R. Klein

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 childs 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.

EFFECT OF PHENYLALANINE DEFICIENT DIET ON BONE MARROW AND AMINO ACID METABOLISM.

Summary Normal premature infants fed a diet deficient in phenylalanine developed changes in their bone marrow within 24 to 48 hours. These marrow changes consisted specifically in cytoplasmic vacuolization of ery-throid precursors. Vacuoles also occurred in the myeloid elements. The vacuoles of the red cell precursors were associated with marked depression of serum phenylalanine concentrations to levels of 4 and 6 micromoles per liter. These effects were reversible within 48 hours by the addition of 100 mg per kg of phenylalanine to the diet. Any possible effects of the phenylalanine deficiency on other amino acids was obscured by the increased serum and urine concentrations of these amino acids resulting from increased intake provided by the proprietary casein hydrolysate preparation. Addition of valine, alanine, and methionine to the normal and deficient diets did not produce marrow changes or other toxic effects. The authors gratefully acknowledge their indebtedness to Miss Meta Bohanan, R.N., and her staff for help in carrying out the observations on the patients and to Drs. H. P. Baker, R. Feigin, F. K. Kennedy, D. Palant, N. Pleva and P. Sexton of the resident staff for major contributions to the care and study of the patients.

Effect of cold on muscle potentials and electrolytes

Abstract External cooling in vivo produces multiple changes in human and rat muscle membrane potentials and electrolytes. The first change noted is the appearance of increasing numbers of spontaneous potentials and repetitive action potentials after a single stimulus as the rat muscle is cooled to 32° C or less. Extracellular action potentials in humans and both intracellular and extracellular action potentials in rats become progressively more prolonged as the muscle cools below 26° C. In the animals this is accompanied by an increase in muscle Na (and Cl) and decrease in muscle K. Further cooling to below 23° C produces a drop in resting membrane potential as well as progressive increase in duration of the action potential. The previous increase in muscle Na is unaffected but muscle K decreases progressively and muscle water increases without change in muscle inulin space. Muscle Mg and Ca were not significantly different from control values. As cooling progresses in both rats and humans there is at first a slight increase in amplitude of the action potential and then a marked and significant diminution in amplitude. Cooling increases the threshold for stimulation and the delay between stimulus and onset of action potential. At temperatures below 8° C no visible contraction could be seen and the membrane became unresponsive to stimuli of greater than 100 v. The repetitive action potentials noted with minimal cooling diminished rapidly in amplitude. Repetitive action potentials became undemonstrable before the single stimulated action potential did. The possible interrelation of electrolyte changes, muscle membrane potentials and muscle contraction is considered.

Cardiac Glycoside Effects on Rat Skeletal Muscle Potentials and Electrolytes

Summary The effect of cardiac glycosides on rat skeletal muscle intracellular action potenials was studied and correlated with changes in serum and muscle electrolytes and water. In the early minutes after subcutaneous administration of ouabain, 25-200 μg, there was a significant shortening of depolarization and repolarization times. After 15-min repolarization lengthened and after 50 min depolarization also becomes prolonged. The early phase of shortening is more easily demonstrated with 25-50 μg doses, and the latter prolongation of the action potential is more marked and consistent with the larger doses. There is also a biphasic action on muscle water content. This is apparently an increase in intracellular water as no change was seen in inulin space. The time relationship to this effect is unrelated to the time of changes in action potentials. Muscle water was increased for the first hour after injection of ouabain, returned to normal 1 to 2 hr after huge doses of ouabain, 400-600 μg, and was decreased 5 hr after the last of 3 doses of digitoxin over a 24-hr period. Muscle sodium increased significantly and progressively from 15 to 120 min after ouabain and was normal 5 hr after 3 doses of digitoxin. Muscle potassium was decreased after 15 min and became progressively lower over the next 105 min. It was also low 5 hr after 3 doses of digitoxin. Serum and muscle electrolyte and water changes are not demonstrable during the phase of shortening of the stimulated action potential. Prolongation of the action potential correlates in time only with diminution of muscle potassium content. Shortening of the action potential is thought to represent the therapeutic effect of cardiac glycosides, prolongation the toxic effect. Possible correlations with increased active sodium transport and with inhibition of Na and K dependent ATPase are discussed.

Chloramphenicol and L-Phenylalanine Therapy in Experimental Klebsiella pneumoniae Infection in Mice.

Summary Parenteral administration of phenylalanine in a dose equivalent to that of chloramphenicol enhanced the antibacterial effect of chloramphenicol in mice infected with Klebsiella pneumoniae. Larger doses of phenylalanine, however, reduced the drugs antibacterial efficacy. The interaction of phenylalanine and chloramphenicol is discussed in relation to bacterial and mammalian cell protein synthesis.

Maternal Thyroid Deficiency During Pregnancy and Subsequent Neuropsychological Development of the Child

When both the fetus and mother have thyroid deficiency, it can be expected that neuropsychological development will be compromised, but it is not clear whether similar problems occur when only the mother is hypothyroid. This study reviewed thyrotropin (TSH) values in stored sera from >25,000 pregnant women. Forty-seven had serum TSH values at or above the 99.7th percentile for all pregnant women, and 15 others had levels between the 98th and 99.6th percentiles as well as a low thyroxine level (below 99.7 nmol/liter). The hypothyroid women were matched with 124 women whose TSH values were normal, and their children underwent 15 tests when they were 7 to 9 years of age. These tests evaluated intelligence, language function, attention, reading ability, visuomotor function, and performance at school. None of the infants in this study had congenital hypothyroidism. The hypothyroid and normothyroid women were comparable demographically and in their pregnancies. Case children performed less well than control children on all of the neuropsychological tests. Full-scale Wechsler IQ scores were an average of 4 points lower in the children of hypothyroid mothers than in the comparison group; 15 and 5 percent, respectively, had scores of 85 or below. IQ scores of the children of the 48 women not treated for hypothyroidism during pregnancy were an average of 7 points lower than those of control children, and 19 percent had scores of 85 or less. When examined 11 years after delivery, 64 percent of untreated women and 4 percent of control women had confirmed hypothyroidism. These findings suggest that it may be worthwhile to routinely screen for hypothyroidism in early pregnancy. Testing at the first prenatal visit and prompt follow-up of those with positive results would permit timely treatment and could prevent adverse neuropsychological effects during early child development. N Engl J Med 1999;341:549–555