Anne Pastuszak

Outcome after maternal varicella infection in the first 20 weeks of pregnancy.

BACKGROUND Infection with the varicella-zoster virus during pregnancy can produce an embryopathy characterized by limb hypoplasia, eye and brain damage, and skin lesions. The risk is greatest when infection occurs during the first 20 weeks of pregnancy, but the magnitude of the risk is uncertain. METHODS We studied 106 women with clinically diagnosed varicella infection in the first 20 weeks of pregnancy and compared the outcomes with those in 106 age-matched, nonexposed controls. RESULTS Among the women with varicella, there was a trend toward more elective terminations of pregnancy (14 percent, vs. 7.5 percent among the controls; P = 0.1), corresponding to a significantly higher perception of teratogenic risk (P = 0.03). The proportions of miscarriages and live births and the mean birth weights were similar in the two study groups; there were more premature births (< or = 37 weeks) among the women with varicella infection (14.3 percent vs. 5.6 percent, P = 0.05). Congenital defects occurred in four infants born to the women with varicella (varicella embryopathy, hydrocephalus, meningocele and clubfeet, and hammer toe) and two infants born to the controls (ventricular septal defect and hip dislocation). The risk of varicella embryopathy after infection in the first 20 weeks was 1.2 percent (95 percent confidence interval, 0 to 2.4 percent). When we pooled our results with those from other prospective studies, the mean risk of embryopathy after infection with varicella-zoster virus in the first trimester was 2.2 percent (95 percent confidence interval, 0 to 4.6 percent). CONCLUSIONS The absolute risk of embryopathy after maternal varicella infection in the first 20 weeks of pregnancy is about 2 percent.

The safety of mesalamine in human pregnancy: A prospective controlled cohort study

BACKGROUND & AIMS Mesalamine is a first-line drug in the treatment of inflammatory bowel disease. Information regarding human pregnancy experience with mesalamine has been scarce and uncontrolled despite its frequent use in women of childbearing age. The aim of this study was to examine the fetal safety of mesalamine. METHODS The Motherisk Program prospectively enrolled and followed up 165 women exposed to mesalamine during pregnancy, 146 of whom had first trimester exposure. Pregnancy outcome was compared with that of a matched control group, who were counseled for nonteratogenic exposure. RESULTS There was no increase in major malformations (1 of 127 [0.8%] for mesalamine vs. 5 of 131 [3.8%] for nonteratogenic controls; P = 0.23). There was an increase in the rate of preterm deliveries (13.0% for mesalamine vs. 4.7% for nonteratogenic controls; P = 0.02), a decrease in the mean maternal weight gain during pregnancy (13.1 +/- 6.3 kg for mesalamine vs. 15.6 +/- 6.0 kg for nonteratogenic controls; P = 0.0002), and a decrease in the mean birth weight (3253 +/- 546 g for mesalamine vs. 3461 +/- 542 g for nonteratogenic controls; P = 0.0005). There were no significant differences in the maternal obstetric history, rates of live births, miscarriages, pregnancy terminations, ectopic pregnancies, delivery method, or fetal distress between the groups. CONCLUSIONS This study suggests that mesalamine does not represent a major teratogenic risk in humans when used in the recommended doses.

Moderate to heavy caffeine consumption during pregnancy and relationship to spontaneous abortion and abnormal fetal growth: a meta-analysis.

The objective was to determine the association of moderate to heavy caffeine consumption during pregnancy on spontaneous abortion and birth weight in humans. Data sources used included a computerized literature search of MEDLINE (1966-July 1996); EMBASE (1988-November 1996); Psychlit I (1974-1986); Psychlit II (1987-1996); CINAHL (1982-May 1996) and manual search of bibliographies of pertinent articles. Inclusion criteria were: English language research articles; pregnant human females; case control or cohort design; documented quantity of caffeine consumption during pregnancy; control group with minimal or no caffeine consumption (0 to 150 mg caffeine/d); documented data regarding spontaneous abortion and/or fetal growth. The exclusion criteria were: case reports; editorials; review papers. The methods section of each study was examined independently by two blinded investigators with a third investigator adjudicating disagreements. Two independent investigators extracted data onto a standardized form. A third investigator adjudicated discrepancies. We compared a caffeine-exposed group (>150 mg/d) and controls (0 to 150 mg/d), using Mantel-Haenszel pooling. Of the 32 studies meeting inclusion criteria, 12 had extractable data (6 for spontaneous abortion, 7 for low birth weight, 1 common study). Mantel-Haenszel odds ratio (CI95%) was 1.36 (1.29-1.45) for spontaneous abortion in 42,988 pregnancies. The overall risk ratio was 1.51 (1.39-1.63) for low birthweight (<2500 g) in 64,268 pregnancies. Control for confounders such as maternal age, smoking, and ethanol use was not possible. We concluded that there is a small but statistically significant increase in the risks for spontaneous abortion and low birthweight babies in pregnant women consuming >150 mg caffeine per d. A possible contribution to these results of maternal age, smoking, ethanol use, or other confounders could not be excluded.

