Talk:Abnormal Development - Drugs
BMJ - Children of mothers prescribed macrolide antibiotics during early pregnancy are at an increased risk of major birth defects, particularly heart defects, compared with children of mothers prescribed penicillin, say UK researchers. The team say these findings show that macrolides should be used with caution during pregnancy and if feasible alternative antibiotics should be prescribed until further research is available.
Fan H, Li L, Wijlaars L & Gilbert RE. (2019). Associations between use of macrolide antibiotics during pregnancy and adverse child outcomes: A systematic review and meta-analysis. PLoS ONE , 14, e0212212. PMID: 30779772 DOI. Associations between use of macrolide antibiotics during pregnancy and adverse child outcomes: A systematic review and meta-analysis
Abstract BACKGROUND: Evidence on adverse effects of maternal macrolide use during pregnancy is inconsistent. We conducted a systematic review and meta-analysis to investigate the association between macrolide use during pregnancy and adverse fetal and child outcomes. METHODS AND FINDINGS: We included observational studies and randomised controlled trials (RCTs) that recorded macrolide use during pregnancy and child outcomes. We prioritized comparisons of macrolides with alternative antibiotics (mainly penicillins or cephalosporins) for comparability of indication and effect. Random effects meta-analysis was used to derive pooled odds ratios (OR) for each outcome. Subgroup analyses were performed according to specific types (generic forms) of macrolide. Of 11,186 citations identified, 19 (10 observational, 9 RCTs) studies were included (21 articles including 228,556 participants). Macrolide prescribing during pregnancy was associated with an increased risk of miscarriage (pooled ORobs 1·82, 95% CI 1·57-2·11, three studies, I2 = 0%), cerebral palsy and/or epilepsy (ORobs 1·78, 1·18-2·69; one study), epilepsy alone (ORobs 2·02, 1·30-3·14, one study; ORRCT 1.03, 0.79-1.35, two studies), and gastrointestinal malformations (ORobs 1·56, 1·05-2·32, two studies) compared with alternative antibiotics. We found no evidence of an adverse effect on 12 other malformations, stillbirth, or neonatal death. Results were robust to excluding studies with high risk of bias. CONCLUSIONS: Consistent evidence of an increased risk of miscarriage in observational studies and uncertain risks of cerebral palsy and epilepsy warrant cautious use of macrolide in pregnancy with warnings in drug safety leaflets and use of alternative antibiotics where appropriate. As macrolides are the third most commonly used class of antibiotics, it is important to confirm these results with high quality studies. PMID: 30779772 PMCID: PMC6380581 DOI: 10.1371/journal.pone.0212212
Azuine RE, Ji Y, Chang HY, Kim Y, Ji H, DiBari J, Hong X, Wang G, Singh GK, Pearson C, Zuckerman B, Surkan PJ & Wang X. (2019). Prenatal Risk Factors and Perinatal and Postnatal Outcomes Associated With Maternal Opioid Exposure in an Urban, Low-Income, Multiethnic US Population. JAMA Netw Open , 2, e196405. PMID: 31251378 DOI. Prenatal Risk Factors and Perinatal and Postnatal Outcomes Associated With Maternal Opioid Exposure in an Urban, Low-Income, Multiethnic US Population
IMPORTANCE: The opioid epidemic increasingly affects pregnant women and developing fetuses, resulting in high rates of neonatal abstinence syndrome. However, longitudinal studies that prospectively observe newborns with neonatal abstinence syndrome or with maternal opioid use and examine their long-term physical and neurodevelopmental outcomes are lacking. OBJECTIVE: To examine prenatal risk factors associated with maternal opioid use during pregnancy and the short-term and long-term health consequences on their children. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed data from the Boston Birth Cohort, an urban, low-income, multiethnic cohort that enrolled mother-newborn pairs at birth at Boston Medical Center (Boston, Massachusetts) starting in 1998, and a subset of children were prospectively observed at Boston Medical Center pediatric primary care and subspecialty clinics from birth to age 21 years. Data analysis began in June 2018 and was completed in May 2019. EXPOSURES: In utero opioid exposure was defined as maternal self-reported opioid use and/or clinical diagnosis of neonatal abstinence syndrome. MAIN OUTCOMES AND MEASURES: Pregnancy outcomes, postnatal child physical health, and major neurodevelopmental disabilities, documented in maternal and child medical records. RESULTS: This study included 8509 Boston Birth Cohort mother-newborn pairs for prenatal and perinatal analyses. Of those, 3153 children continued to receive pediatric care at Boston Medical Center and were included in assessing postnatal outcomes. Overall, 454 of the 8509 children (5.3%) in the Boston Birth Cohort had in utero opioid exposure. At birth, opioid exposure was associated with higher risks of fetal growth restriction (odds ratio [OR], 1.87; 95% CI, 1.41-2.47) and preterm birth (OR, 1.49; 95% CI, 1.19-1.86). Opioid exposure was associated with increased risks of lack of expected physiological development (OR, 1.80; 95% CI, 1.17-2.79) and conduct disorder/emotional disturbance (OR, 2.13; 95% CI, 1.20-3.77) among preschool-aged children. In school-aged children, opioid exposure was associated with a higher risk of attention-deficit/hyperactivity disorder (OR, 2.55; 95% CI, 1.42-4.57). CONCLUSIONS AND RELEVANCE: In this sample of urban, high-risk, low-income mother-child pairs, in utero opioid exposure was significantly associated with adverse short-term and long-term outcomes across developmental stages, including higher rates of physical and neurodevelopmental disorders in affected children. Efforts to prevent the opioid epidemic and mitigate its health consequences would benefit from more intergenerational research. PMID: 31251378 DOI: 10.1001/jamanetworkopen.2019.6405
Birth defects in children of men exposed in utero to diethylstilbestrol (DES)
Therapie. 2018 Oct;73(5):399-407. doi: 10.1016/j.therap.2018.02.007. Epub 2018 Mar 3.
Tournaire M1, Devouche E2, Epelboin S3, Cabau A4, Dunbavand A5, Levadou A6. Author information Abstract OBJECTIVE: Prenatal exposure to diethylstilbestrol (DES) is associated with adverse effects, including genital anomalies and cancers in men and women. Animal studies showed birth defects and tumors in the offspring of mice prenatally exposed to DES. In humans, birth defects, such as hypospadias were observed in children of prenatally exposed women. The aim of this research was to assess the birth defects in children of prenatally exposed men. METHODS: In a retrospective study conceived by a patients' association (Réseau DES France), the reports of men prenatally exposed to DES on adverse health effects in their children were compared with those of unexposed controls and general population. RESULTS: An increased incidence of two genital anomalies, cryptorchidism (OR=5.72; 95% CI 1.51-21.71), and hypoplasia of the penis (OR=22.92; 95% CI 3.81-137.90), was observed in the 209 sons of prenatally exposed men compared with controls, but hypospadias incidence was not increased in comparison with either the controls or the general population. No increase of genital anomalies was observed in daughters. CONCLUSION: With caution due to the methods and to the small numbers of defects observed, this work suggests an increased incidence of two male genital tract defects in sons of men prenatally exposed to DES. This transgenerational effect, already observed in animals and in the offspring of women prenatally exposed to DES, could be the result of epigenetic changes transmitted to the subsequent generation through men. Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved. KEYWORDS: Birth defects; Cancer; DES; Diethylstilbestrol; Epigenetic alterations; Estrogens; Pregnancy PMID: 29609831 DOI: 10.1016/j.therap.2018.02.007
Impact of chloroform exposures on reproductive and developmental outcomes: A systematic review of the scientific literature
Birth Defects Res. 2018 Oct 16;110(17):1267-1313. doi: 10.1002/bdr2.1382. Epub 2018 Oct 22.
