Sabine M.P.F. de Muinck Keizer-Schrama

Reference data for bone density and body composition measured with dual energy x ray absorptiometry in white children and young adults

Aims: To obtain normative data on bone mineral density and body composition measured with dual energy x ray absorptiometry (DXA) from early childhood to young adulthood. Methods: Cross sectional results from 444 healthy white volunteers (4–20 years) in the Netherlands were combined with the results from 198 children who agreed to participate in the follow up study approximately four years later. DXA (Lunar, DPXL) of lumbar spine and total body was performed to assess bone density and body composition. Results: Bone density and lean body mass (LBM) increased with age. Maximal increase in bone density and LBM occurred around the age of 13 years in girls and approximately two years later in boys. Bone density of total body and lumbar spine showed an ongoing slight increase in the third decade. Mean fat percentage in boys remained at 10.5% throughout childhood, but increased in girls. Conclusions: Most of the skeletal mass in lumbar spine and total body is reached before the end of the second decade, with a slight increase thereafter. This study provides reference values for bone density and body composition measured with DXA for children and young adults.

Maternal Thyroid Function during Early Pregnancy and Cognitive Functioning in Early Childhood: The Generation R Study

CONTEXT Thyroid hormones are essential for neurodevelopment from early pregnancy onward. Yet population-based data on the association between maternal thyroid function in early pregnancy and childrens cognitive development are sparse. OBJECTIVE Our objective was to study associations of maternal hypothyroxinemia and of early pregnancy maternal TSH and free T(4)(FT(4)) levels across the entire range with cognitive functioning in early childhood. DESIGN AND SETTING We conducted a population-based cohort in The Netherlands. PARTICIPANTS Participants included 3659 children and their mothers. MAIN MEASURES In pregnant women with normal TSH levels at 13 wk gestation (SD = 1.7), mild and severe maternal hypothyroxinemia were defined as FT(4) concentrations below the 10th and 5th percentile, respectively. Childrens expressive vocabulary at 18 months was reported by mothers using the MacArthur Communicative Development Inventory. At 30 months, mothers completed the Language Development Survey and the Parent Report of Childrens Abilities measuring verbal and nonverbal cognitive functioning. RESULTS Maternal TSH was not related to the cognitive outcomes. An increase in maternal FT(4) predicted a lower risk of expressive language delay at 30 months only. However, both mild and severe maternal hypothyroxinemia was associated with a higher risk of expressive language delay across all ages [odds ratio (OR) = 1.44; 95% confidence interval (CI) = 1.09-1.91; P = 0.010 and OR = 1.80; 95% CI = 1.24-2.61; P = 0.002, respectively]. Severe maternal hypothyroxinemia also predicted a higher risk of nonverbal cognitive delay (OR = 2.03; 95% CI = 1.22-3.39; P = 0.007). CONCLUSIONS Maternal hypothyroxinemia is a risk factor for cognitive delay in early childhood.

Bone mineral density, body composition, and height in long‐term survivors of acute lymphoblastic leukemia in childhood

BACKGROUND Childhood leukemia has increasing numbers of survivors, so more emphasis is being placed on long-term effects. The ALL-6 protocol of the Dutch Childhood Leukemia Study Group involved high-dose dexamethasone and methotrexate and no cranial irradiation. Therefore, we studied the long-term effects on bone mineral density (BMD), body composition, and growth in survivors of non-high-risk ALL treated with the ALL-6 protocol. PROCEDURE Twenty-three subjects (12.2-25.4 years) participated in this cross-sectional study. Mean follow-up was 9.6 years (range 7.9-11.4 years). BMD of lumbar spine (LS) and total body (TB) and body composition were measured by dual energy X-ray absorptiometry; results are expressed as standard deviation scores (SDS). Bone mineral apparent density (BMAD(LS)) was calculated to correct for bone size. A questionnaire was administered to determine physical activity, calcium intake, and medical history. RESULTS Mean SDS for BMD(LS), BMD(TB), and BMAD(LS) were normal. None of the subjects had BMD below -2 SDS; one subject had BMAD(LS) below -2 SDS. Mean SDS for lean body mass, percentage fat, and height were not significantly different from zero. Calcium intake correlated positively with BMD. Nine subjects reported traumatic fractures (eight during or shortly after therapy). CONCLUSIONS Ten years after ALL-6 treatment, no long-term side effects on height, BMD, or body composition were found in this small group of patients, despite high-dose dexamethasone and methotrexate. This study suggests that ALL treatment without cranial irradiation might not be associated with long-term side effects on growth and BMD.