A multicenter, prospective study of fetal outcome following accidental carbon monoxide poisoning in pregnancy.

We report the results of the first prospective, multicenter study of acute carbon monoxide (CO) poisoning in pregnancy. We collected and followed cases of CO poisoning occurring during pregnancy between December 1985 and March 1989. The sources of CO were malfunctioning furnaces (n = 16), hot water heaters (n = 7), car fumes (n = 6), and methylene chloride inhalation (n = 3). Pregnancy outcome was adversely affected in 3 of 5 pregnancies with severe toxicity; two stillbirths, and one cerebral palsy with tomographic findings consistent with ischemic damage. All adverse outcome occurred in cases treated with high flow oxygen, whereas the 2 cases of severe toxicity with normal outcomes followed hyperbaric oxygen therapy. All 31 babies exposed in utero to mild or moderate CO poisoning exhibited normal physical and neurobehavioral development. Severe maternal CO toxicity was associated with significantly more adverse fetal cases when compared to mild maternal toxicity (P less than 0.001). It is concluded that while severe CO poisoning poses serious short- and long-term fetal risk, mild accidental exposure is likely to result in normal fetal outcome. Because fetal accumulation of CO is higher and its elimination slower than in the maternal circulation, hyperbaric oxygen may decrease fetal hypoxia and improve outcome.

Toxic Neonatal Effects Following Maternal Clomipramine Therapy

Clomipramine is a chlorinated tricyclic antidepressant commonly used in the treatment of depression (1). The drug is widely prescribed in Europe and Canada and has been recently approved for use in the USA. Its safety during pregnancy and breastfeeding, however, has not been fully established. Very few reports on its effect on the fetus and neonate have been published (2,3). We report a case of a mother treated with clomipramine during pregnancy, and the side effects observed in the infant. The correlation between plasma clomipramine concentrations in the babys blood and clinical effects are described. Subsequently, we present the pregnancy outcome of five prospectively collected cases.

Pregnancy outcome after exposure to misoprostol in Brazil: a prospective, controlled study.

BACKGROUND Misoprostol, a synthetic prostaglandin E1 analog is labeled for the treatment of gastric and duodenal ulcers. In Brazil, where abortion is not a legal procedure, there is a widespread popular misuse of this drug in abortion attempts. This misuse and the fact that, in many cases the desired pregnancy termination does not occur, raise concerns about fetal safety. Case reports of congenital anomalies after maternal use of misoprostol have been published. The objective of this work was to compare pregnancy outcome following misoprostol exposure with a matched control group. This is the first prospective controlled study on fetal safety after misoprostol use. METHODS A prospective, observational cohort study with 86 exposed and 86 pair-matched, non-exposed controls. RESULTS There was no significant difference in the rates of major or minor birth between exposed compared to non-exposed infants (2/67 vs 2/81, major defects; 7/67 vs. 3/81, minor anomalies) There were significantly more miscarriages in the exposed group (17.1% vs. 5.8%; relative risk, 2.97; 95% confidence interval, 1.12 to 7.88). There was no statistical difference in gestational age at delivery, birth weight, sex ratio, rate of prematurity, low birth weight, or rates of cesarean section between groups. CONCLUSIONS Our study, despite its limited statistical power, does not suggest a potent teratogenic action of misoprostol exposure during pregnancy.