Williams AL1, Bates CA1, Pace ND2, Leonhard MJ3, Chang ET4, DeSesso JM1,5. Author information Abstract AIMS: We assessed the animal and epidemiological data to determine if chloroform exposure causes developmental and/or reproductive toxicity. RESULTS AND DISCUSSION: Initial scoping identified developmental toxicity as the primary area of concern. At levels producing maternal toxicity in rats and mice, chloroform caused decrements in fetal weights and associated delays in ossification. In a single mouse inhalation study, exposure to a high concentration of chloroform was associated with small fetuses and increased cleft palate. However, oral exposure of mice to chloroform at a dose 4 times higher was negative for cleft palate; multiple inhalation studies in rats were also negative. Epidemiologic data on low birth weight and small for gestational age were generally equivocal, preventing conclusions from being drawn for humans. The animal data also show evidence of very early (peri-implantation) total litter losses at very high exposure levels. This effect is likely maternally mediated rather than a direct effect on the offspring. Finally, the epidemiologic data indicate a possible association of higher chloroform exposure with lower risk of preterm birth (<37 weeks gestation). CONCLUSIONS: The available animal data suggest that exposures lower than those causing maternal toxicity should be without developmental effects in the offspring. Also, most studies in humans rely on group-level geographic exposure data, providing only weak epidemiologic evidence for an association with development outcomes and fail to establish a causal role for chloroform in the induction of adverse developmental outcomes at environmentally relevant concentrations. © 2018 Wiley Periodicals, Inc. KEYWORDS: birth defects; chloroform; developmental toxicity; epidemiology; teratogenicity PMID: 30350414 DOI: 10.1002/bdr2.1382
Dose-Dependent Teratology in Humans: Clinical Implications for Prevention
Paediatr Drugs. 2018 Aug;20(4):331-335. doi: 10.1007/s40272-018-0294-0.
Koren G1,2,3,4, Berkovitch M5,6, Ornoy A7. Author information Abstract Since the inception of clinical teratology, the vast majority of scientific work has focused on identification of drugs and environmental agents causing malformations in humans as a dichotomous variable (i.e. yes or no), as well as the relative and absolute risks of such occurrences. Generally, the dose dependency of such events has not been investigated. With the establishment of large pregnancy databases, dose-dependence relationships are being uncovered for increasing numbers of medications, including valproic acid, carbamazepine, phenobarbital, lamotrigine, topiramate, and lithium. In this review we discuss newly recognized dose-dependent human teratogens and the implications to counseling and clinical management of pregnant women. The option of limiting the dose below a teratogenic threshold for women who may need these drugs may be important in managing such pregnancies. Similarly, in women that were exposed before they realized they had conceived, this new knowledge may lead to significant improvement in risk assessment. A common denominator of all studies calculating dose-dependent teratogenicity in humans is their use of total daily drug dose. None of these studies have standardized their calculations for women's body weight. It is quite possible that the teratogenic dose threshold may be below the clinically effective dose levels for specific women, and hence such information needs to be considered and applied individually. With large administrative databases now reporting on drug safety in pregnancy, more accurate data will likely emerge on dose dependency of human teratogens, and these will likely increase the accuracy of risk assessment. PMID: 29725877 DOI: 10.1007/s40272-018-0294-0
Ibuprofen is deleterious for the development of first trimester human fetal ovary ex vivo
Hum Reprod. 2018 Feb 2. doi: 10.1093/humrep/dex383.
Leverrier-Penna S1, Mitchell RT2, Becker E1, Lecante L1, Ben Maamar M1, Homer N2, Lavoué V3, Kristensen DM4, Dejucq-Rainsford N1, Jégou B5,6, Mazaud-Guittot S1.
STUDY QUESTION: Does ibuprofen use during the first trimester of pregnancy interfere with the development of the human fetal ovary? SUMMARY ANSWER: In human fetuses, ibuprofen exposure is deleterious for ovarian germ cells. WHAT IS KNOWN ALREADY: In utero stages of ovarian development define the future reproductive capacity of a woman. In rodents, analgesics can impair the development of the fetal ovary leading to early onset of fertility failure. Ibuprofen, which is available over-the-counter, has been reported as a frequently consumed medication during pregnancy, especially during the first trimester when the ovarian germ cells undergo crucial steps of proliferation and differentiation. STUDY DESIGN, SIZE, DURATION: Organotypic cultures of human ovaries obtained from 7 to 12 developmental week (DW) fetuses were exposed to ibuprofen at 1-100 μM for 2, 4 or 7 days. For each individual, a control culture (vehicle) was included and compared to its treated counterpart. A total of 185 individual samples were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian explants were analyzed by flow cytometry, immunohistochemistry and quantitative PCR. Endpoints focused on ovarian cell number, cell death, proliferation and germ cell complement. To analyze the possible range of exposure, ibuprofen was measured in the umbilical cord blood from the women exposed or not to ibuprofen prior to termination of pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: Human ovarian explants exposed to 10 and 100 μM ibuprofen showed reduced cell number, less proliferating cells, increased apoptosis and a dramatic loss of germ cell number, regardless of the gestational age of the fetus. Significant effects were observed after 7 days of exposure to 10 μM ibuprofen. At this concentration, apoptosis was observed as early as 2 days of treatment, along with a decrease in M2A-positive germ cell number. These deleterious effects of ibuprofen were not fully rescued after 5 days of drug withdrawal. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This study was performed in an experimental setting of human ovaries explants exposed to the drug in culture, which may not fully recapitulate the complexity of in vivo exposure and organ development. Inter-individual variability is also to be taken into account. WIDER IMPLICATIONS OF THE FINDINGS: Whereas ibuprofen is currently only contra-indicated after 24 weeks of pregnancy, our results points to a deleterious effect of this drug on first trimester fetal ovaries ex vivo. These findings deserve to be considered in light of the present recommendations about ibuprofen consumption pregnancy, and reveal the urgent need for further investigations on the cellular and molecular mechanisms that underlie the effect of ibuprofen on fetal ovary development. © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. KEYWORDS: TP53; apoptosis; cell proliferation; ibuprofen; necrosis; oogonia; ovary PMID: 29408962 DOI: 10.1093/humrep/dex383
Maternal antibiotic exposure during pregnancy and hospitalization with infection in offspring: a population-based cohort study
Int J Epidemiol. 2018 Feb 4. doi: 10.1093/ije/dyx272. [Epub ahead of print]
Miller JE1, Wu C2, Pedersen LH3,4, de Klerk N5, Olsen J6, Burgner DP1,7,8.
