 | 0–5 | breast milk | |||
| 6 | 418 | No | 0–5 | 10–15 | breast milk and formula |
| 7 | 2122 | Yes | 30–35 | 50–55 | breast milk |
| 8 | 723 | Yes | 30–35 | 0–5 | breast milk |
| 9 | 80–85 | breast milk | |||
| 10 | No | 75–80 | breast milk and formula | ||
| 11 | 55–60 | 60–65 | formula | ||
| 12 | 425 | 10–15 | 10–15 | formula | |
| 13 | 452 | ||||
| 14 | 10–15 | 0–5 | breast milk and formula | ||
| 15 | 95–100 | breast milk and formula | |||
| 16 | 502 | breast milk and formula |
Laboratory reference ranges are shown in parentheses for biochemical values. Blank cells indicate that data were not available.
Among the four children with radiographs, two were indicated to rule out child abuse. Among these one child had no fractures identified and in the other the presence of fractures could not be determined. There were no signs of osteopenia. The other 2 radiographs were to evaluate for possible rickets, which was found in both cases. Due to lack of additional radiographs, we do not know whether other infants and children had radiographic evidence of osteopenia or rickets.
Ten of the 16 children (63%) experienced a hypocalcemic complication between December and April, months with limited sun exposure in Minnesota. Five of the 16 children (31%) experienced a hypocalcemic complication between 1996 and 2000, five (31%) between 2001 and 2005, two (13%) between 2006 and 2010, three (19%) between 2011 and 2015, and 1 (6%) after 2015.
Of the 16 patients in the study group, only three (19%) had serum 25(OH)D measured. Two (patients 7 and 8 in Table 3) had 25(OH)D values ≤6 ng/mL (15 nmol/L) (reference range 20–50 ng/mL [50–125 nmol/L]), and both received treatment with calcitriol. Patient 7 was 3–6 months old when hospitalized during winter for a respiratory illness. Within two days of admission, the infant developed tetany and respiratory arrest from hypocalcemic laryngospasm. This infant was exclusively breastfed and had no record of vitamin D supplementation prior to hospitalization. Patient 8 presented in winter at 6–9 months old with cardiac arrest, respiratory failure and tonic seizures. Three weeks earlier, the infant had experienced two apneic spells accompanied by arm and leg stiffening and eye fixation during an upper respiratory tract infection. The infant’s diet included breast milk and baby foods but no vitamin D supplementation, and the infant was underweight.
Although all 16 patients had hypocalcemia, 3 were treated with oral or intravenous calcium chloride or calcium carbonate including patients 7 and 8. Only patients 7 and 8 had radiographic assessment for rickets, and both had rickets. Patients 6 and 10 had radiographs for other reasons, and no evidence of rickets was found. Four patients died within nine days of the index date, but the two patients with confirmed rickets both survived. The 2 infants with rickets had the lowest serum total calcium measurements among the cohort and had elevated alkaline phosphatase values consistent with rickets. Three others had elevated alkaline phosphatase values but did not have 25-hydroxyvitamin D measured or radiographs to exclude VDD or rickets.
Five children were exclusively breastfed, and two of these children had documentation in their medical records recommending vitamin D supplementation. Forty percent of children were less than the 5th percentile for length/height and 36% (of 14 children) were less than the 5th percentile for weight, which are considered short stature and underweight, respectively.
Of children aged 0 to 5 years in Olmsted County during the study period, the incidence of hypocalcemia and a potentially life-threatening complication was 6.1 per 100,000 person-years (95% CI 3.5–10.0). Race-specific incidence of hypocalcemia and a potentially life-threatening complication for those 0 to 4 years of age was 3.1 (95% CI 1.1–8.8), 39.7 (95% CI 18.9–83.3), and 7.2 (95% CI 1.5–34.6) per 100,000 person-years for white, black, and other race, respectively. Blacks had a significantly higher incidence compared with whites or others (p-values <0.001 and P = .033, respectively). There was no significant difference between whites and other race (p=0.29).
Discussion
For the majority of children with life-threatening complications of hypocalcemia, it is unknown whether VDD contributed to their hypocalcemia, because serum 25(OH)D was never measured. Despite this, we confirmed two cases of hypocalcemic cardiac and respiratory arrest due to severe VDD, which was associated with rickets. Their 25(OH)D values ≤6 ng/mL placed them profoundly below the lower end of the recommended minimum of 20 ng/mL. Both were breastfed and experienced hypocalcemic complications during winter. Details of one of these cases have been previously published (27).
