Maternal thyroid deficiency and pregnancy complications: implications for population screening.

OBJECTIVE: To examine the relation between certain pregnancy complications and thyroid stimulating hormone (TSH) measurements in a cohort of pregnant women. METHODS: TSH was measured in sera obtained from women during the second trimester as part of routine prenatal care. Information was then collected about vaginal bleeding, premature delivery, low birthweight, abruptio placentae, pregnancy induced hypertension, need for cesarean section, low Apgar scores, and fetal and neonatal death. RESULTS: Among 9403 women with singleton pregnancies, TSH measurements were 6 mU/l or greater in 209 (2.2%). The rate of fetal death was significantly higher in those pregnancies (3.8%) than in the women with TSH less than 6 mU/l (0.9%, odds ratio 4.4, 95% confidence interval 1.9-9.5). Other pregnancy complications did not occur more frequently. CONCLUSION: From the second trimester onward, the major adverse obstetrical outcome associated with raised TSH in the general population is an increased rate of fetal death. If thyroid replacement treatment avoided this problem this would be another reason to consider population screening.

Atypical hypothyroidism and the very low birthweight infant.

Results of thyroid screening tests were examined retrospectively on 311,282 infants born in Massachusetts from January 1, 1993 to December 31, 1996. During this period, 118 infants were found to have typical hypothyroidism, characterized by a low thyroxine (T4) and an elevated thyrotropin (TSH) on the initial newborn-screening specimen. Of these, 98 were normal birthweight (NBW, > or = 2,500 g), 9 were low birthweight (LBW, 1,501-2,499 g), and 11 were very low birthweight (VLBW, < or = 1,500 g). Atypical hypothyroidism as defined here is characterized by a low T4 and normal TSH concentration on the initial screening specimen, followed by and elevated TSH level on a repeat blood specimen. This phenomenon occurred in 18 infants, of whom 4 were NBW, 4 were LBW, and 10 were VLBW. The incidence of combined typical and atypical hypothyroidism was: NBW, 1:3051; LBW, 1:1589; VLBW, 1:153, with the highest incidence of atypical hypothyroidism in the VLBW category (48% of cases in this weight category, 56% of all cases of atypical hypothyroidism). In addition, screening programs using a primary TSH screen will miss infants with atypical hypothyroidism. In view of these results, it is suggested that T4 measurements be obtained routinely in all LBW and VLBW infants, with additional routine repeat blood specimens.

Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child.

BACKGROUND: When thyroid deficiency occurs simultaneously in a pregnant woman and her fetus, the child's neuropsychological development is adversely affected. Whether developmental problems occur when only the mother has hypothyroidism during pregnancy is not known. METHODS: In 1996 and 1997, we measured thyrotropin in stored serum samples collected from 25,216 pregnant women between January 1987 and March 1990. We then located 47 women with serum thyrotropin concentrations at or above the 99.7th percentile of the values for all the pregnant women, 15 women with values between the 98th and 99.6th percentiles, inclusive, in combination with low thyroxine levels, and 124 matched women with normal values. Their seven-to-nine-year-old children, none of whom had hypothyroidism as newborns, underwent 15 tests relating to intelligence, attention, language, reading ability, school performance, and visual-motor performance. RESULTS: The children of the 62 women with high serum thyrotropin concentrations performed slightly less well on all 15 tests. Their full-scale IQ scores on the Wechsler Intelligence Scale for Children, third edition, averaged 4 points lower than those of the children of the 124 matched control women (P= 0.06); 15 percent had scores of 85 or less, as compared with 5 percent of the matched control children. Of the 62 women with thyroid deficiency, 48 were not treated for the condition during the pregnancy under study. The full-scale IQ scores of their children averaged 7 points lower than those of the 124 matched control children (P=0.005); 19 percent had scores of 85 or less. Eleven years after the pregnancy under study, 64 percent of the untreated women and 4 percent of the matched control women had confirmed hypothyroidism. CONCLUSIONS: Undiagnosed hypothyroidism in pregnant women may adversely affect their fetuses; therefore, screening for thyroid deficiency during pregnancy may be warranted.

Cortisol in dried blood screening specimens from newborns with raised 17-hydroxyprogesterone and congenital adrenal hyperplasia.