BACKGROUND: The early life microbiome contributes to immune development. Antibiotics during pregnancy alter the microbiome and may influence disease risks in the offspring. We investigated the relationship between maternal antibiotic exposure before and during pregnancy, and risk of childhood hospitalization with infection. METHODS: We used population-based Danish national databases for pregnancies between 1995 and 2009. Infants were followed from birth until their first infection-related hospitalization, death, 14th birthday, emigration or end-2009. Exposure was maternal antibiotics prescribed before and during pregnancy. Outcome was infection-related hospitalization. RESULTS: 141 359 (18%) mothers had at least one antibiotic prescription during pregnancy, 230 886 (29.4% of those with complete data) in the 18 months before pregnancy. Of 776 657 live-born singletons, 443 546 infection-related hospitalizations occurred in 222 524 (28.6%) children. Pregnancy antibiotic exposure was associated with increased risk of childhood infection-related hospitalization [hazard ratio (HR) 1.18, 95% confidence interval (CI) 1.17-1.19]. In mothers prescribed antibiotics only during pregnancy whose child did not receive pre-hospitalization antibiotics, this association was present only in those born vaginally. Higher risks of infection-related hospitalization occurred when pregnancy antibiotic prescriptions were closer to birth and in mothers receiving more pregnancy antibiotics. Children born to mothers exposed to antibiotics before (but not during) pregnancy also had increased risk of infection-related hospitalization (HR 1.10, 95% CI 1.07-1.12). CONCLUSIONS: Antibiotic exposure before or during pregnancy was associated with increased risk of childhood hospitalized infections. Alteration of the maternally derived microbiome and shared heritable and environmental determinants are possible contributory mechanisms. KEYWORDS: antibiotic; child; hospitalization; infection; microbiome; pregnancy PMID: 29415232 DOI: 10.1093/ije/dyx272
Characteristics of drug use among pregnant women in the United States: Opioid and non-opioid illegal drug use
Drug Alcohol Depend. 2018 Feb 1;183:261-266. doi: 10.1016/j.drugalcdep.2017.11.010. Epub 2017 Dec 27.
Metz VE1, Brown QL2, Martins SS3, Palamar JJ4.
BACKGROUND: The opioid epidemic in the US is affecting pregnant women and their offspring, with rising numbers of maternal and neonatal treatment episodes. The aim of this study was to characterize pregnant drug users in order to inform intervention strategies based on sociodemographic, mental health, and substance use characteristics. METHODS: Data on pregnant women aged 18-44 reporting past-year, nonmedical opioid use or use of non-opioid illegal drugs (other than marijuana) were analyzed from the National Survey on Drug Use and Health (2005-2014). Women (N = 818) were categorized into 3 groups: 1) use of opioids only (n = 281), 2) opioid-polydrug users (n = 241), and 3) other (non-opioid) illegal drug users (n = 296). Characteristics between the 3 groups of women were compared using bivariable analyses. RESULTS: Most women were non-Hispanic White (67.6%), had a high school diploma or less education (61.0%), a household income <$20,000/year (72.2%), and health insurance coverage (84.3%). No significant differences between the three groups were found regarding sociodemographic characteristics. Past-30-day marijuana use was less prevalent among opioid-only users (10.9%) compared to opioid-polydrug users (43.6%) and other pregnant illegal drug users (27.6%) (P < 0.001) and past-year drug/alcohol treatment was less prevalent among opioid-only users (6.3%) compared to opioid-polydrug users (20.3%) and other illegal drug users (8.3%) (P = 0.002). Opioid-only users also reported lower prevalence of past-year depression (P < 0.001) and anxiety (P = 0.039). CONCLUSIONS: Pregnant drug-using women were often of low socioeconomic status, with mental health and substance use patterns suggesting the need for targeted mental health/substance use screening and interventions before and during pregnancy, particularly for opioid-polydrug users. Copyright © 2017. Published by Elsevier B.V. KEYWORDS: Anxiety; Depression; Opioid abuse; Polydrug use; Pregnancy; Sociodemographic characteristics PMID: 29310077 PMCID: PMC5803362 [Available on 2019-02-01] DOI: 10.1016/j.drugalcdep.2017.11.010
Opiate Drugs with Abuse Liability Hijack the Endogenous Opioid System to Disrupt Neuronal and Glial Maturation in the Central Nervous System
Front Pediatr. 2018 Jan 23;5:294. doi: 10.3389/fped.2017.00294. eCollection 2017.
Hauser KF1,2,3, Knapp PE1,2,3.
The endogenous opioid system, comprised of multiple opioid neuropeptide and receptor gene families, is highly expressed by developing neural cells and can significantly influence neuronal and glial maturation. In many central nervous system (CNS) regions, the expression of opioid peptides and receptors occurs only transiently during development, effectively disappearing with subsequent maturation only to reemerge under pathologic conditions, such as with inflammation or injury. Opiate drugs with abuse liability act to modify growth and development by mimicking the actions of endogenous opioids. Although typically mediated by μ-opioid receptors, opiate drugs can also act through δ- and κ-opioid receptors to modulate growth in a cell-type, region-specific, and developmentally regulated manner. Opioids act as biological response modifiers and their actions are highly contextual, plastic, modifiable, and influenced by other physiological processes or pathophysiological conditions, such as neuro-acquired immunodeficiency syndrome. To date, most studies have considered the acute effects of opiates on cellular maturation. For example, activating opioid receptors typically results in acute growth inhibition in both neurons and glia. However, with sustained opioid exposure, compensatory factors become operative, a concept that has been largely overlooked during CNS maturation. Accordingly, this article surveys prior studies on the effects of opiates on CNS maturation, and also suggests new directions for future research in this area. Identifying the cellular and molecular mechanisms underlying the adaptive responses to chronic opiate exposure (e.g., tolerance) during maturation is crucial toward understanding the consequences of perinatal opiate exposure on the CNS. KEYWORDS: fetal abstinence syndrome; glial maturation; human immunodeficiency virus; neural stem cells; neuronal maturation; opioid drug abuse; pediatric acquired immunodeficiency syndrome; perinatal development
PMID: 29410949 PMCID: PMC5787058 DOI: 10.3389/fped.2017.00294
Effects of valproic acid on the placental barrier in the pregnant mouse: Optical imaging and transporter expression studies
Epilepsia. 2016 May 3. doi: 10.1111/epi.13392. [Epub ahead of print]
Meir M1, Bishara A1, Mann A1, Udi S1, Portnoy E1, Shmuel M1, Eyal S1.
