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Teratogen Update Vol. 12: Fall, 1995 Reviewed Jan, 2000 |
Phenylketonuria (PKU) is an autosomal recessive disorder of amino acid metabolism affecting approximately 1/10,000"-1"5,000 infants in North America. It is most often due to deficiency of the enzyme phenylalanine hydroxylase which causes the accumulation of harmful metabolites, including phenylketones. If untreated, PKU leads to mental retardation, seizures, psychoses, eczema and a distinctive "mousy" odor.
A diet low in phenylalanine has been proven to prevent neurological and intellectual deterioration, if initiated in early infancy. Historically, this diet was discontinued at age 6 since it was felt the brain was fully developed by that time and would not be susceptible to the effects of excess phenylalanine and its derivatives.
Currently, it is recommended that diet therapy be continued throughout an affected person's lifetime to prevent the decline in intellect that has been documented in some cases, as well as harm to fetuses of affected women.
In 1961, newborn screening for PKU was begun which enabled the initiation of dietary treatment before neurologic deterioration occurred. With successful dietary therapy, most people with PKU live normal lives, including having children.
Unfortunately, if women with successfully treated PKU are not on dietary therapy during pregnancy, their children are exposed to high levels of phenylalanine in utero, which causes embryologic/fetal brain (and other organ) injury.
Statistically, there are greater than 3,000 women of reproductive age in the United States who have PKU diagnosed after a positive newborn screen and are at risk of delivering infants with the effects of untreated maternal PKU. In addition, there are still women of reproductive age who were born prior to newborn screening for PKU, and those with variants of PKU who are also at risk to have children with maternal PKU syndrome.
Therefore, there are approximately 6,000 women in the United States who will potentially have one or more children affected by exposure to high phenylalanine levels during fetal development.
The characteristic features of maternal PKU syndrome include mental retardation, microcephaly, intrauterine growth retardation, and congenital heart defects. The risk for these defects is approximately 90%, 75%, 50% and 15% respectively, in infants of mothers with untreated classical or atypical PKU (maternal plasma phenylalanine levels >20 mg/dL).
The incidence of these anomalies is considerably lower (approximately 20%) in children of women treated with diet during pregnancy or those with milder forms of hyperphenylalaninemia (maternal plasma phenylalanine levels < 16 mg/dL), but still increased over the occurrence of these defects in the general population. In addition, many women with PKU commonly experience pregnancy loss.
The fetal nervous system is susceptible to nutritional variations, including deficiencies and excesses, as well as toxins. It has not been determined if an excess of phenylalanine and its metabolites, a deficiency of tyrosine due to the absence or inactivity of phenylalanine hydrolase, an amino acid imbalance, or a combination effect cause the disruption of normal development and fetal growth throughout pregnancy. There is also a fetal-maternal plasma gradient for phenylalanine across the placenta causing increased concentrations of phenylalanine in the fetal compartment. Unfortunately, diets low in phenylalanine also may not be ideal for appropriate fetal development because they may be deficient in important nutrients, including zinc, selenium and iron.
Various studies have shown that the best way to prevent fetal malformations and decrease fetal mortality is to initiate a strict, low phenylalanine diet prior to conception. Women who have uncontrolled phenylalanine levels prior to conception but initiate diet therapy after pregnancy is confirmed are still at increased risk of delivering a baby with malformations. This risk closely resembles the incidence of malformations in infants whose mothers received no dietary treatment throughout pregnancy. Current guidelines indicate that maternal plasma phenylalanine levels should be maintained by dietary control at 2-8 mg/dL and a supplement of L-tyrosine provided to achieve maternal blood tyrosine levels of >0.5 mg/dL.
Optimally, an extensive plan for women with PKU should be developed by a multidisciplinary team of physicians, nurses, nutritionists, genetic counselors, patients and their families, which provides counseling, information and support prior to, during and after pregnancy. In addition, an effort needs to be made to identify women who may not know they are at risk to have a child affected by exposure to excessive amounts of phenylalanine prenatally who would greatly benefit from the vast amount of information, treatment and support that is available. We suggest providers contact the clinical genetics unit in their area for advice in managing women with hyperphenylalaninemia.
See References: Phenylketonuria
Approximately 100,000 pregnant women in the US are treated for diabetes annually. This includes women who are insulin-dependent prior to conception and women who develop gestational diabetes and require insulin, oral or diet therapy in pregnancy. The focus of this discussion is on women with pre-gestational insulin-dependent diabetes mellitus (IDDM).
During pregnancy, the woman's metabolism adapts to provide adequate nutrition for her, the fetus and the placenta. Glucose levels are influenced by pregnancy-related increases in estrogen and progesterone. An increase in insulin secretion increases the use of peripheral glucose, causing maternal fasting glucose levels to fall. Therefore, pregnant women with IDDM experience periodic hypoglycemia, reduced levels of circulating amino acids, and increased levels of fatty acids, triglycerides and ketones in the first trimester.
