Neurocognitive outcomes following fetal exposure to chemotherapy for gestational breast cancer: A Canadian multi-center cohort study.

BACKGROUND: Limited knowledge exists on outcomes of children exposed prenatally to chemotherapy for breast cancer (BC). The purpose of this study was to compare long-term neurocognitive, behavioral, developmental, growth, and health outcomes of children exposed in-utero to chemotherapy for BC. METHODS: This is a multi-center matched cross-sectional cohort study involving seven cancer centers across the region of Southern Ontario (Canada), and the Hospital for Sick Children (Toronto, Ontario). Using standardized psychological and behavioral tests, we compared cognitive and behavioral outcomes in children exposed to chemotherapy during pregnancy for BC to age-matched pairs exposed to known non-teratogens. RESULTS: We recruited 17 parent-child pairs and their matched controls. There were more preterm deliveries in the chemotherapy-exposed group compared to controls (p < 0.05). Full Scale IQ of children in the chemotherapy group was significantly confounded by maternal IQ and prematurity. Exposed children born at term were not different in cognitive outcomes. Children from both groups were similar in their developmental milestones, pediatric anthropometric measurements and health problems. There were no cases of autoimmune cytopenia. CONCLUSIONS: This is the first Canadian prospective comparative study designed to assess pediatric cognition following prenatal exposure to chemotherapy for BC. Chemotherapy was not found to be neurotoxic in this cohort and did not affect pediatric health. The decision to plan a preterm birth for initiating or continuing chemotherapy treatment must be taken into consideration in context of pediatric implications. While these results may assist in such decision making, replication with a larger sample is needed for more conclusive findings.

Paternal exposure to recreational drugs before conception and its effect on live-born offspring: A scoping review.

BACKGROUND: Men of reproductive age increasingly use recreational drugs. While many of these substances may reduce the quantity and quality of sperm, less is known about the effects of these exposures on their offspring. We performed a scoping review to summarize the available literature and identify areas for future research on the outcome of live-born offspring of fathers who were exposed to recreational drugs before conception. METHODS: A systematic search was conducted of the Medline, EMBASE, and Web of Science databases, which included keywords for the following substances: cannabis-related products, cocaine, heroin, hallucinogens, ecstasy and amphetamines. In total, 2,983 records were screened, and 129 publications were selected for full-text assessment. Publications were included if (a) the timing of exposure included the preconceptional period, and (b) if outcomes in live-born offspring were compared with an unexposed group. RESULTS: We included 30 publications, of which 15 animal studies and 15 human studies. Animal studies showed neurocognitive abnormalities, in particular in male offspring. Interestingly, these outcomes depend significantly on the method of exposure (i.e., fixed-dose administration vs. variable self-administration, which mimics addiction). Human studies were limited to specific congenital malformations and childhood cancers, which showed small increased odds ratios. CONCLUSIONS: While animal studies describe impaired neurocognitive outcomes following paternal exposure to recreational drugs, data in humans is currently lacking. Human studies require sound methodology in order to confirm findings on congenital malformations and childhood cancers. In addition, future neurocognitive studies require parental neurocognitive assessments to correct for confounding effects (i.e., role of genetics).

No. 245-Alcohol Use and Pregnancy Consensus Clinical Guidelines.

OBJECTIVE: To establish national standards of care for the screening and recording of alcohol use and counselling on alcohol use of women of child-bearing age and pregnant women based on the most up-to-date evidence. EVIDENCE: Published literature was retrieved through searches of PubMed, CINAHL, and the Cochrane Library in May 2009 using appropriate controlled vocabulary (e.g., pregnancy complications, alcohol drinking, prenatal care) and key words (e.g., pregnancy, alcohol consumption, risk reduction). Results were restricted to literature published in the last five years with the following research designs: systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no language restrictions. Searches were updated on a regular basis and incorporated in the guideline to May 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment (HTA) and HTA-related agencies, national and international medical specialty societies, clinical practice guideline collections, and clinical trial registries. Each article was screened for relevance and the full text acquired if determined to be relevant. The evidence obtained was reviewed and evaluated by the members of the Expert Workgroup established by the Society of Obstetricians and Gynaecologists of Canada. The quality of evidence was evaluated and recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care. VALUES: The quality of evidence was rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table 1). SPONSOR: The Public Health Agency of Canada and the Society of Obstetricians and Gynaecologists of Canada. ENDORSEMENT: These consensus guidelines have been endorsed by the Association of Obstetricians and Gynecologists of Quebec; the Canadian Association of Midwives; the Canadian Association of Perinatal, Women's Health and Neonatal Nurses (CAPWHN); the College of Family Physicians of Canada; the Federation of Medical Women of Canada; the Society of Rural Physicians of Canada; and Motherisk. SUMMARY STATEMENTS: RECOMMENDATIONS.