Our aim was to evaluate the effects of valproic acid (VPA) on the function of the placental barrier in vivo, in pregnant mice. Studies were conducted on gestational days 12.5 (mid-gestation) or 17.5 (late gestation), following intraperitoneal treatment with 200 mg/kg VPA or the vehicle. Indocyanine green (ICG; 0.167 mg, i.v.) was used as a marker for the placental barrier permeability. Transporter expression was evaluated by quantitative -PCR. VPA treatment was associated with a 40% increase (p < 0.05) in accumulation of ICG in maternal liver in mid-pregnancy and a decrease by one fifth (p < 0.05) in late pregnancy. Ex vivo, VPA treatment led to a 20% increase (p < 0.05) in fetal ICG emission in mid-pregnancy. Also in mid-pregnancy, the placental expression of the L-type amino acid transporter, the organic anion-transporting polypeptide (Oatp)4a1 (thyroid hormone transporter), and the reduced folate carrier was lower in VPA-treated mice (p < 0.05). In late pregnancy, hepatic Oatp4a1 levels were 40% less than in controls (p > 0.05). The observed changes in placental transporter expression and function support further research into the potential role of the placenta in the adverse pregnancy outcomes of VPA. Near-infrared imaging provides a noninvasive, nonradioactive tool for future studies on the effects of epilepsy and antiepileptic drugs on tissue transport functions. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy. KEYWORDS: Indocyanine green; Near-infrared imaging; Organic anion-transporting polypeptides; Placenta; Pregnancy; Valproic acid
Maternal use of oral contraceptives and risk of birth defects in Denmark: prospective, nationwide cohort study
BMJ. 2016 Jan 6;352:h6712. doi: 10.1136/bmj.h6712.
Charlton BM1, Mølgaard-Nielsen D2, Svanström H2, Wohlfahrt J2, Pasternak B2, Melbye M3.
Is oral contraceptive use around the time of pregnancy onset associated with an increased risk of major birth defects?
In a prospective observational cohort study, data on oral contraceptive use and major birth defects were collected among 880 694 live births from Danish registries between 1997 and 2011. We conservatively assumed that oral contraceptive exposure lasted up to the most recently filled prescription. The main outcome measure was the number of major birth defects throughout one year follow-up (defined according to the European Surveillance of Congenital Anomalies classification). Logistic regression estimated prevalence odds ratios of any major birth defect as well as categories of birth defect subgroups.
STUDY ANSWER AND LIMITATIONS:
Prevalence of major birth defects (per 1000 births) was consistent across each oral contraceptive exposure group (25.1, never users; 25.0, use >3 months before pregnancy onset (reference group); 24.9, use 0-3 months before pregnancy onset (that is, recent use); 24.8, use after pregnancy onset). No increase in prevalence of major birth defects was seen with oral contraceptive exposure among women with recent use before pregnancy (prevalence odds ratio 0.98 (95% confidence interval 0.93 to 1.03)) or use after pregnancy onset (0.95 (0.84 to 1.08)), compared with the reference group. There was also no increase in prevalence of any birth defect subgroup (for example, limb defects). It is unknown whether women took oral contraceptives up to the date of their most recently filled prescription. Also, the rarity of birth defects made disaggregation of the results difficult. Residual confounding was possible, and the analysis lacked information on folate, one of the proposed mechanisms.
WHAT THIS STUDY ADDS:
Oral contraceptive exposure just before or during pregnancy does not appear to be associated with an increased risk of major birth defects.
FUNDING, COMPETING INTERESTS, DATA SHARING:
BMC was funded by the Harvard T H Chan School of Public Health's Maternal Health Task Force and Department of Epidemiology Rose Traveling Fellowship; training grant T32HD060454 in reproductive, perinatal, and paediatric epidemiology and award F32HD084000 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development; and grant T32CA09001 from the National Cancer Institute. The authors have no competing interests or additional data to share.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Risks of congenital malformations in offspring exposed to valproic acid in utero: A systematic review and cumulative meta-analysis
Clin Pharmacol Ther. 2015 Jun 5. doi: 10.1002/cpt.158. [Epub ahead of print]
Tanoshima M1,2, Kobayashi T1,3, Tanoshima R1,4, Beyene J5,6, Koren G1, Ito S1.
Despite extensive research efforts over decades, the teratogenic profile of valproic acid (VPA) remains obscure. We performed cumulative and conventional meta-analyses of cohort studies to determine the time profiles of signal emergence of VPA-associated congenital malformations (CMs) and to define risk estimates of each of the CMs. Fifty nine studies were identified and analyzed. We found that the significant risk signals began to emerge over the last 10-20 years even before large-scale studies were performed: neural tube defect (the significant risk signal emerged in 1992); genitourinary and musculoskeletal anomalies (2004); cleft lip and/or palate (2005); and congenital heart defects (2006). At present, risks of VPA-associated CMs are 2 to 7 fold higher than other common antiepileptic drugs. VPA should not be used as a first-line therapy in women of childbearing age unless it is the only option for the patient. This article is protected by copyright. All rights reserved. © 2015 American Society for Clinical Pharmacology and Therapeutics. KEYWORDS: congenital malformations; cumulative meta-analysis; neural tube defects; teratogenicity; valproic acid
Statins and congenital malformations: cohort study
BMJ 2015; 350 doi: http://dx.doi.org/10.1136/bmj.h1035 (Published 17 March 2015) Cite this as: BMJ 2015;350:h1035
Abstract Objective To examine the teratogenic potential of statins.
Design Cohort study.
Setting United States.
Participants A cohort of 886 996 completed pregnancies linked to liveborn infants of women enrolled in Medicaid from 2000 to 2007.
Methods We examined the risk of major congenital malformations and organ specific malformations in offspring associated with maternal use of a statin in the first trimester. Propensity score based methods were used to control for potential confounders, including maternal demographic characteristics, obstetric and medical conditions, and use of other drugs.
Results 1152 (0.13%) women used a statin during the first trimester. In unadjusted analyses, the prevalence of malformations in the offspring of these women was 6.34% compared with 3.55% in those of women who did not use a statin in the first trimester (relative risk 1.79, 95% confidence interval 1.43 to 2.23). Controlling for confounders, particularly pre-existing diabetes, accounted for this increase in risk (1.07, 0.85 to 1.37). There were also no statistically significant increases in any of the organ specific malformations assessed after accounting for confounders. Results were similar across a range of sensitivity analyses.
Conclusions Our analysis did not find a significant teratogenic effect from maternal use of statins in the first trimester. However, these findings need to be replicated in other large studies, and the long term effects of in utero exposure to statins needs to be assessed, before use of statins in pregnancy can be considered safe.
Fetal valproate syndrome
Indian J Hum Genet. 2014 Apr;20(2):187-8. doi: 10.4103/0971-6866.142898.
Chandane PG, Shah I.
Antenatal use of anticonvulsant valproic acid can result in a well-recognized cluster of facial dysmorphism, congenital anomalies and neurodevelopmental retardation. In this report, we describe a case with typical features of fetal valproate syndrome (FVS). A 26-year-old female with epilepsy controlled on sodium valproate 800 mg/day since 3 years, gave birth to a male child with characteristic features of FVS. She also had 3 spontaneous first-trimester abortions during those 3 years. Sodium valproate, a widely used anticonvulsant and mood regulator, is a well-recognized teratogen that can result in facial dysmorphism, craniosynostosis, neural tube defects, and neurodevelopmental retardation. Therefore, we strongly recommend avoidance of valproic acid and supplementation of folic acid during pregnancy. KEYWORDS: Anticonvulsant; pregnancy; sodium valproate
Birth Defects After Early Pregnancy Use of Antithyroid Drugs: A Danish Nationwide Study
J Clin Endocrinol Metab. 2013 Oct 22. [Epub ahead of print]
Andersen SL, Olsen J, Wu CS, Laurberg P. Source Department of Endocrinology (S.L.A., P.L.), Aalborg University Hospital, DK-9000 Aalborg, Denmark; and Section for Epidemiology (J.O., C.S.W.), Department of Public Health, Aarhus University, DK-8000 Aarhus, Denmark.