Peak bone mineral density, lean body mass and fractures

BACKGROUND During childhood and adolescence, bone mass and lean body mass (LBM) increase till a plateau is reached. In this longitudinal and cross-sectional study, the age of reaching the plateau was evaluated for lumbar spine and total body bone mass measurements and lean body mass. The association between fractures and bone mineral density (BMD) was studied. PATIENTS AND METHODS We included 501 healthy participants, 141 males and 360 females, aged 13-29 years. Of these 90 had participated in a previous longitudinal study of 444 participants, aged 4-20 years (for the first measurement) and 198 participants, aged 8-25 years (for a second measurement). BMD and body composition were measured with dual energy X-ray absorptiometry (DXA). Volumetric BMD (bone mineral apparent density, BMAD) was calculated. All the data were used to determine the age of reaching the plateau. RESULTS The plateau for lumbar spine BMD, BMAD, total body BMD, bone mineral content and LBM was reached between 18 and 20 years of age in females and between 18 and 23 years in males. The prevalence of fractures was 37% in males and 28% in females. Total body BMD Z-score was significantly lower in all participants who had had a fracture (p<0.05), whereas lumbar spine BMD and BMAD was only significantly lower in females who had had fractures (p=0.007 and p<0.001, respectively). Mean lumbar spine BMAD Z-score at the previous measurement was significantly lower in the participants who had a first fracture between the last two measurements (p=0.04). CONCLUSION Peak BMD and peak LBM were attained between 18 and 20 years in females and between 18 and 23 years in males in this study using longitudinal and cross sectional data in the age range of 4 to 30 years. A significantly lower total body BMD was seen in participants who had had a fracture and a lower lumbar spine BMD and BMAD in females who had had a fracture. Lumbar spine BMAD Z-score seems to be a good predictor for future fractures.

Hypothyroxinemia and TPO-Antibody Positivity Are Risk Factors for Premature Delivery: The Generation R Study

CONTEXT Premature delivery is an important risk factor for child mortality and psychiatric, metabolic, and cardiovascular disease later in life. In the majority of cases, the cause of prematurity cannot be identified. Currently, it remains controversial whether abnormal maternal thyroid function during pregnancy increases the risk of premature delivery. Therefore, we investigated the relation between maternal serum thyroid parameters and the risk of premature delivery in a large prospective population-based study. DESIGN Serum TSH, free T4 (FT4), T4, and TPO antibodies (TPOAbs) were determined during early pregnancy in 5971 pregnant women from the Generation R study. Data were available on maternal age, parity, smoking, socioeconomic status, ethnicity, maternal anthropometrics, and urinary iodine levels. RESULTS Of all women, 5.0% had a premature delivery (<37 weeks), 4.4% had a spontaneous premature delivery, and 1.4% had a very premature delivery (<34 weeks). High TSH levels and subclinical hypothyroidism were associated with premature delivery but not with spontaneous premature delivery. Maternal hypothyroxinemia was associated with a 2.5-fold increased risk of premature delivery, a 3.4-fold increased risk of spontaneous premature delivery, and a 3.6-fold increased risk of very premature delivery (all P < .01). TPOAb positivity was associated with a 1.7-fold increased risk of premature delivery (P = .01), a 2.1-fold increased risk of spontaneous premature delivery (P = .02), and a 2.5-fold increased risk of very premature delivery (P = .04). These effects remained similar after correction for TSH and FT4 levels. CONCLUSIONS Hypothyroxinemia and TPOAb positivity are associated with an increased risk of premature delivery. The increased risk in TPOAb-positive women seems to be independent of thyroid function.