BACKGROUND AND OBJECTIVE: Screening for congenital adrenal hyperplasia (CAH) in newborns has become a routine part of many programmes by measuring levels of 17 alpha-hydroxyprogesterone (17-OHP) in the newborn filter-paper blood specimen. Unfortunately, raised levels of 17-OHP, which are largely the consequence of cross-reacting metabolites, are also found in low birth weight, premature and ill neonates. We speculated that differences in concentrations of cortisol in the newborn screening specimen would aid in distinguishing between CAH positive and CAH negative infants among those with raised levels of 17-OHP. DESIGN: Comparison of cortisol concentrations was made between newborns with CAH and those without but with raised 17-OHP levels. PATIENTS: Newborn filter-paper blood specimens from 31 infants with transient 17-OHP elevations and 16 infants with confirmed CAH were analysed for cortisol. In addition, assay performance was validated by comparing cortisol values obtained from dried whole blood on filter-paper with the corresponding plasma from 31 adults and six neonates. MEASUREMENTS: Cortisol in filter-paper blood specimens was determined by adapting a commercial radioimmunoassay kit that had been designed for the determination of cortisol in serum. RESULTS: The mean cortisol level in the CAH negative group was significantly higher than the mean value in the group with documented CAH (means 1190 +/- 795 nmol/l vs 627 +/- 210 nmol/l; P < 0.01). However, approximately half of the CAH negative infants had cortisol values that overlapped those from the CAH positive group. There was no relationship between the magnitude of the 17-OHP elevation and cortisol concentrations. CONCLUSION: The measurements of cortisol in dried blood on filter-paper using a commercial radioimmunoassay kit has been shown to be reliable and simple to carry out. The level of cortisol in newborn blood specimens can be used to exclude some infants with elevated 17 alpha-hydroxyprogesterone levels from further testing for CAH. However, overlapping cortisol values between CAH positive and negative infants precludes the assay of cortisol from being used routinely as a reliable means of decision making.

Thyroid function in very low birth weight infants.

OBJECTIVES: The purpose of this study was to test the hypothesis that low circulating thyroxine concentrations characteristic of very low birth weight (VLBW) neonates (< 1500 g) are the result of decreased protein binding of thyroid hormones and to elucidate the mechanism(s) responsible and possible significance thereof. DESIGN: Cross-sectional comparison of thyroid related measurements in cord blood specimens from VLBW infants and from full term infants. Longitudinal comparison in cord and 2- and 4-week blood specimens from VLBW infants. PATIENTS: Cord blood specimens were analysed from 47 VLBW and 45 full term infants weighing > or = 2500 g. Repeat analyses in venous bloods from 32 of the VLBW infants were analysed at 2 weeks of age and again at 4 weeks in 23. The first cohort of patients was studied in 1994 and comprised 28 VLBW and 24 full term infants (Cohort A). The studies were repeated in 1995-96 in 19 VLBW infants and 21 full term infants (Cohort B). MEASUREMENTS: T4, free T4 (FT4), T3, thyroxine binding globulin (TBG), and TSH were measured in cord blood and 2- and 4-week venous specimens from VLBW infants and in cord blood specimens of full term infants. Molar ratios of T4/TBG were calculated. RESULTS: (1) Cord blood TBG, T4 and T3 concentrations of VLBW infants were each 60% of those of term infants. TBG concentrations were 397 +/- 111 vs 680 +/- 172 nmol/l (P < 0.0005). T4 concentrations were 76 +/- 22 vs 139 +/- 26 nmol/l (P < 0.0005). FT4 concentrations were in the normal adult range in both neonatal groups. T4/TBG ratios did not differ between the neonatal groups but were significantly less than that of adults (P < 0.001). (2) TSH concentrations in VLBW infants at 2 and 4 weeks were less than 50% of cord blood values. At 2 weeks, TBG concentrations of VLBW infants were unchanged from cord blood concentrations but mean T4 concentration fell by 18% and T4/TBG ratios by 21% (P < 0.005). Mean FT4 rose by 78% (P < 0.02). The changes in mean T4 and FT4 were due largely to FT4 concentrations of 37-113 pmol/l and T4 concentrations of 13-48 nmol/l in 5 infants. These infants also had lower T4/TBG ratios and were smaller and more ill than the remainder of the cohort. The changes disappeared by 4 weeks in 3 of the 4 infants tested. CONCLUSIONS: Cord T4/TBG ratios are the same in very low birth weight and term infants and are significantly lower than in adult blood. These are more than compensated for in term infants by a 236% increase in thyroxine binding globulin concentrations. The lower thyroxine binding globulin concentrations in very low birth weight infants explain their much lower T4 concentrations. Cord FT4 concentrations of full term and very low birth weight infants are in the normal adult range. T4 concentrations are further depressed and free T4 concentrations elevated in the most ill very low birth weight infants at 2 weeks of age in a manner analogous to that of the 'sick euthyroid syndrome'.

