Clinical Endocrinology (1999) 50, 809–814 Case report 809  1999 Blackwell Science Ltd Fetal pituitary negative feedback at early gestational age Yardena Rakover*, Ehud Weiner², Netanel Mosh* and Eliezer Shalev² *Paediatric Endocrine Unit and ² Department of Obstetrics & Gynecology, Ha’Emek Medical Centre, Afula, affiliated to the Rappaport Faculty of Medicine, Technion, Haifa, Israel (Received 22 July 1998; returned for revision 19 August 1998; finally revised 25 September 1998; accepted 21 October 1998) Summary We describe an early prenatal diagnosis and the successful treatment of fetal Graves’ disease from transplacental transfer of maternal thyroid stimulating autoantibodies (TSAb). The diagnosis of fetal thyro- toxicosis was made by umbilical cord sampling (UBS) at 20 weeks gestation, based on suppressed TSH with elevated FT4 levels. Therapy with propylthiouracil (PTU) improved fetal thyroid function tests as well as the clinical signs of fetal Graves’ disease. Three more UBS were conducted before delivery indicating persisting mild fetal hyperthyroidism. Undetectable concentrations of thyrotrophin in fetal serum in the presence of markedly elevated FT4, suggests pituitary negative feedback at as early as 20 weeks gestation. Amniotic fluid thyrotrophin levels were measured at 20,24 and 26 weeks and were shown to correlate better with (elevated) maternal rather than (suppressed) fetal TSH values; therefore, we believe that amniotic fluid thyrotrophin measurement is unreliable for prediction of fetal thyroid status. Our observation is the first documentation of an intact feedback mechanism so early in fetal develop- ment and it suggests that pituitary maturation occurs earlier than previously believed. Graves’ disease occurs in one in 500 pregnancies (Burrow, 1985), while neonatal Graves’ disease occurs in only 1·5–12% of infants born to affected mothers (Bruise et al., 1988; Fisher, 1990). However, in affected infants, a mortality rate of 12–16% has been reported (Hollingsworth & Mabry, 1976). The foetus is at risk of thyrotoxicosis from transplacental transfer of thyroid stimulating antibodies (TSAb) and hypothyroidism from transplacental transfer of thyroid blocking antibodies (TBAb) and antithyroid drugs (McKenzie & Zakarija, 1992; Perelman & Clemons, 1992). It has been shown that prenatal diagnosis and treatment of fetal goitre, thyrotoxicosis or hypothyroidism, improve the outcome of pregnancies complicated by Graves’ disease (Porreco & Bloch, 1990; Wenstrom et al., 1990; McKenzie & Zakarija, 1992; Perelman & Clemons, 1992; Polk, 1994; Hadi & Stickland, 1995; Wallace et al., 1995; Treadwell et al., 1996). UBS has become a simple and frequently used procedure providing data on fetal thyroid development and function at various gestational ages (Ballabio et al., 1989; Radunovic et al., 1991; Thorpe-Beeston et al., 1991). The finding of elevated serum concentrations of thyrotrophin in the presence of a progressive increase in thyroid hormone concentrations in fetal cord blood suggests that the sensitivity of the fetal pituitary gland to negative feedback is limited (Thorpe-Beeston et al., 1991). We describe a case of in utero diagnosis and treatment of Graves’ disease, which challenges the concept of limited negative feedback of the fetal pituitary. Methods Umbilical blood and amniotic fluid TSH were measured by time-resolved fluoroimmunoassay using a commercial kit (DELFIA-Wallac), which is a highly sensitive method (the detection limit is 0·005 mU/l). Maternal and newborn TSH were measured by enzyme immunoassay (ELIZA) using a commer- cial kit (Enzymun, Boehringer Mannheim, Germany). FT4 was measured by enzyme immunoassay (ELIZA) using a commer- cial kit (Enzymun, Boehringer Mannheim). Thyroid binding immunoglobulins (TBII) were assayed by RIA using a commercial kit (Cis, bio international) based on binding assay. TSAb were estimated by measuring the capacity of serum immunoglobulin preparation to stimulate cAMP in cultured human thyroid cells, as previously described (Kraeim et al., 1988).TSH receptor blocking antibodies (TBAb) were assayed by measuring the degree of inhibition of TSH- stimulated cAMP production of cultured human thyroid cells by serum immunoglobulin preparations, as described in detail previously (Kraiem et al., 1987). A normal reference for amniotic fluid thyrotrophin was established in our laboratory Correspondence: Dr Yardena Rakover, Paediatric Endocrine Unit, Ha’Emek Medical Centre, Afula, Israel. Fax: þ 972 66524128