To offset this state of "accelerated starvation", the woman's metabolism increases protein catabolism and renal gluconeogenesis. There is a decreased sensitivity to insulin during pregnancy and with placental growth, larger amounts of contra-insulin factors are produced. Women with IDDM cannot respond to this stress and require increasing insulin therapy as pregnancy continues.
In pregnancies complicated by IDDM, fetal hyperglycemia is induced by maternal hyperglycemia. Elevated levels of glucose stimulate the fetal pancreas, resulting in fetal hyperinsulinemia. This appears to play an important role in inducing excessive fetal growth, and an increased risk of intrauterine death, respiratory distress syndrome and neonatal hypoglycemia. Therefore, there are several considerations concerning the origin of diabetic embryopathy. These include altered "fuel" production by the IDDM woman that can disrupt normal patterns of embryonic development, multifactorial causes involving synergistic or additive interactions of several circulating factors and the effect of maternal hyper- and hypoglycemia on fetal development.
Most studies of IDDM during pregnancy indicate a two- to three-fold increase in the rate of major malformations in exposed infants, over the 3-5 % general population risk. The malformations associated with IDDM involve most organ systems. Maternal hyperglycemia appears to be the most likely culprit of the cause of malformations and produces effects prior to the seventh week of gestation. Hyperketonemia and hypoglycemia have also been suggested as possible etiologies of IDDM-associated birth defects.
An accurate measure of potential fetal risk is maternal serum hemoglobin A1C (HgbA1C) level in the first trimester. In infants whose mother's HgbA1C value was 8.5% or less in the first trimester, the risk of major and minor malformations is approximately 3.4% and 2.6%, respectively. If the maternal HgbA1C value is greater than 8.5% in the first trimester, the risk of major and minor malformations is significantly greater; approximately 22.4% and 11.8% respectively. This risk is a seven-fold increase over the general population risk.
Therefore, patients in good diabetic control in the first trimester do not appear to have a significantly greater risk of having a child with birth defects over the general population risk, although if there is poor control, the risk is much greater than originally thought.
The major malformations typically associated with IDDM in pregnancy include neural tube defects (anencephaly, spina bifida), other central nervous system malformations (holoprosencephaly, microcephaly, hydrocephaly) and congenital heart disease, especially ventricular septal defects and transposition of great vessels.
Other major defects that have been reported include cleft lip and/or cleft palate, eye defects, pyloric stenosis, limb defects and urogenital malformations. Caudal regression/sacral agenesis is a rare defect that is most characteristic of diabetic embryopathy but not the most common.
These congenital malformations are termed IDDM embryopathy. Later fetal complications include macrosomia, delayed pulmonary maturity, respiratory distress syndrome, hypoglycemia, hyperbilirubinemia and hypocalcemia at birth. These later complications are referred to as IDDM fetopathy.
Current recommendations include achieving good diabetic control preconceptionally. The specific recommendations to monitor pregnant IDDM women include maintaining euglycemia with diet and insulin, measurement of HgbA1C throughout the first and second trimesters, genetic counseling to assess potential fetal risk and discuss prenatal diagnosis options, serial targeted ultrasounds, fetal echocardiography, maternal serum alpha-fetoprotein level at 16 - 18 weeks gestation, and antepartum surveillance of fetal well being.
Most large hospitals have incorporated a multidisciplinary program for the management of pregnant diabetic women in their obstetrical service, which includes obstetricians, internists, nurse educators, genetic counselors and nutritionists.
See References: Diabetes Mellitus
Systemic Lupus Erythematosus and Antiphospholipid Antibodies
Systemic lupus erythematosus (SLE) is an inflammatory connective tissue disease that primarily affects women of child-bearing age. Estrogen is known to have a potent influence on the immune system, which contributes to the overwhelming majority of female SLE patients. The clinical findings of SLE vary from person to person and over time. They include acute infection, facial 'butterfly' erythema and other cutaneous lesions, alopecia, thrombocytopenia, photosensitivity, pericarditis, renal and other organ involvement.
Women with SLE typically have antiphospholipid antibodies (anticardiolipin antibodies and/or lupus anticoagulant). Forty-four percent of SLE patients have anticardiolipin antibodies and 34% have lupus anticoagulant. The lupus anticoagulant activity results from interference of prothrombin activator complex activation. This leads to prolonged prothrombin and whole blood clotting times which may result in thrombotic episodes.