Thyroid function in very low birth weight infants: effects on neonatal hypothyroidism screening.

OBJECTIVES: To supply normative data for screening thyroxine (T4) and thyrotropin concentrations correlated with birth weight and age at screening of infants with birth weights ranging from 400 to 5500 gm, and to document the effects of screening of very low birth weight (VLBW) infants, because VLBW infants comprise 0.86% of surviving newborn infants and have very low total T4 concentrations with normal or elevated free T4 concentrations as a result of deficient protein binding of thyroid hormones. STUDY DESIGN: Both retrospective and prospective studies were used. We conducted retrospective analyses of screening of T4 and thyrotropin concentrations in 9,324 term, 18,946 low birth weight, and 3,450 VLBW infants in Massachusetts, and a prospective study of T4 and thyrotropin concentrations in 48 VLBW infants at 2 weeks of age. Forty of the infants also had hormone measurements at 4 weeks, 29 at 8 weeks of age, and 24 had analysis of cord blood samples. RESULTS: Median T4 concentrations for each weight group (in 250 gm increments) increased progressively and significantly up to 2500 gm. Of the surviving VLBW infants, 1.5% had screening T4 concentrations that were unmeasurably low (<3.9 nmol/L (0.3 microgram/dl)). The mean T4 concentration varied with age at screening, increasing from cord blood concentrations to a peak at 1 to 3 days of age and thereafter decreasing to a nadir at about 2 weeks in both low birth weight and VLBW infants. In VLBW infants the mean concentrations return to the level of 1 to 3 days by 4 to 8 weeks of age. The incidence of screening thyrotropin concentrations > or = 40 mU/L correlates inversely with weight. The incidence of early, transient hypothyroidism in VLBW infants defined by this thyrotropin concentration was eight times that in term infants. Two infants had late-onset, transient hypothyroidism at 2 and 7 weeks, respectively. CONCLUSIONS: The normative data related to birth weight and age at screening allow proper interpretation of VLBW results for primary T4 and primary thyrotropin screening programs. Screening of the concentrations of T4 and thyrotropin in VLBW increases the number of secondary measurements of T4 in a primary thyrotropin screening program and the number of secondary thyrotropin measurements in a primary T4 screening program by 6% and 9%, respectively. We recommend screening analyses for VLBW infants in the latter part of the first week of life and again at 2 and 4 to 6 weeks of age. This protocol would increase the number of screening analyses by 1.6%.

Measurement of thyroglobulin in newborn screening specimens from normal and hypothyroid infants.

