Is lithium a real teratogen? What can we conclude from the prospective versus retrospective studies? A review.

BACKGROUND: Lithium is a drug used mainly for the treatment of Bipolar Disorder (BD). Case reports and several retrospective studies have demonstrated possible teratogenicity, but the data in the different studies was inconclusive. METHODS: We summarized all published studies in English, including case reports. RESULTS: We found 24 case reports, of which six infants had congenital anomalies, five having cardiac anomalies, one of them being Ebstein's anomaly. In the retrospective studies there were, in the Lithium Baby Registry, 225 registered cases with 25 anomalies, 18 of them being cardiac, of which six had Ebstein's anomaly. An additional retrospective study on 59 cases found seven anomalies, four of them being cardiac. On the other hand, none of the prospective studies (296 liveborn infants) demonstrated any increase in the rate of congenital anomalies, although two had Ebstein's anomaly. All case control studies regarding Ebstein's anomaly were negative, and among 222 infants with Ebstein's anomaly and 44 with tricuspid atresia none of the mothers had taken lithium during pregnancy. CONCLUSIONS: Considering the serious limitations of the retrospective and case control studies that are also retrospective, lithium does not seem to be a significant teratogen, and hence should be given, if indicated, in pregnancy. It is, however, advisable to perform a fetal echocardiography to exclude the possibility of cardiac anomalies. Lamotrigine seems to be a possible alternative.

Antiphosphatidylserine antibodies affect rat yolk sacs in culture: a mechanism for fetal loss in antiphospholipid syndrome.

PROBLEM: A variety of reproductive impairments have been reported in the context of the antiphospholipid syndrome (APS). APS is associated with the presence of antibodies to negatively charged phospholipids that may affect the outcome of pregnancy. METHOD OF STUDY: Rat embryos were cultured within their yolk sacs. The effects of two antiphosphatidylserine monoclonal aPS antibodies (HL5B, RR7F) regarding their influence on growth and apoptotic events of the yolk sacs, as well as on growth and the morphology of the embryos, were studied. RESULTS: Exposure of rat embryos and their yolk sacs to aPS inhibited yolk sac growth. Moreover, increased number of apoptotic events of giant cells in the aPS-exposed ectoplacental cone was found in comparison with control IgG-exposed giant cells (P < 0.05). No significant damage was observed in the embryos. CONCLUSIONS: The results suggest that aPS affect growth and apoptosis of rat ectoplacental cone.

Effect of sera from women with systemic lupus erythematosus or antiphospholipid syndrome and recurrent abortions on human placental explants in culture.

BACKGROUND: Systemic lupus erythematosus (SLE) with or without evidence of antiphospholipid antibodies (aPA) and antiphospholipid syndrome (APS) is associated with a high rate of spontaneous abortions. The placenta is thought to be the site of pathological damage in many of these abortions. To test this hypothesis, we studied the effects of sera obtained from women with SLE with or without treatment on human placental explants in culture. METHODS: We cultured 5.5- to 7.5-week-old human placental explants in a culture medium containing F-12 DMEM and 10% FCS or in 90% human serum obtained from nonpregnant women with SLE prior to or after treatment. Culture was carried out for 96 hr. At the end of the culture period, we studied the secretion of the placental hormones estrogen (E2), progesterone (PGN), and human chorionic gonadotropin (hCG). In addition, we studied the proliferation rate (using PCNA staining) and the rate of apoptosis (using ApoTag) of the trophoblastic cells. RESULTS: Placentae grew better in normal human serum than in a chemically defined medium of F-12 DMEM and 10% FCS. Enhanced growth and higher secretion rates for hCG and estradiol (E2) were manifested in placentae cultured in control sera with no change in PGN secretion. Secretion rates of hCG and PGN (but not of E2 in the treated group) by placental explants were similar to that of controls. However, the serum levels prior to culture were not measured. Further, explants in serum from untreated women with SLE produced a significant decrease in the proliferation rate of the trophoblastic cells and an increase of apoptosis. Treatment significantly reduced the apoptotic rate and increased cell proliferation, but the cell proliferation rate was still lower than that noted in controls. CONCLUSIONS: We conclude that sera from women with SLE may directly damage the developing placenta reducing proliferation and enhancing apoptosis. Successful treatment of the women reduces that damage.