Misrepresentation and miscommunication of teratogenic risk of drugs; analysis of three highly publicized international cases.
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Abnormalities, Drug-Induced↗
Biomedical subjects
G Koren
Publications and source records attributed to G Koren.
Glyburide and fetal safety; transplacental pharmacokinetic considerations.
Oral hypoglycemics have been avoided in pregnancy due to their potential to cause fetal hyperinsulinemia/hypoglycemia. A recent human study has shown glyburide to minimally cross the placenta, allowing a safe new treatment for gestational diabetes. The mechanisms for the minimal placental passage of this small molecule are not clear. In this presentation, the role of pKa, molecular weight, lipid solubility, and protein binding is considered. Out of these physical and pharmacologic characteristics, the very extensive plasma protein binding and short elimination half-life of glyburide appear to be major determinants of its minimal transplacental transfer.
Adult↗
Fetal effects of cocaine: an updated meta-analysis.
BACKGROUND: A very large number of women in the reproductive age group consume cocaine, leading to grave concerns regarding the long term health of millions of children after in utero exposure. The results of controlled studies have been contradictory, leading to confusion, and, possible, misinformation and misperception of teratogenic risk. OBJECTIVE: To systematically review available data on pregnancy outcome when the mother consumed cocaine. METHODS: A meta-analysis of all epidemiologic studies based on a priori criteria was conducted. Comparisons of adverse events in subgroups of exposed vs. unexposed children were performed. Analyses were based on several exposure groups: mainly cocaine, cocaine plus polydrug, polydrug but no cocaine, and drug free. RESULTS: Thirty three studies met our inclusion criteria. For all end points of interest (rates of major malformations, low birth weight, prematurity, placental abruption, premature rupture of membrane [PROM], and mean birth weight, length and head circumference), cocaine-exposed infants had higher risks than children of women not exposed to any drug. However, most of these adverse effects were nullified when cocaine exposed children were compared to children exposed to polydrug but no cocaine. Only the risk of placental abruption and premature rupture of membranes were statistically associated with cocaine use itself. CONCLUSIONS: Many of the perinatal adverse effects commonly attributed to cocaine may be caused by the multiple confounders that can occur in a cocaine using mother. Only the risk for placental abruption and PROM could be statistically related to cocaine. For other adverse effects, additional studies will be needed to ensure adequate statistical power.
Abnormalities, Drug-Induced↗
A call for action--prevention of fetal exposure to isotretinoin. A position paper by The Organization of Teratology Information Services Public Affairs Committee.
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Abnormalities, Drug-Induced↗
The transfer, of cocaethylene across the human term placental cotyledon perfused in vitro.
Cocaethylene is produced by transesterification of cocaine in the presence of ethanol, and there is evidence that it is more neurotoxic than cocaine. Because many women of reproductive age use cocaine and because many cocaine users also consume alcohol, the fetal toxicology of cocaethylene is of great concern. At the present time the placental transfer of cocaethylene has not been fully characterized. The objective of this article was to measure the transfer of cocaethylene across the human term placenta. The transfer of cocaethylene was measured using the in vitro dual perfusion of the human term placental cotyledon. Using a "closed-circuit" design, the extraction fraction of cocaethylene was measured to be 0.009 microgram/mL.min-1 and the transfer fraction was measured to be 0.013 microgram/mL.min-1, suggesting that the placental tissue retained some of the administered dose. Using an "open circuit" design, the clearance of the compound by the placenta was found to be 78 +/- 14% that of antipyrine clearance. The metabolism of cocaethylene by the perfused placental cotyledon was also measured using an "open circuit" design and was found to be negligible. These results indicate that the placenta does not serve as a significant physical or metabolic barrier to cocaethylene transfer from mother to child. As compared to previously reported results, the transfer of this compound across the human placenta is similar to that of cocaine. Variability in placental handling of cocaethylene may therefore determine fetal exposure to this compound.
Cocaine↗
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.
Abortion, Spontaneous↗
Transplacental pharmacokinetics of cocaine and benzoylecgonine in plasma and hair of rhesus monkeys.