BACKGROUND AND OBJECTIVE: Thyroglobulin (Tg) has been found in varying concentrations in infants and children with congenital hypothyroidism. Our primary goal was to ascertain whether Tg in filter paper blood specimens used for routine newborn screening would be a useful adjunct in the early diagnosis of newborn children with congenital hypothyroidism. Our secondary objective was to correlate the results of the Tg determinations with the results of thyroid scintigraphy in the same cohort of infants with congenital hypothyroidism. DESIGN: An RIA kit with high sensitivity for the measurement of Tg in serum was modified for use with filter paper blood specimens. Results of thyroid scintigraphy were obtained from the family physicians on 10 infants with ectopic thyroid glands and 18 who were considered to be athyreotic. MEASUREMENTS: Determinations of Tg were carried out retrospectively on newborn screening filter paper blood specimens from 61 full-term normal infants and 42 newborns with confirmed congenital hypothyroidism. RESULTS: Thyroglobulin concentrations during the first week of life in the normal controls ranged between 17 and 160 micrograms/l, with a median of 66 micrograms/l. Tg values for infants with ectopic thyroid glands ranged between 38 and 282 micrograms/l, with a median of 160 micrograms/l, with a median of 66 micrograms/liters. Tg values for infants who were considered athyreotic had Tg values ranging between undetectable and 104 micrograms/l with a median of 15 micrograms/l. Fifty per cent of the athyreotic patients and 50% of patients with ectopic thyroid glands had Tg values above or below the normal range and thus fell within the diagnostic category of hypothyroidism on the basis of Tg alone. Fifty per cent of patients who were considered athyreotic by scintigraphy had Tg concentrations ranging from 20 to 104 micrograms/l. CONCLUSION: These studies have shown that thyroglobulin can be measured in the same filter paper blood specimens used for routine newborn screening. Estimation of thyroglobulin in screening specimens from hypothyroid and normal infants indicated that some infants with congenital hypothyroidism could be identified solely on the basis of the thyroglobulin concentration. Comparison of the result of scintigraphy with thyroglobulin levels in the same hypothyroid patients suggested that thryoglobulin provided a more reliable marker for the presence or absence of the thyroid gland than did scintigraphy.

Early minimal feedings promote growth in critically ill premature infants.

Critically ill premature infants requiring mechanical ventilation and an umbilical artery catheter usually do not receive enteral feedings during the acute phase of their illness. We studied the safety and benefit of early minimal enteral feedings during this time in a prospective, controlled, and randomized study. Twenty-nine infants were randomly assigned to receive only standard intravenous fluid and nutrition (nothing per OS, NPO group; n = 13), or in addition to receive small-volume hypocaloric continuous feedings (1 ml/kg/h), beginning at 24 h of age (early-feeding group; n = 16). Standard enteral feedings were begun in both groups at the resolution of the acute phase of the illness and advanced by protocol. The two groups were of comparable birth weight, gestational age, and Apgar scores. There were no significant differences in the episodes of feeding intolerance. Two infants in the NPO group developed clinical signs of necrotizing enterocolitis. Serum diamine oxidase and somatomedin C were measured weekly until 30-60 days of age and were not different between the two groups. The early-feeding group required fewer days to reach 120 ml/kg/day enteral intake (early-feeding group 10 +/- 3 days, NPO group 13 +/- 4 days; p < 0.05). On day 30 of life the early-feeding group was 223 +/- 125 g above birth weight, while the NPO group was 95 +/- 161 g above birth weight (p < 0.05). The average intake (kcal/kg/day) from day 6 to day 30 was not different between the two groups. We conclude that early minimal feedings in critically ill very-low-birth-weight infants requiring mechanical ventilation are well tolerated and result in reduced time to reach 120 ml/kg/day of enteral feeding and in a greater weight gain by day 30 of life.

Prevalence of thyroid deficiency in pregnant women.

OBJECTIVE: The present study was designed to determine the current prevalence of gestational hypothyroidism, since maternal thyroxine deficiency is associated with poor obstetric outcomes and mental retardation in the surviving offspring. DESIGN: TSH concentrations were measured in the sera of women at 15-18 weeks of gestation. Those sera with TSH concentrations above 6 mU/l and the two sera closest in order with TSH concentrations below 6 mU/l were further analysed for T4, FT4, TBG, and antithyroid antibodies. Study criteria for hypothyroidism were sera with elevated concentrations of TSH plus both a free T4 concentration and a total T4 concentration and/or T4/TBG ratio more than two standard deviations below the mean for the control pregnant women. PATIENTS: The sera were from 2000 consecutive women in Maine being tested for alpha-fetoprotein concentration at 15-18 weeks of gestation. RESULTS: TSH concentrations above 6 mU/l were found in the sera of 49 women, 2.5% of the pregnant women. Six women with elevated TSH concentrations (range 6.9-54 mU/l) had both a FT4 concentration and a T4/TBG ratio and/or a T4 concentration more than two standard deviations below the respective control means, meeting the study criteria for thyroid deficiency, and thus giving a prevalence of 0.3%. The remaining 43 women with elevated TSH concentrations were classified as having compensated thyroid disease although some may have been hypothyroid. Fifty-eight per cent of women with TSH concentrations above 6 mU/l and 90% of the women with elevated TSH concentrations and at least one thyroxine index more than two standard deviations below the control means had positive titres of antithyroid antibodies as opposed to 11% of the controls. CONCLUSIONS: Although it is not known what severity of maternal thyroid deficiency is necessary to cause fetal brain damage, the present data indicate a sufficiently high prevalence of thyroid dysfunction to demand investigation of the mental development of the offspring of women with thyroid dysfunction and of the effect of replacement therapy.