Pregnancy Outcomes Following In Utero Exposure to Lamotrigine: A Systematic Review and Meta-Analysis.

INTRODUCTION: Lamotrigine is used in pregnancy to control epilepsy and mood disorders. The reproductive safety of this widely used drug remains undefined and may represent a significant public health concern. OBJECTIVE: We aimed to perform a systematic review and meta-analysis of existing knowledge related to malformation rates and maternal-neonatal outcomes after in utero exposure to monotherapy with lamotrigine. METHODS: Relevant studies were identified through systematic searches conducted in MEDLINE (Ovid), Embase (Ovid), CENTRAL (Ovid), and Web of Science (Thomson Reuters) from database inception to July 2016; no language or date restrictions were applied. All publications of clinically relevant outcomes of pregnancies following in utero exposure to lamotrigine were included in this systematic review and meta-analysis. RESULTS: A total of 21 studies describing immediate pregnancy outcomes and rates of congenital malformations fulfilled the inclusion criteria. Compared with disease-matched controls (n = 1412, total number of patients) and healthy controls (n = 774,571, total number of patients), in utero exposure to lamotrigine monotherapy was found to be associated with significantly decreased rates of inborn defects (odds ratio [OR] 1.15; 95% confidence interval [CI] 0.62-2.16 and OR 1.25; 95% CI 0.89-1.74, respectively). Rates of miscarriages, stillbirths, preterm deliveries, and small for gestational age (SGA) neonates were not found to have been increased after in-utero exposure to LTG compared to the general population. Similarly, in utero exposure to lamotrigine monotherapy was not found to be associated with increased rates of inborn defects compared with in utero exposure to carbamazepine, and lamotrigine was found to be statistically significantly less teratogenic than valproic acid (n = 12,958 and 10,748; OR 0.84; 95% CI 0.68-1.03 and OR 0.32; 95% CI 0.26-0.39, respectively). CONCLUSION: No association was found between prenatal lamotrigine monotherapy and increased rates of birth defects and other explored variables related to adverse pregnancy outcomes.

Methylphenidate in Pregnancy: A Multicenter, Prospective, Comparative, Observational Study.

INTRODUCTION: Methylphenidate is a central nervous system stimulant medicinally used in the treatment of attention-deficit disorder with or without hyperactivity (ADD/ADHD). Data on its use in human pregnancy are limited. The primary objective of the study was to evaluate the risk of major congenital anomalies after pregnancy exposure to methylphenidate for medical indications. METHODS: In a prospective, comparative, multicenter observational study performed in 4 participating Teratology Information Services (in Jerusalem, Berlin, Newcastle upon Tyne, and Toronto) between 1996 and 2013, methylphenidate-exposed pregnancies were compared with pregnancies counseled for nonteratogenic exposure (NTE) after matching by maternal age, gestational age, and year at initial contact. RESULTS: 382 methylphenidate-exposed pregnancies (89.5% in the first trimester) were followed up. The overall rate of major congenital anomalies was similar between the groups (10/309 = 3.2% [methylphenidate] vs 13/358 = 3.6% [NTE], P = .780). The rates of major congenital anomalies (6/247 = 2.4% [methylphenidate] vs 12/358 = 3.4% [NTE], P = .511) and cardiovascular anomalies (2/247 = 0.8% [methylphenidate] vs 3/358 = 0.8% [NTE], P = .970) were also similar after exclusion of genetic or cytogenetic anomalies and limiting methylphenidate exposure to the period of organogenesis (weeks 4-13 after the last menstrual period). There was a higher rate of miscarriages and elective terminations of pregnancy in the methylphenidate group. Significant predictors for the miscarriages using Cox proportional hazards model were methylphenidate exposure (adjusted hazard ratio [HR] = 1.98; 95% CI, 1.23-3.20; P = .005) and past miscarriage (adjusted HR = 1.35; 95% CI, 1.18-1.55; P < .001). CONCLUSIONS: The present study suggests that methylphenidate does not seem to increase the risk for major malformations. Further studies are required to establish its pregnancy safety and its possible association with miscarriages.

Hematologic Malignancies in Pregnancy: Management Guidelines From an International Consensus Meeting.