Although hypocalcemia should usually prompt measurement of 25(OH)D levels vitamin D status was not assessed in the majority of children in our study. Yet, many children with hypocalcemic complications possessed risk factors for VDD. Thus it is possible that VDD contributed to hypocalcemia in additional children in our cohort. A majority of infants in our study were exclusively breastfed. Human milk is a poor source of vitamin D, and breastfeeding without supplementation is an independent predictor of VDD in infants (1, 28, 29). Maternal VDD was the main etiologic factor for complications of neonatal hypocalcemia in some parts of the world (30). According to the American Academy of Pediatrics, all breastfed and partially breastfed infants should receive 400 IU/day of supplemental vitamin D starting in the first few days of life (31). The National Academy of Medicine (formerly Institute of Medicine) and a global consensus report both recommend an adequate intake of 400 IU/day for all infants zero to 12 months of age, regardless of their mode of feeding (6, 32). Additionally, an Endocrine Society clinical practice guideline suggests lactating women need 1400–1500 IU/day, some of which may come from a maternal supplement to meet their child’s vitamin D needs if their child receives routine supplementation, or 4000–6000 IU/day if their infant is not receiving his or her own vitamin D supplement (4). Although less than half of children who were exclusively breastfed had documentation in their medical records recommending vitamin D supplementation, it is possible that other individuals were, in fact, advised to take supplemental vitamin D. Regardless, the hypocalcemia in all of these children suggest that health care providers should not only recommend vitamin D supplementation to those who are breastfed but should also follow up with parents to ensure supplementation is being administered appropriately.
Forty-four percent of children in our study were black or African American, compared with approximately 6.5% of children <5 years of age in Olmsted County. This supports evidence that 25(OH)D deficiency is more prevalent among dark-skinned individuals than light-skinned (33) and that 25(OH)D deficiency may have a greater role in causing hypocalcemia in black compared with white children. White children presented, on average, at a younger age than black children, suggesting potentially different causes of hypocalcemia according to race. Whatever the cause, this finding highlights the importance of ensuring that all children, regardless of race or degree of skin pigmentation, receive appropriate vitamin D supplements and/or fortification. The greater than expected proportion of children with short stature or underweight prompt one to consider whether factors like inadequate nutrition, intestinal malabsorption, or confounding health problems influenced growth and vitamin D status in the group with hypocalcemic complications.
Three quarters of the children in our study had life-threatening complications of hypocalcemia at an age below two years. In another study, vitamin D deficient children aged 0 to 16 years who presented with symptoms of hypocalcemia were exclusively under 3 or over 10 years of age, ages associated with relatively increased growth velocity (34). Our data support the assertion that during periods of rapid growth, there is an increased requirement for calcium, which can lead to manifestations of hypocalcemia in patients with VDD.
The risk of VDD in temperate climates is greatest during winter and spring months (35–37). Given Olmsted County is located at 44°N latitude, individuals cannot synthesize enough cutaneous vitamin D during winter to meet their requirements (3). In our study, the majority of complications of hypocalcemia occurred during winter and spring, supporting the contention that seasonality is an important contributor to VDD.
A major strength of our study is that it provides population-based data regarding the rate of hypocalcemic complications over a span of more than 20 years. There are also a number of limitations to this study. Our study group was small, which limits the precision of our incidence estimate and our ability to test for patterns in time of year, diet, and trends over time.
Additionally, we investigated patients who had hypocalcemic measurements taken within 14 days of their index date. We likely missed additional children with hypocalcemia who did not have their serum calcium or 25(OH)D measured, and our incidence rate likely underestimates the true burden of VDD. Excluding neonates also potentially underestimates the impact of VDD as maternal VDD can cause neonatal VDD, resulting in hypocalcemic manifestations. Although it is possible that children who never presented for medical care were not included in the incidence denominator, we speculate that this number is likely small, because children in this age group routinely present for health care maintenance visits. Because we recorded 25(OH)D and alkaline phosphatase measurements within six months of the index date, some values may reflect a different season than the time of presentation, thereby limiting their interpretability. Although our study centered on hypocalcemia as a cause of potentially life-threatening complications, it is possible that in some cases the complication could have caused hypocalcemia. Among the patients we excluded for prematurity, complications during the neonatal period, and hypocalcemia not occurring within 14 days of complication, VDD could have been the cause of their complication. Lastly, we had a relatively low proportion of blacks in our population compared with the U.S. average. Because blacks are at greater risk for VDD and complications of hypocalcemia, the incidence of hypocalcemic complications may be even greater in the larger U.S. population.
These results suggest that VDD is an often under-investigated and, therefore, potentially under-recognized cause of severe hypocalcemic complications in young children. Our data show that if clinicians do not check 25(OH)D status in children with hypocalcemia, VDD will not be identified. To reduce the risk of hypocalcemia and VDD, we encourage the education of parents about risk factors for VDD and its potential dangers as well as the benefits of appropriate sunlight exposure, vitamin D-rich diets, and when indicated, vitamin D supplementation, for their children. Among children in our study with complications likely caused by hypocalcemia, measurement of 25(OH)D was uncommon. We recommend clinicians measure serum calcium, 25(OH)D, and alkaline phosphatase in children with known complications of hypocalcemia to identify and treat life-threatening VDD swiftly and appropriately.
Acknowledgments
Supported by the National Institutes of Health’s National Center for Advancing Translational Sciences (UL1 TR002377). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors declare no conflicts of interest.
Abbreviations and Acronyms:
- 25(OH)D
25-hydroxyvitamin D
Footnotes
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Portions of this study were presented as a poster at the North American Primary Care Research Group annual meeting, November 10, 2018, Chicago, Illinois.
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