Introduction:Hyperthyroidism in pregnant women should be adequately treated to prevent maternal and fetal complications, but teratogenic effects of antithyroid drug (ATD) treatment have been described. Evidence is still lacking in regard to the safety and choice of ATD in early pregnancy.Objective:Our objective was to determine to which degree the use of methimazole (MMI)/carbimazole (CMZ) and propylthiouracil (PTU) in early pregnancy is associated with an increased prevalence of birth defects.Methods:This Danish nationwide register-based cohort study included 817 093 children live-born from 1996 to 2008. Exposure groups were assigned according to maternal ATD use in early pregnancy: PTU (n = 564); MMI/CMZ (n = 1097); MMI/CMZ and PTU (shifted in early pregnancy [n = 159]); no ATD (ATD use, but not in pregnancy [n = 3543]); and nonexposed (never ATD use [n = 811 730]). Multivariate logistic regression was used to estimate adjusted odds ratio (OR) with 95% confidence interval (95% CI) for diagnosis of a birth defect before 2 years of age in exposed versus nonexposed children.Results:The prevalence of birth defects was high in children exposed to ATD in early pregnancy (PTU, 8.0%; MMI/CMZ, 9.1%; MMI/CMZ and PTU, 10.1%; no ATD, 5.4%; nonexposed, 5.7%; P < .001). Both maternal use of MMI/CMZ (adjusted OR = 1.66 [95% CI 1.35-2.04]) and PTU (1.41 [1.03-1.92]) and maternal shift between MMI/CMZ and PTU in early pregnancy (1.82 [1.08-3.07]) were associated with an increased OR of birth defects. MMI/CMZ and PTU were associated with urinary system malformation, and PTU with malformations in the face and neck region. Choanal atresia, esophageal atresia, omphalocele, omphalomesenteric duct anomalies, and aplasia cutis were common in MMI/CMZ-exposed children (combined, adjusted OR = 21.8 [13.4-35.4]).Conclusions:Both MMI/CMZ and PTU were associated with birth defects, but the spectrum of malformations differed. More studies are needed to corroborate results in regard to early pregnancy shift from MMI/CMZ to PTU. New ATD with fewer side effects should be developed.
Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism
JAMA. 2013 Apr 24;309(16):1696-703. doi: 10.1001/jama.2013.2270.
Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M. Source Department of Neurology, Aarhus University Hospital, Norrebrogade 44, DK-8000 Aarhus C, Denmark. email@example.com
IMPORTANCE: Valproate is used for the treatment of epilepsy and other neuropsychological disorders and may be the only treatment option for women of childbearing potential. However, prenatal exposure to valproate may increase the risk of autism. OBJECTIVE: To determine whether prenatal exposure to valproate is associated with an increased risk of autism in offspring. DESIGN, SETTING, AND PARTICIPANTS: Population-based study of all children born alive in Denmark from 1996 to 2006. National registers were used to identify children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders (childhood autism [autistic disorder], Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders). We analyzed the risks associated with all autism spectrum disorders as well as childhood autism. Data were analyzed by Cox regression adjusting for potential confounders (maternal age at conception, paternal age at conception, parental psychiatric history, gestational age, birth weight, sex, congenital malformations, and parity). Children were followed up from birth until the day of autism spectrum disorder diagnosis, death, emigration, or December 31, 2010, whichever came first. MAIN OUTCOMES AND MEASURES: Absolute risk (cumulative incidence) and the hazard ratio (HR) of autism spectrum disorder and childhood autism in children after exposure to valproate in pregnancy. RESULTS: Of 655,615 children born from 1996 through 2006, 5437 were identified with autism spectrum disorder, including 2067 with childhood autism. The mean age of the children at end of follow-up was 8.84 years (range, 4-14; median, 8.85). The estimated absolute risk after 14 years of follow-up was 1.53% (95% CI, 1.47%-1.58%) for autism spectrum disorder and 0.48% (95% CI, 0.46%-0.51%) for childhood autism. Overall, the 508 children exposed to valproate had an absolute risk of 4.42% (95% CI, 2.59%-7.46%) for autism spectrum disorder (adjusted HR, 2.9 [95% CI, 1.7-4.9]) and an absolute risk of 2.50% (95% CI, 1.30%-4.81%) for childhood autism (adjusted HR, 5.2 [95% CI, 2.7-10.0]). When restricting the cohort to the 6584 children born to women with epilepsy, the absolute risk of autism spectrum disorder among 432 children exposed to valproate was 4.15% (95% CI, 2.20%-7.81%) (adjusted HR, 1.7 [95% CI, 0.9-3.2]), and the absolute risk of childhood autism was 2.95% (95% CI, 1.42%-6.11%) (adjusted HR, 2.9 [95% CI, 1.4-6.0]) vs 2.44% (95% CI, 1.88%-3.16%) for autism spectrum disorder and 1.02% (95% CI, 0.70%-1.49%) for childhood autism among 6152 children not exposed to valproate. CONCLUSIONS AND RELEVANCE: Maternal use of valproate during pregnancy was associated with a significantly increased risk of autism spectrum disorder and childhood autism in the offspring, even after adjusting for maternal epilepsy. For women of childbearing potential who use antiepileptic medications, these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control. Comment in Risks of in utero exposure to valproate. [JAMA. 2013] PMID 23613074
Propylthiouracil is teratogenic in murine embryos
PLoS One. 2012;7(4):e35213. doi: 10.1371/journal.pone.0035213. Epub 2012 Apr 18.
Benavides VC, Mallela MK, Booth CJ, Wendler CC, Rivkees SA. Source
Section of Developmental Endocrinology and Biology, Yale Pediatric Thyroid Center, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, United States of America.
BACKGROUND: Hyperthyroidism during pregnancy is treated with the antithyroid drugs (ATD) propylthiouracil (PTU) and methimazole (MMI). PTU currently is recommended as the drug of choice during early pregnancy. Yet, despite widespread ATD use in pregnancy, formal studies of ATD teratogenic effects have not been performed. METHODS: We examined the teratogenic effects of PTU and MMI during embryogenesis in mice. To span different periods of embryogenesis, dams were treated with compounds or vehicle daily from embryonic day (E) 7.5 to 9.5 or from E3.5 to E7.5. Embryos were examined for gross malformations at E10.5 or E18.5 followed by histological and micro-CT analysis. Influences of PTU on gene expression levels were examined by RNA microarray analysis. RESULTS: When dams were treated from E7.5 to E9.5 with PTU, neural tube and cardiac abnormalities were observed at E10.5. Cranial neural tube defects were significantly more common among the PTU-exposed embryos than those exposed to MMI or vehicle. Blood in the pericardial sac, which is a feature indicative of abnormal cardiac function and/or abnormal vasculature, was observed more frequently in PTU-treated than MMI-treated or vehicle-treated embryos. Following PTU treatment, a total of 134 differentially expressed genes were identified. Disrupted genetic pathways were those associated with cytoskeleton remodeling and keratin filaments. At E 18.5, no gross malformations were evident in either ATD group, but the number of viable PTU embryos per dam at E18.5 was significantly lower from those at E10.5, indicating loss of malformed embryos. These data show that PTU exposure during embryogenesis is associated with delayed neural tube closure and cardiac abnormalities. In contrast, we did not observe structural or cardiac defects associated with MMI exposure except at the higher dose. We find that PTU exposure during embryogenesis is associated with fetal loss. These observations suggest that PTU has teratogenic potential.
