Wrongful births. When is there liability for prenatal injury?

Every jurisdiction recognizes the right of a child to recover damages for prenatal injury caused by the negligence of a third party. This concept of liability for prenatal injury has been extended to include the right of parents (and sometimes the child) to recover damages from a physician who negligently deprives them of the opportunity to prevent the "wrongful birth" of an affected child. The most troubling question to arise, however, is whether a pregnant woman has a legal duty to avoid negligent behavior that may injure her future child. The unique and compelling conflicts that surround the recognition of such a prematernal duty encompass the child's right to be born free of any negligently induced injury and the pregnant woman's rights to personal privacy and bodily autonomy.

Citrullinemia: prenatal diagnosis of an affected fetus.

We monitored a pregnancy in a family at risk for citrullinemia due to argininosuccinic acid (ASA) synthetase deficiency. ASA synthetase activity in cultured epithelioid amniotic fluid cells from the fetus at risk was less than 2% of control epithelioid amniotic fluid cell activity. An increased concentration of citrulline was found in the at-risk amniotic fluid (0.14 mumol/ml) as compared with fluid from six controls and one at-risk but unaffected pregnancy (trace). The pregnancy was terminated, and the in utero diagnosis was confirmed by assay of ASA synthetase activity in cultured fetal skin fibroblasts (4.4% of control activity). In addition, all five fetal tissues studied had significant accumulation of citrulline, whereas control fetal tissues had none. These data provide evidence that, if precise control is maintained over tissue culture variables, citrullinemia can be diagnosed successfully in utero by microassay of ASA synthetase activity in cultured amniotic fluid cells. They also suggest that amniotic fluid citrulline concentrations provide strong adjunctive evidence for this prenatal diagnosis.

Maternal homocystinuria: studies of an untreated mother and fetus.

A 20-year-old woman with untreated homocystinuria was examined when she was 18 weeks' pregnant. Amniocentesis was performed and raised levels of homocystine and methionine were present in the amniotic fluid. Assay of cystathionine synthetase activity in cultured amniotic fluid cells showed the carrier state for homocystinuria. An abortion was performed because of the possible adverse effects of continuing the pregnancy both for the mother and the fetus. No pathological abnormality was found in the aborted fetus. Further data are needed to assess the possible teratogenic effects of maternal homocystinuria and the adverse consequences of pregnancy in the affected mother.

Carnosinase deficiency: a new variant with high residual activity.

Plasma carnosinase deficiency was discovered in a 12-yr-old male with profound mental retardation, severe athetoid spastic quadriparesis, optic atrophy, sensory peripheral neuropathy, and suprabulbar signs. Amino acid analysis revealed persistent carnosinuria but no detectable carnosinemia. After ingestion of L-carnosine (100 mg/kg), the patient had carnosine in his plasma and excreted 28% of the administered load as carnosine (an agematched control excreted 1.3% as carnosine). Urinary 1-methylhistidine was measurable in the patient and increased greatly during a high anserine diet. Plasma carnosinase activity in the patient was 0.28 mumoles per ml plasma per hr (control mean, 2.00; range, 1.10--2.85), his parents had activity of 1.36 and 1.30, and 2 sibs had activities of 1.10 and 1.86. Carnosinase activity in liver from the patient was 43% of control liver. We have demonstrated that carnosinase activity is present in human nerve and that sural nerve from the patient had activity that was 46% of control nerve. Histopathologic examination of the patient's nerve showed axonal degeneration. Histidine levels in the patient's liver and nerve were normal, and neither beta-alanine nor carnosine was detectable. The unusually high residual carnosinase activity in plasma and tissues from this patient may explain his apparent ability to metabolize anserine and would suggest that this represents a new variant form of carnosinase deficiency. Speculation. Carnosinuria due to plasma carnosinase deficiency may be merely associated with the strinking neurologic findings that have been reported rather than causally related.

Argininosuccinic aciduria: prenatal studies in a family at risk.

We have monitored two successive pregnancies in a family which we found to be at risk for argininosuccinic aciduria. We measured argininosuccinic acid (ASA) concentrations in amniotic fluid and utilized an indirect assay of ASA lyase activity in cultured amniotic fluid cells. The assay procedure is based on the uptake of 14C from [14C]citrulline and of [3H]leucine into protein. ASA was easily measured in amniotic fluid from the first fetus at risk, whereas none was detectable in control fluids. Amniotic fluid cells cultured from this fetus had only 5.5% of control ASA lyase activity. The pregnancy was terminated, and hepatic ASA lyase activity in the fetus was shown to be about 1.3% of control values. In addition, eight fetal tissues were analyzed for ASA, and all had significant accumulation. ASA was not detected in amniotic fluid from the second fetus at risk, and ASA lyase activity in cultured cells was 80% of control activity. Enzymatic analysis of erythrocyte lysate confirmed the diagnosis of an unaffected child (ASA lyase = 46% of control) and indicated heterozygosity. Thus, we provide further evidence that argininosuccinic aciduria can be diagnosed successfully in utero by indirect assay of ASA lyase activity in cultured amniotic fluid cells. In addition, high amniotic fluid ASA concentrations provide strong adjunctive evidence for such a prenatal determination, and may prove to be sufficient for diagnosis.

Fetal tissue amino acid concentrations in argininosuccinic aciduria and in "maternal homocystinuria".

Free amino acid concentrations have been measured in the tissues of a fetus at risk for argininosuccinic aciduria and of an obligate heterozygous fetus in a mother homozygous for homocystinuria. Argininosuccinic acid was detected in all tissues studied of the homozygous affected fetus from the heterozygous mother. Abnormal concentrations of methionine and cystathionine were observed in the tissues of the fetus who was an obligate heterozygote for homocystinuria. These abnormal free amino acid concentrations occur early in fetal development and may be related to later brain dysfunction.

Cystathionine beta-synthase deficiency: a qualitative abnormality of the deficient enzyme modified by vitamin B6 therapy.

The thermostability of cystathionine synthase and the effect of pyridoxal phosphate (PLP) on this thermostability were investigated in extracts of normal human liver and in extracts of liver, both before and during pyridoxine (vitamin B6) therapy, from members of a family with three clinically and biochemically typical, B6-responsive, synthase-deficient sibs. Incubation of crude extracts of normal liver at 55 degrees (preincubation) for 3-4 min before assay consistently resulted in a more than 2-fold increase in specific activity (activation) of cystathionine synthase (Fig. 1). With periods of preincubation longer than 4 min, thermal inactivation occurred. When PLP was added to the preincubation mixture, slightly more activation occurred in the first 3-4 min, and there was no observable loss of activity for an additional 25 min. The activation phenomenon was not observed in extracts of liver which had been obtained from three synthase-deficient sibs before therapy with vitamin B6 (Index of activation, Table 1). When extracts of liver obtained during vitamin B6 therapy were studied, however, significant activation was observed. Synthase activity in extracts of liver from the patients' parents, obligate heterozygotes for synthase deficiency, and from a potentially heterozygous sister demonstrated activation similar to that found in control liver extracts. With periods of preincubation longer than 5 min, the inactivation of synthase in liver extracts from patients receiving pyridoxine-HCl occurred at the same rate as in liver extracts from heterozygotes and from normal subjects (Index of inactivation, Table 1). PLP completely prevented heat inactivation of enzyme from normal liver.