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OBJECTIVE: To present a review of the literature and research on the pharmacogenetics of congenital defects, with a focus on the need for predictive maternal genotype assays. DATA SOURCE: MEDLINE searches (January 1985-January 1999), past reference reviews, and unpublished research. STUDY SELECTION: Review of relevant human, animal, and basic science studies. DATA EXTRACTION: Data on research on polymorphisms, genotyping, cytochrome P450 enzyme systems, epoxide hydrolase, folate metabolism, metabolism of anticonvulsant medications, molecular genetics of neural tube defects, variations in drug metabolism, and environmental exposures were evaluated. DATA SYNTHESIS: Data synthesis includes not only a review of the literature but suggests ways such data might be used to facilitate the development of maternal genotype assays, with the goal of preventing birth defects. CONCLUSIONS: Individuals vary in how they metabolize drugs and handle toxic environmental exposures. In an ideal pregnancy, there is no or limited exposure to medications and environmental agents. However, in women with chronic medical conditions such as heart disease and seizures, this is often not possible. Unfortunately, no techniques have been available to identify those at risk in this population. Gene polymorphisms for a specific enzyme may result in an absence or reduction in the level of enzyme activity or in no change at all, with little effect on the structure/function of the gene product(s); they are not associated with clinical phenotypes in either the mother or the fetus. Other polymorphisms may be only markers. Thus, developing genotyping assays for women that are predictive of phenotype expression in the fetus is the key to screening for polymorphisms. As more mutations are identified and clinical, pharmacologic, biologic, and pharmacokinetic relationships are established, using these polymorphisms to develop a genotyping assay for women may become a clinical reality, possibly leading to preventive prepregnancy or prenatal treatment that may play an increasingly effective role in maternal care.

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A randomized prospective trial has shown that folic acid started before conception and continued for the first trimester reduces the risk of recurrence of neural tube defects by 72% in women with a previously affected child. Carbamazepine exposure in utero is associated with a 1% risk of spina bifida. Long-term follow-up of antenatal exposure to phenobarbital and carbamazepine in two groups of infants shows no neurologic differences between the two groups. Magnesium sulfate is more effective in prevention of recurrent eclamptic seizures than phenytoin. During pregnancy, the need for thyroxine increases in many women. Vitamin B6 and ginger are both effective for nausea and vomiting in early pregnancy. Low-dose aspirin does not change the course of preeclampsia when it is started after the diagnosis is made. Angiotensin-converting enzyme inhibitors cause significant disturbances of fetal and neonatal renal function. Prophylactic beta-adrenergic agents fail to prevent prematurity in twins. Oral tocolysis with magnesium chloride or ritodrine is no more effective than observation alone. The risk of primary pulmonary hypertension in the newborn after indomethacin tocolysis is increased with prolonged therapy. Lithium causes polyhydramnios from fetal diabetes insipidus in utero. Treatment of Ureaplasma urealyticum infection with erythromycin during pregnancy does not eliminate the organism from the lower genital tract and does not improve perinatal outcome.

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A randomized prospective trial was performed to compare the efficacy and safety of ritodrine and indomethacin in the long-term treatment of preterm labor. Forty patients with intact membranes in preterm labor at 23 to 34 weeks' gestation were randomized to receive either intravenous ritodrine or oral indomethacin as the first-line tocolytic agent. Successful intravenous ritodrine therapy was followed by oral terbutaline therapy, and indomethacin-treated patients continued to receive oral indomethacin. Treatment failures were defined as progressive preterm labor or patient intolerance, and these patients were treated with intravenous magnesium sulfate. Ritodrine and indomethacin were equally successful in delaying preterm birth as defined by interval to delivery, gestational age at delivery, delivery delayed greater than 7 days, attainment of 35 weeks of gestation, percentage of patients who required magnesium sulfate therapy, percentage of patients who were readmitted with premature rupture of membranes, absence of recurrent preterm labor, and infant birth weight. More than 80% of mothers who received ritodrine voiced complaints of beta-sympathomimetic side effects, and one patient discontinued treatment as the result of intolerance. There were minimal patient complaints with indomethacin use. No statistically significant differences were noted in neonatal outcome as defined by Apgar scores, umbilical cord pH, intensive care days, ventilator days, or neonatal deaths. However, three cases of primary pulmonary hypertension were observed in the indomethacin group. We had not previously observed this problem with short-term (24 to 48 hours) indomethacin therapy.

