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.

Update on counseling the family with a first-degree relative with a congenital heart defect.

Updated recurrence risks figures are presented for genetic counseling of families with a congenital heart defect (CHD) in a first-degree relative. Substantial changes are recommended for counseling the family in which a parent has CHD. The risk is much greater if it is the mother rather than the father who has the heart defect. The updated figures for recurrence risks in sibs have been revised, but are not greatly changed. Our central tenet in counseling is to base risk projections on the genetic and teratogenic history in the individual family and pregnancy.

A syndrome of multiple congenital anomalies associated with teratogenic exposure.

A study of 19 patients with multiple congenital anomalies described by the acronym VACTERL (Vertebral, Anal, Cardiac, Tracheoesophageal, Renal, and Limb) revealed exposure at the vulnerable period of embryogenesis to a progestogen/estrogen compound or a progestogen alone in 13 patients. These hormones were taken as a "pregnancy test," and for a variety of other reasons. Comparison of VACTERL patients with paired and matched controls, one group with chromosomal anomalies (other than Down syndrome) and another group with functional murmurs, revealed a significant difference with respect to exposure to hormonal contraceptives. The multiple anomalies of skeletal, cardiovascular, and gastrointestinal structures recapitulate the systems involved in the thalidomide syndrome, but present a variation of the pattern. Until more definitive data are available it would be prudent to emphasize the need to verify the absence of pregnancy before initiation of oral contraception and to discontinue hormonal agents as tests for pregnancy.

Contraceptive hormones and congenital heart disease.

PIP: 4 retrospective case-control studies and a retrospective cohort study in addition to an ongoing prospective study of the relationship between contraceptive hormones and congenital heart disease have been conducted. The following observations are reported. No patient with transportation of the great arteries (TGAs) has been found in any VACTERL patient. In the first 100 patients of the prospective study there were no TGAs but there was 1 VACTERL syndrome. An increase of TGAs in 1 retrospective study was thought to be related to exposure in early gestation rather than to specific drug malformation. No unusual increase in TGAs was found in the other retrospective studies. It was thought that a history of drug exposure during pregnancies terminating more than a year prior to taking the history were unreliable especially with missed medication, menstrual irregularities, and hormonal agents used as pregnancy tests. In the Yasuda study a hypothetical teratogen producing malformations in only .6-1% of pregnancies would have been unnoticed.^ieng

Recurrence risks in children having one parent with a congenital heart disease.

The risk of recurrence of a congenital cardiovascular malformation in a child having one parent with congenital heart disease has been determined for each of the seven most common anomalies presently compatible with survival to reproductive age. The range of risk is 2.5% to 4.3% depending on the lesion. This is within the range of expectation for the model of multifactorial inheritance previously used to predict recurrence in other first-degree relatives of probands (siblings and parents) with congenital heart disease. The cardiovascular abnormality occurring in the child was most often the same as in the parent or was a closely related variant of it.

Editorial: Can the pill cause birth defects?

PIP: Potential establishment of a causal relationship between a syndrome of multiple congenital anomalies (vertebral, anal, cardiac, tracheoesophageal, renal, and limb, i.e., "VACTERL") and maternal progesterone/estrogen exposure has been made by retrospective and prospective studies. A study providing etiologic evidence between oral contraceptives and birth defects (limb anomalies especially) found only males affected; the proportion of males in another cluster of VACTERL pa tients was also very high (10 out of 15). It was suggested that if oral contraceptives are teratogenic, it is with people who are predisposed. Unlike thalidomide, there is no high risk at each exposure but there are a high number of exposures from widespread use. The importance of eliciting accurate drug exposure histories from mothers is streesed; only 1/3 of the patients who had established exposure to oral contraceptives at a vulnerable embryonic period had this exposure recorded in their charts. It was concluded that hormonal pregnancy tests should be stopped.^ieng

Familial congenital complete heart block and maternal systemic lupus erythematosis.

A family is reported in which two siblings had congenital complete heart block with resultant congestive heart failure, the father and paternal grandfather show adult-onset conduction defects, and the mother has systemic lupus erythematosis. The interaction of heredity and environment is discussed in this context. A review of the literature on familial complete heart block suggests that so-called pure congenital-onset familial heart block, originally felt to be genetic, may in fact have an important enivronmental component, specifically related to ongoing maternal factors such as systemic lupus erythematosis.

Exogenous sex hormones and birth defects: continuing the dialogue.

PIP: 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.^ieng

Genetic--epidemiologic study of early-onset ischemic heart disease.

A genetic-epidemiologic study was undertaken of a white Colorado population of 207 patients who had a myocardial infarction before age 55 years. Nineteen independent variables were compared between the 207 cases and 621 controls, matched 3:1. The highest risk ratios were associated with a positive family history for ischemic heart disease (IHD). The heritability of IHD was 63% when families with the monogenic forms of hyperlipoproteinemia were included, and 56% when they were excluded. A risk index was developed that incorporates family history into a data base of risk factors, which can be readily assessed by the clinician obtaining a screening history, physical and standard laboratory tests. A scale of 0-10 was devised and the predictive value of the index was tested against another data set. The efficiency of the index was maximal at a screening level of 5. This study suggests that it is logistically feasible to seek patients at high risk for intensive management in a clinical setting (high-risk strategy) using risk indices similar to the one developed for this study, which emphasize the very important familial component to IHD.

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.

Collaborative office rounds: continuing education in the psychosocial/developmental aspects of child health.

OBJECTIVES: In recent years there has been increasing emphasis on the mental health aspects of primary health care for children and adolescents. The Health Resources and Services Administration's Maternal and Child Health Bureau has contributed to efforts aimed at strengthening primary care not only in early identification and beginning intervention with mental disorders, but also in prevention of emotional and behavioral problems and in promotion of positive psychosocial development. The Collaborative Office Rounds (COR) Program is a noteworthy part of these efforts. METHODS: The COR program supports small discussion groups that meet at regular intervals over sustained periods of time to address the mental health aspects of pediatric care. The groups are jointly led by pediatricians and child psychiatrists. Although they vary in a number of ways, all are concerned with the day-to-day psychosocial issues that confront primary care providers serving children, adolescents, and their families. RESULTS: COR groups have addressed a wide range of areas including numerous problems and disorders, health supervision issues, family and community topics, personal challenges and practical complexities, and clinical management issues. Evaluation information indicates a positive response on the part of participants and moderators. This is reflected in group stability, high attendance rates, universal readiness to recommend the COR experience, and a variety of collateral accomplishments. CONCLUSIONS: Experience to date points to the COR group as a useful tool for addressing psychosocial issues in primary care. Its potential may be more fully realized by applying this approach more widely, even as further assessment is pursued.