There is large variability in the rate and extent of fetal damage from cocaine in humans; however, the sources of such variability are not presently known. In order to study the relationship between maternal cocaine pharmacokinetics at the end of pregnancy and maternal or infant cocaine and benzoylecgonine hair concentrations at birth, ten rhesus monkeys were administered cocaine intramuscularly throughout pregnancy. Cocaine and benzoylecgonine hair concentrations were determined at birth and correlated with maternal pharmacokinetics during pregnancy. There were no correlations between either maternal cocaine Cmax or AUC0-infinity and maternal and infant hair cocaine or benzoylecgonine concentrations. There were no significant correlations between maternal hair benzoylecgonine concentrations and either maternal benzoylecgonine AUC0-120 (r = 0.60; P = 0.07) or benzoylecgonine Cmax (r = 0.60; P = 0.07). No correlations existed between infant hair benzoylecgonine concentrations and either maternal benzoylecgonine AUC0-120 (r = 0.30; P = 0.40) or benzoylecgonine Cmax (r = 0.30; P = 0.40). Also, no correlation was found between maternal cocaine dose and maternal or infant cocaine and benzoylecgonine hair concentrations. In comparison to toxicants such as nicotine and carbon monoxide for which there is a good correlation between maternal systemic exposure and neonatal concentrations, the lack of a similar relationship for cocaine is consistent with the role of the placenta in contributing to the variability in the amounts of cocaine reaching the fetus and hence, potentially to the risk of adverse fetal outcome.
Animals↗
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.
Abnormalities, Drug-Induced↗
The perception of teratogenic risk by women with nausea and vomiting of pregnancy.
This study determined the advice reported to be received by women suffering from nausea and vomiting of pregnancy (NVP) from their caregivers regarding management, the teratogenic risk perception of these women and their choice of antiemetic drug use in pregnancy. A secondary objective was to determine prospectively the effect of counseling on malformation risk perception in women with NVP. The women were prospectively followed-up and questioned about the use of pharmacotherapy or other management choices as well as their perception of teratogenic risk through structured telephone interviews. The results showed that at the initial call, around 6 weeks of gestation, over three quarters of the 260 participants reported that therapy of NVP increased their teratogenic risk. This risk perception was decreased significantly after counseling. Women who reported their physicians' advice to change their diet and/or lifestyle attributed an increased risk for major malformations with antiemetics for NVP (P = 0.001), whereas women who reported advice to take antiemetic medications known to be safe to the fetus attributed no change in risk for major malformations with drugs for NVP (P = 0.002). We came to the conclusion that women are commonly hesitant to treat NVP pharmacologically due to unfounded fears of teratogenic risk. Evidenced-based counseling resulted in reduced numbers of women who considered drug therapy for NVP to increase the risk of major malformations.
Abnormalities, Drug-Induced↗
The association between maternal cigarette smoking and psychiatric diseases or criminal outcome in the offspring: a precautionary note about the assumption of causation.
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Causality↗
Prenatal exposure to organic solvents and child neurobehavioral performance.
The present study compared the cognitive and behavioral functioning of 3- to 7-year-old children (n=33) whose mothers worked with organic solvents during pregnancy with a group of unexposed children (n=28) matched on age, gender, parental socioeconomic status (SES), and ethnicity. Participants were recruited prospectively by the Motherisk Program, an antenatal counseling service in Canada. An exposure index was estimated using questionnaire data obtained at the time of initial contact. Groups were compared on a variety of tasks, including subtests from the NEPSY, a visual CPT, as well as on parent-rated measures of children's behavior. Regression analyses indicated lower composite scores in children with increased exposure on Receptive language (P<.01), Expressive language (P<.01), and Graphomotor ability (P=.001), adjusted for demographics. No group differences were observed on measures of Attention (P=.97), Visuo-spatial ability (P=.33), and Fine-motor ability (P=.33). On the Child Behavior Checklist (CBCL), overall mean differences on broad- and narrow-band scales were not significant, but significantly more exposed children were rated as having mild or severe problem behaviors. The findings suggest that maternal occupational exposure to organic solvents during pregnancy is associated with poorer outcome in selective aspects of cognitive and neuromotor functioning in offspring.
Adult↗
Characteristics of pregnant women who use ecstasy (3, 4-methylenedioxymethamphetamine).