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Fetal dysmorphic syndromes have been described with exposure to most commonly used anticonvulsants, most recently carbamazepine (Tegretol, Ciba-Geigy, Basel, Switzerland). Fetal genetic susceptibility may determine which infants are affected. Long-term use of heparin in pregnancy may cause significant osteoporosis, which appears to be reversible. Pharmacokinetic studies of ritodrine have resulted in recommendations for more appropriate infusion regimens, including a role for intramuscular therapy for patients undergoing maternal transport. Nifedipine shows promise as a tocolytic with fewer side effects than ritodrine but equivalent efficacy. Indomethacin is also an effective tocolytic, and clinically significant side effects have not been seen with 48 hours or less of treatment. Indomethacin has also been used successfully for treatment of polyhydramnios.

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Pharmacologic inhibition of uterine contractions remains the mainstay of treatment for preterm labor despite the ongoing controversy regarding its effectiveness. A diverse variety of tocolytic medications have been proposed for clinical use, with betamimetics and magnesium sulfate being the common therapeutic agents of choice in the United States today. The clinician using these agents should be aware of the significant maternal and fetal side-effects associated with these particular medications. New classes of pharmacologic agents, including prostaglandin synthetase inhibitors, calcium channel blockers and phosphodiesterase inhibitors, have been proposed as tocolytic agents and are currently undergoing critical clinical evaluation. The purpose of this review is to provide a compilation of the available clinical studies that document the safety and efficacy of these various tocolytic agents.

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The relationship between the use of prenatal care and factors that may impede access to care was examined in a sample of low-income, inner-city women. Situational and financial barriers to care were not important correlates of utilization. In unadjusted analyses, only insurance status and employment status were associated with utilization. Of the sociodemographic characteristics studied, only parity was strongly associated with the use of prenatal care. When the apparent associations between utilization and insurance status and utilization and employment were analyzed controlling for parity, the estimated strength and statistical significance of these relationships diminished considerably. Multiparous women who were more likely than primiparous women to be underutilizers were also more likely to be on medical assistance and to be unemployed. These findings suggest that situational and financial barriers are not important correlates of utilization for low-income, adult women living in urban areas where there are accessible clinic facilities and public transportation. Efforts to identify and surmount other kinds of barriers may prove to be a more effective approach to prenatal outreach for women in these circumstances.

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A retrospective analysis utilizing historical data collected as part of our computerized data base was performed to assess the impact of marijuana use in pregnancy on pregnancy outcome. Records of 8350 patients were reviewed and 417 patients gave a history of only marijuana use for a prevalence of 5%. There was no association between marijuana use and prematurity or congenital anomalies. Marijuana use was strongly associated with the use of alcoholic beverages and smoking. Previously reported associations may represent the concomitant use of these other drugs.

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Twenty-five patients undergoing nipple stimulation contraction stress tests were enrolled in this study. Plasma 13,14-dihydro, 15-keto prostaglandin F2 alpha and plasma prolactin concentrations were analyzed before and during the contraction stress tests. Prolactin concentrations were significantly higher (p less than 0.01) in patients who responded with a successful stress test versus those who did not. No significant changes were observed in the mean concentration of plasma 13,14-dihydro, 15-keto prostaglandin F2 alpha levels between the two groups.