Obstetric toxicology: teratogens
Emerg Med Clin North Am. 2012 Nov;30(4):977-90. doi: 10.1016/j.emc.2012.08.008.
Levine M, O'Connor AD. Source Section of Medical Toxicology, Department of Emergency Medicine, University of Southern California, 1200 North State Street, Room 1011, Los Angeles, CA 90033, USA; Department of Medical Toxicology, Banner Good Samaritan Medical Center, 925 East McDowell Road, Second Floor, Phoenix, AZ 85006, USA. Electronic address: firstname.lastname@example.org.
The emergency physician frequently encounters women who seek care because of pregnancy- and nonpregnancy-related complaints. Many medications are safe for use during pregnancy, including several that are listed as potential teratogens based on the Food and Drug Administration's (FDA) pregnancy classification; but it is important that the emergency physician know and recognize which drugs can be given in pregnancy and which drugs are absolutely contraindicated. Expert resources should be identified and used because the FDA's classification of drugs based on pregnancy risk does not represent the most up-to-date or accurate assessment of a drug's safety. Copyright © 2012 Elsevier Inc. All rights reserved.
--Mark Hill 13:05, 19 September 2011 (EST) The Teratogen Information System TERIS a computerized database designed to assist physicians or other health care professionals in assessing the risks of possible teratogenic exposures in pregnant women. (subscription only) External link not added to drugs page as information is not freely available.
Abnormal notochord branching is associated with foregut malformations in the adriamycin treated mouse model
PLoS One. 2011;6(11):e27635. doi: 10.1371/journal.pone.0027635. Epub 2011 Nov 21.
Hajduk P1, Sato H, Puri P, Murphy P.
Oesophageal atresia (OA) and tracheooesophageal fistula (TOF) are relatively common human congenital malformations of the foregut where the oesophagus does not connect with the stomach and there is an abnormal connection between the stomach and the respiratory tract. They require immediate corrective surgery and have an impact on the future health of the individual. These abnormalities are mimicked by exposure of rat and mouse embryos in utero to the drug adriamycin. The causes of OA/TOF during human development are not known, however a number of mouse mutants where different signalling pathways are directly affected, show similar abnormalities, implicating multiple and complex signalling mechanisms. The similarities in developmental outcome seen in human infants and in the adriamycin treated mouse model underline the potential of this model to unravel the early embryological events and further our understanding of the processes disturbed, leading to such abnormalities. Here we report a systematic study of the foregut and adjacent tissues in embryos treated with adriamycin at E7 and E8 and analysed between E9 and E12, comparing morphology in 3D in 149 specimens. We describe a spectrum of 8 defects, the most common of which is ventral displacement and branching of the notochord (in 94% of embryos at E10) and a close spatial correspondence between the site of notochord branching and defects of the foregut. In addition gene expression analysis shows altered dorso-ventral foregut patterning in the vicinity of notochord branches. This study shows a number of features of the adriamycin mouse model not previously reported, implicates the notochord as a primary site of disturbance in such abnormalities and underlines the importance of the model to further address the mechanistic basis of foregut congenital abnormalities.
Valproic Acid Increases Formation of Reactive Oxygen Species and Induces Apoptosis in Postimplantation Embryos: A Role for Oxidative Stress in Valproic Acid-Induced Neural Tube Defects
Mol Pharmacol. 2011 Aug 25. [Epub ahead of print]
Tung EW, Winn L. Source 1 Queen's University;
Exposure to the anticonvulsant valproic acid (VPA) during the first trimester of pregnancy is associated with an increased risk of congenital malformations including heart defects, craniofacial abnormalities, skeletal and limb defects, and most frequently, neural tube defects (NTDs). The mechanisms by which VPA induces teratogenic effects are not fully understood, although previous studies support a role for oxidative stress. To investigate the effects of VPA on early development, a whole embryo culture model was used to evaluate the protective effects of antioxidants, measure intracellular reactive oxygen species (ROS) levels, and assess markers of oxidative damage and apoptosis. Furthermore, in vivo teratological evaluations of antioxidant protection were also completed. VPA (0.60 mM in embryo culture, 400 mg/kg s.c. in vivo) induced significant decreases in embryonic growth and increases in NTDs. Of the antioxidants tested, catalase provided partial protection against VPA-mediated reductions in morphological and developmental growth parameters in both whole embryo culture and in vivo systems. VPA exposure resulted in an increase in ROS staining in the head region, as assessed by whole mount staining with CM-H(2)DCFDA. Markers of embryonic oxidative damage including 8-hydroxyguanosine, 4-hydroxynonenal adducts, and 3-nitrotyrosine were not affected by VPA treatment. Increased ROS levels were correlated with increased staining for apoptotic markers, as assessed by western blotting and immunohistochemistry. Addition of catalase to the media attenuated VPA-induced increases in ROS formation and apoptosis. These studies identify regions of the embryo susceptible to ROS and apoptosis induced by VPA, thus establishing a possible molecular pathway by which VPA exerts teratogenicity.
Evolving knowledge of the teratogenicity of medications in human pregnancy
Am J Med Genet C Semin Med Genet. 2011 Aug 15;157(3):175-82. doi: 10.1002/ajmg.c.30313. Epub 2011 Jul 15.
Adam MP, Polifka JE, Friedman JM. Source University of Washington in Seattle, and Seattle Children's Hospital, 4800 Sand Point Way NE, Seattle, WA 98105-0371, USA. email@example.com
A majority of pregnant women take at least one medication during pregnancy, although the safety of such drugs during pregnancy is not always known. We reviewed the safety during pregnancy of 172 drugs approved by the US Food and Drug Administration (FDA) from 2000 to 2010 using the TERIS risk rating system. We also reviewed safety information for 468 drugs approved by the FDA from 1980 to 2000 to determine if revisions in risk categories had been made in the last 10 years. The teratogenic risk in human pregnancy was "undetermined" for 168 (97.7%) of drug treatments approved between 2000 and 2010. Furthermore, the amount of data available regarding safety in pregnancy was rated as "none" for 126 (73.3%) of these drugs. For those drugs approved between 1980 and 2000, only 23 (5%) changed a full risk category or more in the past 10 years. Sources of data that led to a revised risk were derived from exposure cohort studies performed through record linkage studies, teratogen information services, large population-based case-control studies, and pregnancy registries. The mean time for a treatment initially classified as having an "undetermined" risk to be assigned a more precise risk was 27 years (95% confidence interval 26-28 years). The lack of information needed to assess the safety of drug treatments during human pregnancy remains a serious public health problem. A more active approach to post-marketing surveillance for teratogenic effects is necessary.