To determine the characteristics of pregnant women who use Ecstasy (3,4-methylenedioxymethamphetamine, MDMA), and to identify reproductive risk factors associated with this group of women. Prospective, observational study. Pregnant women who have contacted the Motherisk Alcohol and Substance Use Helpline at The Hospital for Sick Children, in Toronto, about exposure to drugs, chemicals, infection or radiation. All inquiries from December 1998 to October 2000 concerning pregnant women who reported use of MDMA, and control cases of women not exposed to MDMA selected within the same week of the MDMA callers. Age, maternal demographics, pregnancy characteristics, patterns of alcohol, tobacco, and illicit drug use, psychological/emotional status, sexually transmitted disease, MDMA method and pattern of use, and adverse drug reactions after ingestion of MDMA. The 132 pregnant women who used MDMA were significantly younger (mean 23.2 vs. 31.2 years, P<.0001), and had more unplanned pregnancies compared to 122 pregnant nonusers (84.2% vs. 54.3%, P<.05). MDMA users were also more likely to be single (57.0% vs. 18.3%, P<.001), and to be White (82.2% vs. 56.0%, P<.05). Comparably more MDMA users smoked cigarettes (53.8% vs. 19.7%, P<.0001), drank alcohol (66.4% vs. 37.3%, P<.0001), and had significantly more episodes of binge drinking during pregnancy (mean 2.12 vs. 0.05, P<.001). Illicit drugs such as cocaine, marijuana, methamphetamine, ketamine, gamma-hydroxy butyrate, and psilocybin were used more frequently among the MDMA sample. Over a third of MDMA users reported psychiatric/emotional problems, including 6.5% with a clinically diagnosed condition that was being treated with medication and/or counseling. Pregnant women who use MDMA tend to be young, single, and report psychological morbidity, and have a clustering of risk factors that may compromise the pregnancy and fetus. Smoking, heavy alcohol intake, and polydrug use, combined with a higher than expected rate of unplanned pregnancies, increases the risk of fetal exposure to potentially harmful substances. It is important to account for the range of confounding risk factors among women who use MDMA in order to define possible direct effects of MDMA in pregnancy.
Adult↗
The effect of chronic cocaine exposure throughout pregnancy on maternal and infant outcomes in the rhesus monkey.
To explore the effects of gestational cocaine exposure in a nonhuman primate model, pregnant rhesus monkeys were either treated (N = 10) with escalating doses of cocaine up to 7.5 mg/kg (IM), three times per day, 5 consecutive days per week, prior to conception and throughout gestation, or were not treated (N = 10) with cocaine at all. Substantial levels of both cocaine and its major metabolite, benzoylecgonine, were observed in samples of hair taken at birth from mothers and infants of the cocaine-treated group. Despite these differences in cocaine exposure, the experimental groups did not differ significantly with respect to maternal outcome, as measured by body weight again during pregnancy and length of pregnancy. On the other hand, the experimental groups did differ significantly with respect to infant outcome, as measured at birth by body weight, overall length, and crown circumference, all of which were decreased in the cocaine-treated group. A variety of reflexes tested at birth were normal in the cocaine-treated group. It was concluded that, in a rhesus monkey model, chronic cocaine exposure throughout pregnancy had no significant effect on maternal outcome, but did significantly affect infant outcome as assessed in this investigation.
Animals↗
Moderate alcohol consumption during pregnancy and the incidence of fetal malformations: a meta-analysis.
To determine whether there is an association between moderate alcohol consumption in the first trimester of pregnancy and increased risk of fetal malformations, we conducted a literature search using Medline (1966-present), PsycLit (1974-1995), and EMBASE (1988-1995). The following inclusion criteria were used to select the studies to be evaluated: 1) pregnant women; 2) moderate alcohol consumption (> 2 drinks/week to 2 drinks/day); 3) case-control or cohort studies; 4) presence of an abstainer group (0 to 2 drinks/wk); 5) outcome measures include major or minor malformations; 6) papers published in the English language. The exclusion criteria were: 1) studies in which moderate alcohol consumption could not be confirmed; 2) case reports, and editorials. The Methods section of each study was examined independently by two blinded investigators with a third investigator settling any disagreement. The number of malformations in the abstainer and moderate alcohol consuming groups in two by two tables. Out of 24 studies which met the inclusion criteria, only seven had extractable data. The included studies evaluated 130,810 pregnancy outcomes, with 24,007 in the moderate alcohol group and 106,803 in the control group. An overall Mantel-Haenszel odds ratio showed that the relative risk for fetal malformations was 1.01 with 95% confidence limits of 0.94 to 1.08 and a chi-square for homogeneity of 8.26 (p = 0.220). Quality of the studies did not correlate with their showing negative or positive association. Moderate alcohol consumption during the first trimester of pregnancy is not associated with increased risk of fetal malformations.
Abnormalities, Drug-Induced↗
Neurodevelopment after in utero amiodarone exposure.