PURPOSE: The incidence of hematologic malignancies during pregnancy is 0.02%. However, this figure is increasing, as women delay conception until a later age. Systemic symptoms attributed to the development of a hematologic cancer may overlap with physiologic changes of pregnancy. A favorable prognosis is contingent upon early diagnosis and treatment. Therefore, a high index of suspicion is required by health care providers. Although timely, accurate diagnosis followed by appropriate staging is essential and should not be delayed due to pregnancy, management guidelines are lacking due to insufficient evidence-based research. Consequently, treatment is delayed, posing significant risks to maternal and fetal health, and potential pregnancy termination. This report provides guidelines for clinical management of hematologic cancers during the perinatal period, which were developed by a multidisciplinary team including an experienced hematologist/oncologist, a high-risk obstetrics specialist, a neonatologist, and experienced nurses, social workers, and psychologists. METHODS: These guidelines were developed by experts in the field during the first International Consensus Meeting of Prenatal Hematologic Malignancies, which took place in Leuven, Belgium, on May 23, 2014. RESULTS AND CONCLUSION: This consensus summary equips health care professionals with novel diagnostic and treatment methodologies that aim for optimal treatment of the mother, while protecting fetal and pediatric health.

Pregnancy Outcomes Following In Utero Exposure to Second-Generation Antipsychotics: A Systematic Review and Meta-Analysis.

Second-generation antipsychotics (SGAs) are increasingly used for a variety of mental illnesses; however, the data regarding the safety of these medications during pregnancy are inconclusive and contradictory. We examined the risk of adverse pregnancy outcomes associated with in utero exposure to SGAs by conducting a systematic review and meta-analysis. We searched the databases EMBASE and MEDLINE from January 1990 to December 2014. Eligible studies had to report pregnant women who took SGAs during pregnancy (first trimester exposure if analyzing congenital malformations), follow a healthy comparison group in a similar manner, and report data on pregnancy outcomes. There was no restriction on language, sample size, or publication date. The primary outcome analyzed was major congenital malformations, and secondary outcomes included miscarriages, stillbirths, preterm births, small or large for gestational age neonates, and differences in gestational ages and birth weights. A total of 12 studies met our inclusion criteria, totalling 1782 cases and 1,322,749 controls. The use of SGA during the first trimester of pregnancy was associated with a significant increased risk for major congenital malformations (odds ratio, 2.03; 95% confidence interval, 1.41-2.93); however, no specific pattern of malformations was found. An increased risk was also found for preterm births (odds ratio, 1.85; 95% CI, 1.20-2.86). The use of SGA during pregnancy was not found to be associated with an increased risk for secondary outcomes analyzed. The absence of a specific pattern of malformations makes it difficult to identify an explicit risk posed by SGAs, and therefore, further studies sufficiently controlling for confounding factors are needed to validate these findings.

Neurodevelopment of children prenatally exposed to selective reuptake inhibitor antidepressants: Toronto sibling study.

BACKGROUND: The reproductive safety of selective reuptake inhibitor (SRI) antidepressants needs to be established to provide optimal control of maternal depression while protecting the fetus. OBJECTIVE: To define a child's neurodevelopment following prenatal exposure to SRIs and to account for genetic and environmental confounders in a sibling design using the Toronto Motherisk prospective database. METHOD: Intelligence and behavior of siblings prenatally exposed and unexposed to SRIs were assessed by using the Wechsler Preschool and Primary Scale of Intelligence-Third Edition, Child Behavior Checklist, and Conners Parent Rating Scale-Revised and subsequently compared. Mothers, diagnosed with depression using DSM-IV, were assessed for intelligence quotient (IQ) and for severity of depressive symptoms with the Center for Epidemiologic Studies Depression scale. Prenatal drug doses and durations of exposure, child's age, child's sex, birth order, severity of maternal depression symptoms, and Full Scale IQ, the primary outcome measure, of both the mother and the child were considered in the analyses. RESULTS: Forty-five sibling pairs (ages 3 years to 6 years 11 months, prenatally exposed and unexposed to SRIs) did not differ in their mean ± SD Full Scale IQs (103 ± 13 vs 106 ± 12; P = .30; 95% CI, -7.06 to 2.21) or rates of problematic behaviors. Significant predictor of children's intelligence was maternal IQ (P = .043, ß = 0.306). Severity of maternal depression was a significant predictor of Child Behavior Checklist Internalizing (P = .019, ß = 0.366), Externalizing (P = .003, ß = 0.457), and Total scores (P = .001, ß = 0.494). Drug doses and durations of exposure during pregnancy did not predict any outcomes of interest in the exposed siblings. CONCLUSIONS: SRI antidepressants were not found to be neurotoxic. Maternal depression may risk the child's future psychopathology. The sibling design in behavioral teratology aids in separating the effects of maternal depression from those of SRIs, providing stronger evidence in clinical decision-making.

