Audrey H. Nora

Maternal transmission of congenital heart diseases: New recurrence risk figures and the questions of cytoplasmic inheritance and vulnerability to teratogens

A review of 8 studies involving 3,996 offspring of parents who have congenital heart disease revealed that the risk for all defects was substantially higher if the affected parent was the mother rather than the father. The risk ratio ranged from a high of 6.39 for aortic stenosis to a low of 1.48 for patent ductus arteriosus, and the ratio was statistically significant in aortic stenosis (p = 0.025) and ventricular septal defect (p less than 0.001). Despite the relatively large number of cases, there were still too few patients to reveal statistical significance for a malformation such as atrioventricular canal, in which there were 5 affected offspring among 36 children of mothers who had atrioventricular canal and no affected children among 16 offspring of affected fathers (p = 0.12). The possible reasons for the preponderance of affected offspring of mothers with a congenital heart disease was studied in the context of various modes of inheritance and maternal physiology. The preliminary conclusion is that although many familial cases of congenital heart disease are compatible with multifactorial inheritance and vulnerability to teratogens, an important subset of cases, particularly in some high-risk families, may be better explained by cytoplasmic inheritance than by multifactorial or mendelian modes. Current genetic counseling should take into account the differences in risk to offspring of affected mothers while confirmation and further investigation proceeds.

Can the Pill Cause Birth Defects

The difficulties in documenting causal relations between environmental agents and birth defects are well recognized. Epidemiologic surveys and surveillance studies should, in theory, be productive ...

Clinical study of daunomycin and prednisone for induction of remission in children with advanced leukemia.

Abstract Sixty-seven children with acute leukemia and with one or more previous relapses were treated with Daunomycin and prednisone to determine the effectiveness of this combination for inducing clinical and hematologic remissions. Sixty had acute lymphocytic, and seven acute myelocytic leukemia. Of the former, 39 attained complete, and 10 partial, bone-marrow remission. Of the latter, one had complete, and one partial remission. Median time to onset of remission marrow in the 51 children was 27 days. Maintenance of remission by Daunomycin was not studied. Limiting toxicity included leukopenia, thrombocytopenia, oral ulcerations, Cushingoid appearance and chemical cellulitis at the injection site. Daunomycin and prednisone are a highly effective drug combination for induction of remissions in children with leukemia refractory to conventional antileukemic drugs.

Clinical study of daunomycin (NSC-82151) in children with acute leukemia.

Thirty‐nine children with advanced leukemia, resistant to conventional chemotherapy, were treated with daunomycin. Seven patients (18%) achieved partial or complete marrow remissions within a median time of 17 days. Five of the seven children who responded received prednisone concurrently. The remissions lasted only 21–37 days. Limiting toxicity included leukopenia, thrombo‐cytopenia, and oral ulcerations. No renal, hepatic, or cardiac toxicity was noted. It is concluded that daunomycin alone has low‐grade activity for induction of remission in children with advanced acute leukemia and that combination with prednisone may enhance the response rate.

Exogenous sex hormones and birth defects: continuing the dialogue.

Physicians are placed in a difficult situation regarding the use of drugs, specifically exogenous sex hormones, during pregnancy. Equal numbers of studies have been conducted to both support and refute claims of teratogenic effects. The use of low level teratogens during pregnancy, which may cause malformations in only 1-2% of those exposed, poses an unacceptable and unnecessary burden on the individual and on society. Sufficient animal data exists to suggest a causal link between sex hormones and malformations in animal models. Epidemiological studies that fail to find a significant association between sex hormones and birth defects use inappropriate methodology which fails to associate time of exposure to the hormone with the vulnerable period of embryogenesis for the defect in question. The requirement must include cases with malformations to establish that the putative causal exposure occurred at the vulnerable period for production of the defect and exclude cases not resulting in malformations if the hormone exposure occurred outside the vulnerable period. Studies which use the 1st trimester as the vulnerable period when the 1st month is appropriate are subject to a 67% mismodeling bias. The need for precision in design is emphasized. The extent of the presence of sex hormone receptors is of additional concern. Sex hormone receptors may be present in almost all tissues, including the liver and hypothalamus. The potential of a widespread effect of sex hormone influence derived through these axes is obvious. Also the adverse effects of many drugs may not be derived from the drugs themselves but from their metabolites, as with thalidomide. The concerns raised by studies that have shown a strong positive correlation between hormone use and birth defects emphasize the judicious use of indicated hormonal therapy.

Exogenous Progestogen and Estrogen Implicated in Birth Defects

A five-year study of possible teratogenicity of exogenous female sex hormones included three case-control studies and one cohort study. The first case-control study disclosed an estimated relative risk of 8.41 and a highly significant difference in maternal hormonal exposure (P less than .001) between controls and infants with three major anomalies of the VACTERL group (V, vertebral; A, anal; C, cardiac; T, tracheal; E, esophageal; R, renal; and L,limb). Relative risk (RR) estimates of 5.58 (P = .017) and 3.35 (P less than .001) were found in two case-control studies involving maternal hormonal exposure and patients with congenital heart lesions without other malformations. A controlled, single-blind prospective study disclosed an excess of patients with major malformations (RR = 2.75), congenital heart anomalies (RR = 6), and neurological and neural tube disorders preponderant in the presence of a precipitously declining exposure rate during a three-year period in our referral area.