Maternal Thyroid Hormone Parameters during Early Pregnancy and Birth Weight: The Generation R Study

CONTEXT Maternal hyperthyroidism during pregnancy is associated with an increased risk of low birth weight, predisposing to neonatal morbidity and mortality. However, the effects of variation in maternal serum thyroid parameters within the normal range on birth weight are largely unknown. OBJECTIVE The aim was to study the effects of early pregnancy maternal serum thyroid parameters within the normal range on birth weight, as well as the relation between umbilical cord thyroid parameters and birth weight. DESIGN, SETTING, AND PARTICIPANTS In early pregnancy, serum TSH, FT4 (free T(4)), and thyroid peroxidase antibody levels were determined in 4464 pregnant women. Cord serum TSH and FT4 levels were determined in 2724 newborns. Small size for gestational age at birth (SGA) was defined as a gestational age-adjusted birth weight below the 2.5th percentile. The associations between normal-range maternal and cord thyroid parameters, birth weight, and SGA were studied using regression analyses. RESULTS In mothers with normal-range FT4 and TSH levels, higher maternal FT4 levels were associated with lower birth weight [β = -15.4 (3.6) g/pmol · liter, mean (SE); P = 1.6 × 10(-5)], as well as with an increased risk of SGA newborns [odds ratio (95% confidence interval) = 1.09 (1.01-1.17); P = 0.03]. Birth weight was positively associated with both cord TSH [β = 4.1 (1.4) g/mU · liter; P = 0.007] and FT4 levels [β = 23.0 (3.2) g/pmol · liter; P = 9.2 × 10(-13)]. CONCLUSIONS We show that maternal high-normal FT4 levels in early pregnancy are associated with lower birth weight and an increased risk of SGA newborns. Additionally, birth weight is positively associated with cord TSH and FT4 levels. These data demonstrate that even mild variation in thyroid function within the normal range can have important fetal consequences.

Maternal Early Pregnancy and Newborn Thyroid Hormone Parameters: The Generation R Study

CONTEXT Abnormal maternal thyroid parameters are associated with adverse pregnancy outcomes, with consequences for both mother and child. Although various studies have studied maternal thyroid parameters during the first half of pregnancy, little is known about their relations with thyroid parameters of the child. OBJECTIVE The objective was to study maternal thyroid parameters during the first half of pregnancy as well as their relations with cord thyroid parameters. DESIGN, SETTING, AND PARTICIPANTS Serum TSH, free T(4) (FT4), T(4), and thyroid peroxidase antibody (TPOAb) levels were determined once between gestational wk 9 and 18 in 5393 pregnant women from the population-based Generation R study. Cord serum TSH and FT4 levels were determined in 3036 newborns. RESULTS Between gestational wk 9 and 18, the maternal TSH reference range (2.5th to 97.5th percentile) was 0.03-4.04 mU/liter. Gestational age was positively correlated with maternal TSH (r = 0.06, P = 6.3 × 10(-5)) and total T(4) (r = 0.21, P = 1.4 × 10(-44)) and negatively with FT4 (r = -0.27, P=7.3 × 10(-76)) and TPOAb-positivity (r=-0.04, P = 0.01). TPOAb positivity was associated with more subclinical (20.1 vs. 2.4%, P = 1.5 × 10(-39)) and overt hypothyroidism (3.3 vs. 0.1%, P = 1.4 × 10(-10)). Maternal and cord TSH were positively associated (β = 0.47 ± 0.15, P = 1.3 × 10(-5)) as well as maternal and cord FT4 (β = 0.11 ± 0.02, P = 4.5 × 10(-6)). CONCLUSIONS We confirm correlations of maternal thyroid parameters with gestational age during the first half of pregnancy and show a substantially increased risk of (subclinical) hypothyroidism in TPOAb-positive mothers. A substantial part of the mothers had a TSH level above 2.5 mU/liter, underlining the importance of using population-specific reference ranges. Maternal and cord thyroid parameters were positively correlated, the exact biological basis of which remains to be determined.