In addition to an increased incidence of arterial and venous thrombosis, lupus anticoagulant is associated with hypertension, hemolytic anemia and various neoplasms. SLE patients with anticardiolipin antibodies have clinical symptoms similar to persons with circulating lupus anticoagulant, including vascular thrombosis. Anticardiolipin antibodies bind various phospholipids important in the prothrombin clotting process. There appears to be a close association between the presence of anticardiolipin antibodies and lupus anticoagulant.
In one study, approximately one-half of SLE patients had the lupus anticoagulant, and of these patients, 91% also had anticardiolipin antibodies. It has been found that the combination of these antiphospholipid antibodies and their levels is strongly associated with adverse pregnancy outcomes.
Pregnant women with SLE are at an increased risk for maternal complications, including eclampsia, pregnancy-induced hypertension, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count). In addition, there is an increased frequency of fetal loss, preterm birth, intrauterine growth retardation (IUGR), neonatal lupus, congenital heart block and perinatal mortality.
Prospective studies of pregnant SLE patients have a rate of pregnancy loss varying from 11 to 24%. Multiple factors play a role in the increased frequency of fetal loss in these patients. They include activity of lupus at the time of conception, renal disease, the presence of antiphospholipid antibodies, and prior history of fetal loss. Many studies of these factors have revealed conflicting results and therefore making definitive conclusions regarding the degree of their association with pregnancy loss is difficult. Several studies have found that a poor prior obstetric history may be one of the best predictors of future loss. A woman with at least two prior losses and antiphospholipid antibodies is at a significantly higher risk of fetal loss.
The rate of preterm delivery in SLE pregnancies varies from 17-57%, according to several retrospective studies. The primary causes of preterm delivery in these pregnancies include maternal complications as listed above, preterm premature rupture of membranes, fetal distress, oligohydramnios, and preterm labor. Risk factors for preterm delivery in SLE patients are active lupus, presence of antiphospholipid antibodies, and possibly maternal renal disease. It is apparent from these studies that pregnant women with SLE have an increasingly higher risk of poor pregnancy outcome if more than one of these factors is involved.
Not all women with antiphospholipid antibodies are symptomatic. About one-third are diagnosed with SLE and another one-third have thrombotic episodes. Pregnant women with antiphospholipid antibodies are at an increased risk for placental infarction and thrombosis, which plays a major role in the pathogenesis of adverse pregnancy outcomes. If pregnant women with lupus anticoagulant are untreated, the frequency of recurrent spontaneous abortion and fetal death is greater than 90%. The pregnancy loss rate among untreated women with anticardiolipin antibodies is also significantly higher, but the association is not as consistent. Treated and untreated pregnant women with antiphospholipid antibodies are also at increased risk to deliver a growth-retarded child; the risk for IUGR may be as high as 60%.
Neonatal lupus syndrome consists of a combination of a rash similar to those seen in adult SLE patients, thrombocytopenia, and congenital partial or complete heart block. The rash occurs in as many as 25% of liveborn infants of pregnant SLE patients. Congenital heart block may occur in infants of symptomatic and asymptomatic patients. The presence of fetal heart block may lead to the diagnosis of SLE in the infant's mother. Congenital heart block has been treated prenatally. Most infants with congenital heart block survive, do well, and may not need pacemakers, if the condition is recognized prior to delivery.
At least 10% of women with idiopathic recurrent pregnancy loss will have antiphospholipid antibodies. Therefore, part of the work-up for women with recurrent pregnancy loss should include the activated partial prothromboplastin time (APTT) or the Russell viper venom time for the diagnosis of lupus anticoagulant, and radioimmunoassay or ELISA for anticardiolipin antibodies.
The management of women with known SLE and/or antiphospholipid antibodies is complex but has been successful. Management should be a cooperative effort between the patient, a rheumatologist and perinatologist. Pregnant women should be monitored carefully for hypertension, activity of lupus, renal complications and levels of antiphospholipid antibodies. Fetal assessment should include fetal ultrasound in all trimesters, fetal echocardiography, non-stress testing, biophysical profile, and doppler studies of the umbilical and uterine arteries.
Treatment of SLE and/or the presence of antiphospholipids in pregnancy typically includes a combination of low-dose aspirin, heparin, and corticosteriods (usually prednisone). This treatment regimen may cause maternal side effects, including osteopenia, thrombocytopenia, adrenal insufficiency and premature rupture of membranes. Therefore treated women should be monitored carefully.
See References - Systemic Lupus Erythematosus
The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Genetics Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131
Table Of Contents:
Teratogen Update
Introduction
Medications
Substances of Abuse
Maternal Infections
Maternal Disorders
Mutagens
Etiology of Congenital Malformations in Humans:
(Table 1)
Known Human Teratogens: (Table 2)
References
Facts About Neural Tube Defects and Folic Acid
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