The relationship of insulin-like growth factor-I to total thyroxine in normal and low birth weight infants.

IGF-I concentrations were determined by RIA in eluates of dried blood collected on filter paper from infants who ranged in age from 3 to 21 d. The infants were separated into normal (greater than 2.5 kg) and low (less than 2.5 kg) birth wt groups and further subdivided on the basis of normal (greater than 83.7 nmol/liter) or low (less than 64.4 nmol/liter) levels of thyroxine. Both the normal and low birth wt groups whose blood thyroxine was in the normal range had similar mean IGF-I values during the 1st wk of life that were significantly higher (p less than 0.05) than those of either the normal or low birth wt groups whose thyroxine concentrations were below normal. Infants older than 1 wk of age with normal birth wt and normal thyroxine levels had significantly greater (p less than 0.05) mean IGF-I values than those of any of the other groups. Infants in the low birth wt-normal thyroxine group exhibited modest increases in IGF-I levels after the 1st wk of life that were significantly greater (p less than 0.05) than those found in the low birth wt-low thyroxine infants. These studies have demonstrated that IGF-I concentration is correlated positively with total thyroxine and with birth wt and that the latter is confounded by the former.

Somatomedin-C/insulin-like growth factor-1 in infants with congenital hypothyroidism during the first week of life.

Levels of somatomedin-C/insulin-like growth factor-1 (Sm-C/IGF-1) were determined in whole blood collected on filter paper from 41 newborns with congenital hypothyroidism and 183 full-term neonates with normal thyroid function. The mean Sm-C/IGF-1 value of the untreated hypothyroid infants (0.10 U/ml) was virtually identical with that of the normal controls (0.11 U/ml). We are unable to confirm earlier findings of others that Sm-C/IGF-1 concentrations are lower in hypothyroid newborns than in normal infants.

Radioimmunoassay of somatomedin-C in filter paper discs containing dried blood.

We describe a simple radioimmunoassay (RIA) for estimating concentrations of somatomedin-C (Sm-C) in dried blood on filter paper. A single 3.2-mm blood spot specimen on filter paper is eluted overnight into buffer containing antibody and 125I-labeled Sm-C. The following day, bound and free hormones are separated by addition of goat anti-rabbit gamma globulin in 60 g/L polyethylene glycol solution. The correlation between values obtained for such blood-spot discs and the corresponding wet plasma is highly significant (r = 0.90, p less than 0.001). The relative concentrations (arbitrary units) of Sm-C as determined for specimens on filter paper from mothers and infants, and for cord bloods, are similar to those reported by others using acidified serum.

Prolactin levels in hypothyroid and euthyroid infants during the first week of life.

A radioimmunoassay (RIA) procedure was devised for the estimation of PRL in eluates of dried whole blood from filter paper. Levels of PRL were measured in newborn blood obtained during the first week of life from 530 infants of normal birthweight (greater than 2500 g) with normal T4 values, 114 infants of normal birthweight with low T4 values (T4 less than 6.0 micrograms/dl), 47 infants with congenital hypothyroidism, 57 infants of low birthweight (less than 2500 g) with normal T4 values, and 114 infants of low birthweight with low T4 values. Examination of PRL concentrations among comparably aged infants from the various groups revealed that the mean PRL values of the hypothyroid group were consistently greater than those of any of the other groups of infants regardless of the mean T4 levels. With the exception of the hypothyroid infants, the groups with both the lowest mean T4 concentrations and mean body weights also had the lowest mean PRL values.