Copyright © 2011 Wiley-Liss, Inc.
Exposure to Non-Steroidal Anti-Inflammatory Drugs during Pregnancy and the Risk of Selected Birth Defects: A Prospective Cohort Study
PLoS One. 2011;6(7):e22174. Epub 2011 Jul 18.
van Gelder MM, Roeleveld N, Nordeng H. Source Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
BACKGROUND: Since use of non-steroidal anti-inflammatory drugs (NSAIDs) during pregnancy is common, small increases in the risk of birth defects may have significant implications for public health. Results of human studies on the teratogenic risks of NSAIDs are inconsistent. Therefore, we evaluated the risk of selected birth defects after prenatal exposure to prescribed and over-the-counter NSAIDs.
METHODS AND FINDINGS: We used data on 69,929 women enrolled in the Norwegian Mother and Child Cohort Study between 1999 and 2006. Data on NSAID exposure were available from a self-administered questionnaire completed around gestational week 17. Information on pregnancy outcome was obtained from the Medical Birth Registry of Norway. Only birth defects suspected to be associated with NSAID exposure based upon proposed teratogenic mechanisms and previous studies were included in the multivariable logistic regression analyses. A total of 3,023 women used NSAIDs in gestational weeks 0-12 and 64,074 women did not report NSAID use in early pregnancy. No associations were observed between overall exposure to NSAIDs during pregnancy and the selected birth defects separately or as a group (adjusted odds ratio 0.7, 95% confidence interval 0.4-1.1). Associations between maternal use of specific types of NSAIDs and the selected birth defects were not found either, although an increased risk was seen for septal defects and exposure to multiple NSAIDs based on small numbers (2 exposed cases; crude odds ratio 3.9, 95% confidence interval 0.9-15.7).
CONCLUSIONS: Exposure to NSAIDs during the first 12 weeks of gestation does not seem to be associated with an increased risk of the selected birth defects. However, due to the small numbers of NSAID-exposed infants for the individual birth defect categories, increases in the risks of specific birth defects could not be excluded.
Valproic acid inhibits neural progenitor cell death by activation of NF-kappaB signaling pathway and up-regulation of Bcl-XL
J Biomed Sci. 2011 Jul 4;18(1):48. [Epub ahead of print]
Go HS, Seo JE, Kim KC, Han SM, Kim P, Kang YS, Han SH, Shin CY, Ko KH.
BACKGROUND: At the beginning of neurogenesis, massive brain cell death occurs and more than 50% of cells are eliminated by apoptosis along with neuronal differentiation. However, few studies were conducted so far regarding the regulation of neural progenitor cells (NPCs) death during development. Because of the physiological role of cell death during development, aberration of normal apoptotic cell death is detrimental to normal organogenesis. Apoptosis occurs in not only neuron but also in NPCs and neuroblast. When growth and survival signals such as EGF or LIF are removed, apoptosis is activated as well as the induction of differentiation. To investigate the regulation of cell death during developmental stage, it is essential to investigate the regulation of apoptosis of NPCs.
METHODS: Neural progenitor cells were cultured from E14 embryonic brains of Sprague-Dawley rats. For in vivo VPA animal model, pregnant rats were treated with VPA (400 mg/kg S.C.) diluted with normal saline at E12. To analyze the cell death, we performed PI staining and PARP and caspase-3 cleavage assay. Expression level of proteins was investigated by Western blot and immunocytochemical assays. The level of mRNA expression was investigated by RT-PCR. Interaction of Bcl-XL gene promoter and NF-kappaB p65 was investigated by ChIP assay.
RESULTS: In this study, FACS analysis, PI staining and PARP and caspase-3 cleavage assay showed that VPA protects cultured NPCs from cell death after growth factor withdrawal both in basal and staurosporine- or hydrogen peroxide-stimulated conditions. The protective effect of prenatally injected VPA was also observed in E16 embryonic brain. Treatment of VPA decreased the level of IkappaBalpha and increased the nuclear translocation of NF-kappaB, which subsequently enhanced expression of anti-apoptotic protein Bcl-XL.
CONCLUSIONS: To the best of our knowledge, this is the first report to indicate the reduced death of NPCs by VPA at developmentally critical periods through the degradation of IkappaBalpha and the activation of NF-kappaB signaling. The reduced NPCs death might underlie the neurodevelopmental defects collectively called fetal valproate syndrome, which shows symptoms such as mental retardation and autism-like behavior.
The effect of drugs with ion channel-blocking activity on the early embryonic rat heart
Birth Defects Res B Dev Reprod Toxicol. 2010 Oct;89(5):429-40.
Abela D, Ritchie H, Ababneh D, Gavin C, Nilsson MF, Khan MK, Carlsson K, Webster WS.
Department of Anatomy and Histology, Sydney Medical School, University of Sydney, Sydney, Australia.
Abstract This study investigated the effects of a range of pharmaceutical drugs with ion channel-blocking activity on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the blockade of the I(Kr)/hERG channel, that is highly important for the normal functioning of the embryonic rat heart, would cause bradycardia and arrhythmia. Concomitant blockade of other channels was expected to modify the effects of hERG blockade. Fourteen drugs with varying degrees of specificity and affinity toward potassium, sodium, and calcium channels were tested over a range of concentrations. The rat embryos were maintained for 2 hr in culture, 1 hr to acclimatize, and 1 hr to test the effect of the drug. All the drugs caused a concentration-dependent bradycardia except nifedipine, which primarily caused a negative inotropic effect eventually stopping the heart. A number of drugs induced arrhythmias and these appeared to be related to either sodium channel blockade, which resulted in a double atrial beat for each ventricular beat, or I(Kr)/hERG blockade, which caused irregular atrial and ventricular beats. However, it is difficult to make a precise prediction of the effect of a drug on the embryonic heart just by looking at the polypharmacological action on ion channels. The results indicate that the use of the tested drugs during pregnancy could potentially damage the embryo by causing periods of hypoxia. In general, the effects on the embryonic heart were only seen at concentrations greater than those likely to occur with normal therapeutic dosing. Birth Defects Res (Part B) 89:429-440, 2010. © 2010 Wiley-Liss, Inc.
Use of selective serotonin reuptake inhibitors during pregnancy and risk of major and cardiovascular malformations: an update
Postgrad Med. 2010 Jul;122(4):49-65.