Long-Term Effects of Growth Hormone Therapy on Bone Mineral Density, Body Composition, and Serum Lipid Levels in Growth Hormone Deficient Children: A 6-Year Follow-Up Study

Aim: To study the effects of growth hormone (GH) deficiency (GHD) and GH replacement therapy (GHRx) on bone mineral density (BMD) and body composition. Methods: 59 GHD children participated (age range 0.4–16.9 years); the follow-up period was 6 years. Lumbar spine BMD (BMD_LS), total-body BMD (BMD_TB), and body composition were measured prospectively using dual-energy X-ray absorptiometry. Results: Mean BMD_LSand BMD_TB were significantly reduced at the time of the diagnosis. The bone mineral apparent density of the lumbar spine (BMAD_LS) was reduced to a lesser degree. The BMAD_LS increased to normal values after 1 year; BMD_LS and BMD_TB normalized 1 year later. At the time of the diagnosis, the lean body mass was reduced and steadily increased during GHRx. Percentage of body fat was increased at baseline and normalized within 6 months. The severity of GHD was not associated with the BMD at diagnosis or the response to GHRx. Conclusion: Areal BMD_LS and BMD_TB and, to a lesser extent, BMAD_LS are decreased in GHD children, but normalize within 1–2 years.

Bone mineral density and bone metabolism of prepubertal children with asthma after long‐term treatment with inhaled corticosteroids

Little is known about the effect of long‐term treatment with inhaled corticosteroids (ICS) on bone mineral density (BMD) in asthmatic children. In the present cross‐sectional study BMD, bone metabolism, height, body composition, and bone age were evaluated in 40 prepubertal children (21 boys) with asthma, treated with a moderate to high dose of ICS over a period of 3 to 8 years. Body composition and BMD of the lumbar spine and total body were measured by Dual Energy X‐ray Absorptiometry. BMD results were compared with 148 prepubertal healthy children of the same population. Blood samples were taken for the determination of biochemical bone parameters.

Efficacy and safety of oxandrolone in growth hormone-treated girls with turner syndrome.

CONTEXT AND OBJECTIVE GH therapy increases growth and adult height in Turner syndrome (TS). The benefit to risk ratio of adding the weak androgen oxandrolone (Ox) to GH is unclear. DESIGN AND PARTICIPANTS A randomized, placebo-controlled, double-blind, dose-response study was performed in 10 centers in The Netherlands. One hundred thirty-three patients with TS were included in age group 1 (2-7.99 yr), 2 (8-11.99 yr), or 3 (12-15.99 yr). Patients were treated with GH (1.33 mg/m(2) . d) from baseline, combined with placebo (Pl) or Ox in low (0.03 mg/kg . d) or conventional (0.06 mg/kg . d) dose from the age of 8 yr and estrogens from the age of 12 yr. Adult height gain (adult height minus predicted adult height) and safety parameters were systematically assessed. RESULTS Compared with GH+Pl, GH+Ox 0.03 increased adult height gain in the intention-to-treat analysis (mean +/- sd, 9.5 +/- 4.7 vs. 7.2 +/- 4.0 cm, P = 0.02) and per-protocol analysis (9.8 +/- 4.9 vs. 6.8 +/- 4.4 cm, P = 0.02). Partly due to accelerated bone maturation (P < 0.001), adult height gain on GH+Ox 0.06 was not significantly different from that on GH+Pl (8.3 +/- 4.7 vs. 7.2 +/- 4.0 cm, P = 0.3). Breast development was slower on GH+Ox (GH+Ox 0.03, P = 0.02; GH+Ox 0.06, P = 0.05), and more girls reported virilization on GH+Ox 0.06 than on GH+Pl (P < 0.001). CONCLUSIONS In GH-treated girls with TS, we discourage the use of the conventional Ox dosage (0.06 mg/kg . d) because of its low benefit to risk ratio. The addition of Ox 0.03 mg/kg . d modestly increases adult height gain and has a fairly good safety profile, except for some deceleration of breast development.