Course of pregnancy and fetal outcome following maternal exposure to carbamazepine and phenytoin: A prospective study

This prospective study followed the pregnancy course of epileptic women at the Motherisk Program of The Hospital for Sick Children, Toronto. We compared fetal outcome of women treated with carbamazepine (CBZ), those treated with diphenylhydantoin (phenytoin, DPH), and a drug-free control group. Seizures were reported in 15 pregnancies; in a subgroup of 9 women without change in drug or schedule, an increase in seizure frequency was evident in 6, a decrease in 1, and no change in 2, regardless of the drug taken. Of 23 children exposed to CBZ in utero, one was born with a lumbar myelomeningocele and multiple congenital anomalies. Of 21 children exposed to DPH, there was one case of severe developmental delay and four with minor features of fetal hydantoin syndromes (FHS). The three groups did not differ in birth weights or gestational ages of the babies. Although much more experience is needed, as a result of this study and other similar reports, Motherisk now offers women treated with CBZ diagnostic tests to detect neural tube defects during the second trimester of pregnancy.

Use of the retinoid pregnancy prevention program in Canada: Patterns of contraception use in women treated with isotretinoin and etretinate

We sought to describe demographic characteristics of and pattern of contraception use by Canadian women prescribed synthetic retinoids who voluntarily contacted the Motherisk Program in Toronto and to describe the degree of use of the Pregnancy Prevention Program (PPP) for retinoids. Prospectively gathered intake data from isotretinoin-exposed women was statistically compared to that from matched controls selected from our database. Intake data is qualitatively reported for etretinate-exposed women. We included women who voluntarily contacted the Motherisk Program from November 1, 1988, to January 30, 1991, for counseling about reproductive risks of isotretinoin or etretinate. Primary outcome parameters were maternal age, race, marital status, socioeconomic status; gravity, parity, previous miscarriages and elective abortions, maternal tobacco and ethanol exposure, contraception use, and use of PPP (educational components used, patient recollection of warnings). The 26 isotretinoin-exposed women were younger than controls (25.2 [SD 6.7] years vs 28.9 [SD 5.1] years, P = 0.03), tended to be adolescent (30.8% vs. 3.8%, P = 0.014) and sought counselling later in gestation (10.1 [SD 8] weeks vs. 6 [SD 4.2] weeks, P = 0.01). Twenty (77%) knew the drug was teratogenic, yet 10 (38.5%) used no contraception, 6 (23.1%) experienced method failure, and 2 (8%) stopped contraception during isotretinoin therapy. In conclusion, although cognizant of the teratogenicity of isotretinoin, more than one-third of the women in this study used no birth control or experienced contraception failure. In this same group, however, compliance with contraception use appeared to increase in those who saw more of the PPP.

Steady-state pharmacokinetics of isotretinoin and its 4-oxo metabolite : Implications for fetal safety

Isotretinoin is the most potent human teratogen on the market. Women for whom contraception fails may conceive during or soon after discontinuing isotretinoin therapy, making its elimination kinetics a crucial determinant of fetal safety. The steady‐state pharmacokinetics of isotretinoin and its major 4‐oxo metabolite were studied in 16 adult patients treated for acne who were receiving doses that ranged from 0.47 to 1.7 mg/kg daily. This is the first study of the pharmacokinetics of isotretinoin in women of childbearing age (n = 11). The clinical efficacy and tolerability of isotretinoin was investigated, and the correlation between these data and steady‐state serum concentrations of isotretinoin was tested. The concentration‐time data best fitted a two‐compartment open model with linear elimination. There was no correlation between efficacy and tolerability of isotretinoin and steady‐state serum concentrations. There was no correlation between dose of isotretinoin and steady‐state concentration, due to the large variability in apparent clearance. Values for elimination half‐life (t1/2) of isotretinoin and its metabolite were 29 ± 40 hours and 22 ± 10 hours, respectively. These data suggest a longer elimination t1/2 of the parent drug than previously reported. This is probably due to the longer sampling time used in this study (as long as 28 days). This study suggests that a greater variability exists in the safe time after discontinuation of the drug for onset of conception.

Fetal outcome following intrauterine amantadine exposure.

Amantadine hydrochloride is a well-known antiviral agent that has been used for the prevention of influenza A2, the treatment of Parkinson disease, and, more recently, multiple sclerosis. However, very few data exist about its use in pregnant women. We report a 34-year-old woman who had used amantadine to prevent relapse of her multiple sclerosis throughout two of her pregnancies who subsequently delivered two normal infants. We review the available animal data and two other human pregnancy exposure reports.