Tuccori M, Montagnani S, Testi A, Ruggiero E, Mantarro S, Scollo C, Pergola A, Fornai M, Antonioli L, Colucci R, Corona T, Blandizzi C. Unit of Pharmacology, University Hospital of Pisa, Pisa, Italy. firstname.lastname@example.org Abstract General consensus exists about the need to avoid drug intake as much as possible during pregnancy due to the lack of thorough evidence about the safety of pharmacologic treatments during gestation for both mothers and fetuses. In this respect, the overall safety profile of selective serotonin reuptake inhibitors (SSRIs) in pregnancy remains unclear. This article reviews current evidence about the safety of each SSRI during pregnancy in order to describe their specific teratogenic potential, with a particular focus on major and cardiovascular malformations, and to verify whether such toxicity can be considered as a class effect. The literature review included controlled studies and meta-analyses (retrieved using PsychINFO, EMBASE, and Medline from January 1966 to May 2010) from which the risk of major and/or cardiovascular malformations associated with a specific SSRI (ie, fluoxetine, paroxetine, sertraline, citalopram, escitalopram, and fluvoxamine) could be estimated. Although there is evidence to support the association between birth defects and first-trimester exposure to paroxetine, findings from the studies reviewed suggest a teratogenic potential of the whole SSRI class, consistent with preclinical evidence. These teratogenic effects are mainly in the heart region, and they are often described as septal defects. It may be suggested that the higher frequency of teratogenic effects reported for paroxetine might depend on specific pharmacologic features of this drug compared with other SSRIs, although it is difficult to test this hypothesis. It is noteworthy that current evidence on SSRI teratogenicity stems from studies affected by several methodological weaknesses (ie, lack of investigations using control groups of untreated depressed mothers, confounding by indication, and recall bias). Accordingly, we are not yet able to rule out the possibility that positive associations, as determined in some studies, result from analyses of poor quality. PMID: 20675971
Is lamotrigine a significant human teratogen? Observations from the Australian Pregnancy Register
Seizure. 2010 Aug 24. [Epub ahead of print]
Vajda FJ, Graham JE, Hitchcock AA, O'Brien TJ, Lander CM, Eadie MJ. Department of Medicine and Neurology, Royal Melbourne Hospital and University of Melbourne, Parkville, Victoria 3050, Australia. Abstract Lamotrigine (LTG) is increasingly being prescribed in pregnancy for women with epilepsy in place of valproate (VPA), because of the teratogenic risks associated with the latter. It is therefore important to know the teratogenic hazard associated with LTG, relative to VPA and to other commonly used antiepileptic drugs (AEDs). Data from the Australian Register of Antiepileptic Drugs in Pregnancy was examined to determine the incidence of teratogenicity determined 1 year from completion of pregnancy in women who took AEDs in monotherapy during pregnancy. Compared with a 3.4% malformation incidence in women who took no AEDs (N=118), the incidences for LTG (N=243), carbamazepine (CBZ) (N=302) and VPA (N=224) were, respectively, 4.9%, 5.3% and 15.2%, the latter statistically significantly greater than the risk for no AED therapy in pregnant women with epilepsy. Logistic regression analysis showed no tendency for foetal hazard to increase with increasing LTG dose in pregnancy, unlike the situation for VPA. However, seizure control in pregnancy tended to be not as good in the women taking LTG compared with those taking VPA, though the data examined were not adequate to permit definite conclusions regarding this matter. We conclude that LTG monotherapy in pregnancy is safer than valproate monotherapy from the point of view of foetal malformations, and no more hazardous in this regard than therapy with other commonly used AEDs. Copyright © 2010. Published by Elsevier Ltd. PMID: 20739196
Are azole fungicides a teratogenic risk for human conceptus?
Toxicol Lett. 2010 Oct 5;198(2):106-11. Epub 2010 Jul 13.
Giavini E, Menegola E. Università degli studi di Milano, Dipartimento di Biologia, Via Celoria, 26, I-20133 Milano, Italy. email@example.com Abstract Azole fungicides are widely used in agriculture and in human mycosis. Their antifungal activity is based on their ability to inhibit CYP51, a key enzyme in the formation of fungal wall. Several azole fungicides tested in laboratory animals have been found to possess a common teratogenic potential to induce facial, axial skeleton, and limb defects. The mechanism of the teratogenic effect has been hypothesized to be related to the capability of these substances to alter embryonic retinoic acid catabolism. Although a number of human epidemiological studies were unable to demonstrate a definite relationship between azole exposure during pregnancy and birth defects, some case reports indicate a possible teratogenic effect of high doses of azoles in humans. Because of their common mechanism of action, azole fungicides should be regarded with caution for use in pregnant women. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.
Valproic acid embryopathy: report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature
Am J Med Genet. 2001 Jan 15;98(2):168-75.
Kozma C. Source Child Development Center/Department of Pediatrics, Georgetown University Medical Center, Washington, DC 20007-3935, USA. firstname.lastname@example.org
Fetal Valproate Syndrome (FVS) results from prenatal exposure to valproic acid (VPA). It is characterized by a distinctive facial appearance, a cluster of minor and major anomalies, and central nervous system dysfunction. In this study, two siblings who were exposed to monotherapy with VPA are described with documentation of long-term follow up. Both children had craniofacial findings, multiple systemic and orthopedic abnormalities, an overgrowth pattern, and developmental deficits. The literature from 1978-2000 is reviewed. A total of 69 cases that were solely exposed to VPA with adequate phenotypic description were identified. The clinical manifestations of FVS encompass a wide spectrum of abnormalities including consistent facial phenotype, multiple systemic and orthopedic involvement, central nervous system dysfunction, and altered physical growth. The facial appearance is characterized by a small broad nose, small ears, flat philtrum, a long upper lip with shallow philtrum, and micro/retrognathia. In this review, 62% of the patients had musculoskeletal abnormalities, 30% had minor skin defects, 26% had cardiovascular abnormalities, 22% had genital abnormalities, and 16% had pulmonary abnormalities. Less frequently encountered abnormalities included brain, eye, kidney, and hearing defects. Neural tube defects were seen in 3% of the sample. Twelve percent of affected children died in infancy and 29% of surviving patients had developmental deficits/mental retardation. Although 15% of patients had growth retardation, an overgrowth pattern was seen in 9%. The data from this comprehensive review especially the developmental outcome should be added to the teratogenic risk, that arises in association with the use of VPA during pregnancy. Copyright 2001 Wiley-Liss, Inc.
Prenatal adverse effects of various drugs and chemicals. A review of substances of frequent concern to mothers in the community
Med Toxicol Adverse Drug Exp. 1988 Jul-Aug;3(4):307-23.
Bologa-Campeanu M1, Koren G, Rieder M, McGuigan M.
Using the number of calls to the Canadian Motherisk Program as an indicator of the drugs and chemicals frequently of concern to mothers during pregnancy, the risks to the fetus of exposure to these compounds have been reviewed. The drugs which were of concern, and have been proven to be teratogenic, included alcohol, alkylating and antimetabolite agents, stilboestrol, disulfiram, heparin, lithium carbonate, phenytoin, tretinoin (retinoic acid), troxidone and valproic acid. For other compounds studied, there was either no data in the literature or no clear evidence of teratogenicity. The combination of doxylamine and pyridoxine, for example, has been associated with limb reduction defects in isolated case reports: cohort and case-control studies have failed to show a higher-than-baseline risk of malformations. In some cases of exposure to compounds with no known teratogenic potential, other adverse effects to the fetus are possible, and these effects are discussed in detail. In conclusion, when advising a pregnant woman about the potential teratogenic effect of a particular drug or chemical exposure, the health professional should also discuss other factors such as age, obstetric and medical history and the history of other exposures (including alcohol and smoking). In every pregnancy there is a 1 to 5% risk of mayor malformations, and even if the exposure does not appear to increase the teratogenic risk, such a risk still exists.