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Twenty cases of fetal death complicating a multiple pregnancy after 20 weeks' gestation are reviewed. We evaluated gestational age at diagnosis and delivery (29.3 +/- 0.7 and 31.8 +/- 0.9 weeks, respectively), interval from diagnosis to delivery (2.6 +/- 0.6 weeks), and cause of fetal death as a group and by type of placentation (76.5% monochorionic). Eighty-five percent of the surviving fetuses were delivered preterm, and the four neonatal deaths were all due to extreme prematurity, with a mean (+/- SEM) birth weight of 794 +/- 237 g. Perinatal mortality was 585 per 1000, 450 for twin A and 750 for twin B. The causes of fetal death varied. Maternal disseminated intravascular coagulation was not diagnosed in any pregnancy in the present series. The high risk of complications related to preterm birth, compared with the low risk of problems related to continuation of a multiple pregnancy after diagnosis of a fetal death, argues in favor of conservative management in this setting.

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Although evidence for a role for prostaglandins in parturition is abundant, less is known about how prostaglandin levels are regulated at term. Conditions occurring peripartum in the uteroplacental unit can result in reactive oxygen production. We investigated the effect of one reactive oxygen product, hydrogen peroxide, on in vitro activity of uterine segments from the 18-day-pregnant rat. H2O2 (0.3 mmol/L) was found to elicit rhythmic contractions and increase prostaglandins F2 alpha and E2 release by uterine tissue. Indomethacin blocked both of these effects. We conclude that H2O2 stimulates uterine contractions through a prostaglandin release mechanism. A speculative hypothesis of peripartum regulation of prostaglandin production by reactive oxygen is discussed.

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Minor abnormalities of carbohydrate metabolism in pregnancy are a risk factor for delivery of a macrosomic infant. However, the 50-g 1-h oral glucose screen at 28 weeks is not a useful screening test for macrosomia in pregnant patients with normal glucose tolerance tests, because a positive screen does not raise the probability of delivering a macrosomic infant sufficiently to warrant intervention.

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A retrospective analysis of computerized data from 11,815 patients with no history of previous cesarean section revealed an increasing primary cesarean section rate with increasing maternal age. This increase occurred over the entire reproductive age span. Fetal distress as an indication for primary cesarean section may account for this increase.

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To further define the molecules that may mediate spontaneous abortion due to maternal-fetal blood group incompatibility within the P blood group system, we have examined the fine specificities of maternal antibodies and the glycolipid antigens from the placenta of a P infant born to a Pk1 mother. Maternal antibodies obtained during therapeutic plasmapheresis were analyzed to determine their reactivities with placental glycolipid extracts on thin-layer plates. Second antibodies specific for IgM, IgG, and IgA revealed immunoglobulins of all of these classes strongly reactive with one major placental glycolipid that comigrates with globoside. GC/MS analysis confirmed that the major P-active pentaglycosylceramide of placenta has the same structure as that previously shown for the P antigen of red blood cells: GalNAc beta 1-3Gal alpha 1-4Gal beta 1-4Glc-Cer. Serum antibodies partially purified by affinity chromatography on globoside-octyl-Sepharose specifically recognize glycolipids that contain terminal GalNAc beta 1-3Gal . . . residues and also recognize the same sequence as an internal determinant in some, but not all, glycolipids with extended globoside core regions. Thus, in the blood group P incompatible fetus, the major P antigen present in placenta has the same carbohydrate structure as the P antigen present in fetal and adult erythrocytes and might be a target for the maternal immune system.

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Circumcision in neonates is performed, almost universally, without anesthesia or analgesia. It is associated with pain, crying, agitation, and physiologic stress. Twenty infants receiving penile nerve block for circumcision were compared with ten infants having circumcision without anesthesia. Heart rate and blood pressure rose 34 and 15%, respectively, in unblocked infants, and were unchanged in infants receiving local anesthesia. Oxygen saturation declined 16% in unanesthetized infants compared with 6% in blocked infants (P less than .03). Anesthetized infants were less agitated and cried less. Peak plasma concentrations of the local anesthetic lidocaine averaged 0.51 +/- 0.17 microgram/mL (range 0.1-1.6), well below accepted toxic levels. There were no local or systemic complications.

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