It is not known whether amiodarone is neurotoxic to the fetus, as it is to adults. We evaluated neurodevelopment of a historical cohort (N = 10) of children exposed transplacentally to amiodarone. Scores on standardized tests of cognitive and language skills were compared (by Wilcoxon signed rank test) between eight toddlers and matched controls. It was not possible to obtain controls for older amiodarone-exposed children (aged 9.7 and 12.0 years), whose test results were compared descriptively with normative data. There was no difference in IQ scores between amiodarone-exposed toddlers and controls. All had favorable temperaments. However, amiodarone-exposed toddlers showed expressive language skills that were relatively poorer than verbal skills, when compared with controls (p = 0.046). One amiodarone-exposed toddler exhibited global developmental delay. The older amiodarone-exposed children had well-developed social competence, favorable global IQ scores, but problems with reading comprehension, written language, and arithmetic. This picture is reminiscent of the Nonverbal Learning Disability Syndrome. There may be neurotoxicity associated with transplacental exposure to amiodarone. Follow-up is warranted, although most mothers were happy with the development of their children.
Adult↗
A double-blind, randomized, placebo-controlled trial of eutectic lidocaine/prilocaine cream 5% (EMLA) for analgesia prior to cryotherapy of warts in children and adults.
Liquid nitrogen cryotherapy is an effective treatment modality for verrucae in children. However, sometimes the pain of the procedure is too much for the young child. In such instances the availability of an effective topical anesthetic would be of tremendous benefit. Warts are usually present on hardened skin, that is, the palms, periungual areas, and soles. In a double-blind, randomized, placebo-controlled, single-center, parallel-group trial with one visit, children (6-18 years old) and adults (>18 years old) had 2.5 g of lidocaine/prilocaine cream 5% applied under an occlusive dressing to the wart and a 1 to 2 mm area surrounding it 1 hour prior to liquid nitrogen cryotherapy. In both age groups the warts were subdivided by location-hardened skin areas versus nonhardened skin sites. The topical anesthetic was then removed and cryotherapy applied for 5 to 10 seconds. The pain of cryotherapy was assessed by the patient on a visual analogue scale (VAS) immediately after the cryotherapy and 4 and 8 hours later. There was no statistically significant difference in the pain of cryotherapy experienced following the application of active cream (n = 64) and placebo (n = 64). Exploratory subgroup analysis by wart location showed promising results for lidocaine/prilocaine cream 5% over placebo in children with warts on hardened skin sites (palms and soles). The topical anesthetic was safe and generally well-tolerated. Lidocaine/prilocaine cream 5% may provide some anesthesia in children receiving cryotherapy when the wart is on the palms or soles. Further studies are needed to better understand the site and age specificity of the anesthetic properties of lidocaine/prilocaine cream 5% when used to reduce the pain experienced during cryotherapy of warts.
Administration, Topical↗
Safety and pharmacokinetics of EMLA in the treatment of postburn pruritus in pediatric patients: a pilot study.
The purpose of this study was to determine the safety and pharmacokinetics of a eutectic mixture of local anesthetics (EMLA) used to ameliorate postburn pruritus after application onto newly formed, intact skin in children. EMLA was applied once to an itchy site where healed skin had formed. Serial blood samples were collected to measure lidocaine, prilocaine, o-toluidine, and methemoglobin. Maximal plasma concentration, minimal plasma concentration, time to achieve the maximal plasma concentration, elimination half-life, and area under the concentration-time curve were calculated. Vital signs, oxygen saturation, clinical signs of hypoxia, and itch intensity were measured. Five children had 15.7 +/- 2.54 g (+/- SD) of EMLA applied to a skin surface area of 93.0 +/- 37.0 cm2. Lidocaine and prilocaine concentrations were below toxic levels; o-toluidine was not detected. Methemoglobin remained between 1 and 3%; patients did not exhibit any clinical signs of hypoxia. Mean oxygen saturation was 98.9 +/- 0.01%. The mean number of pruritic episodes and antihistamine breakthrough doses were greater in the 2 prestudy control days compared with study day 3 (P = 0.01 and P = 0.03, respectively). Skin at the site of EMLA application remained anesthetized for 12 to 13 hours. In this small pilot study, EMLA seems to be a safe, novel treatment for postburn pruritus in burned children when applied to newly healed, intact skin.
Administration, Topical↗
Use of clinical pharmacists to prevent medication errors in children.
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Child↗