Behavioural effects of fetal antidepressant exposure in a Norwegian cohort of discordant siblings.

OBJECTIVE: Potential adverse effects of prenatal antidepressant exposure on child development are still debated. The possibility that associations are due to genetic or familial environmental risk factors rather than antidepressant use per se cannot easily be ruled out in conventional studies. Our objective was therefore to evaluate the association between prenatal antidepressant exposure and behavioural problems in a sibling controlled study. METHOD: This study used data on 20 180 siblings identified from the population-based Norwegian Mother and Child Cohort Study recruited between 1999 and 2008. The mothers were asked to report antidepressant use at gestational weeks 17 and 30 and 6 months post-partum. Child Behavioral Checklist syndrome scales were used to assess externalizing and internalizing behavioural problems by questionnaires sent to mothers at 18 and 36 months postpartum. We performed unmatched and matched sibling analyses using both random- and fixed-effects linear models, respectively, to determine potential behavioural effects of antidepressant exposure. RESULTS: Prenatal exposure to antidepressants was associated with increased levels of anxiety symptoms in 3 year old children after adjusting for maternal familial effects and confounding by indication (i.e. maternal depression). Effect of prenatal exposure to antidepressants was specific to anxiety, and not associated with emotional reactivity, somatic complaints, sleep problems, attention problems or aggression. CONCLUSION: Using a sibling design, we showed that prenatal antidepressant use was specifically associated with increased anxiety symptoms after adjusting for maternal familial factors and confounding by indication.

Pregnancy outcome following prenatal exposure to triptan medications: a meta-analysis.

BACKGROUND: Migraine is a common disorder among women of childbearing age. Triptan medications are effective and commonly used to treat migraines in pregnancy. However, the reproductive safety of this group of drugs has not yet been confirmed. The aim of this study was to determine the reproductive safety of triptan medications by performing a literature review and a meta-analysis. METHODS: Available publications regarding pregnancy outcomes following prenatal exposure to triptans from 1991 to 2013 were identified and reviewed according to the inclusion criteria. A random-effects meta-analysis model was implemented to combine the available pregnancy outcome data for the exposed and comparison groups. RESULTS: One case-control study and 5 cohort studies met the inclusion criteria. The included studies provided information on duration of gestation, major congenital malformations, and spontaneous abortions of infants following prenatal triptan exposure. The 6 studies included 4208 infants of women who used sumatriptan or other triptan medications, and 1,466,994 children of women who did not use triptans during pregnancy. No significant increases in rates for major congenital malformations (MCMs), prematurity, or spontaneous abortions were found when comparing the triptan-exposed group to the migraine - no triptans control group (odds ratio [OR] = 0.84 [0.61-1.16]; OR = 0.90 [0.35-2.30]; OR = 1.27 [0.58-2.79], respectively). There were no increased rate of MCMs (OR = 1.18 [0.97-1.44]) or prematurity (OR = 1.16 (0.67-1.99) when the triptan-exposed group was compared with the healthy controls; however, there was a significant increase in the rates of spontaneous abortions (OR = 3.54 [2.24-5.59]). When the migraine no-triptan group was compared with healthy controls, a significant increase in the rates of MCMs was found (OR = 1.41 [1.11-1.80]). CONCLUSION: The use of triptans during pregnancy does not appear to increase the rates for MCMs or prematurity. The increased rates of spontaneous abortions in the triptan-exposed group and the increased rates of MCM in the migraine no-triptan group require further research.

The effects of the new antipsychotic medications on mothers and babies.

Second generation antipsychotics are widely used by thousands of pregnant women worldwide in order to control their psychiatric disorders. The clinical profiles of these drugs have improved, specifically the decreased risk of hyperprolactinemia, which has increased fertility in female patients. However, the reproductive safety of second generation antipsychotics remains undefined and controversial. The aim of this presentation is to synthesize the available evidence-based information into a systematic review of the safety in pregnancy of this group of drugs (in mono-and polytherapy).

Fetal alcohol spectrum disorder and the neurobehavioural screening tool: evaluating the effect of maternal depression.

BACKGROUND: The behaviour of children diagnosed with a Fetal Alcohol Spectrum Disorder (FASD) is characterized by very complex and pervasive neurobehavioural effects. In contrast to children exhibiting the full facial dysmorphology who are relatively easy to assess and diagnose, those children presenting with Alcohol Related Neurodevelopmental Disorder (ARND) are much more challenging to diagnose due to poor specificity of the brain dysfunction; hence identifying the neurodevelopmental phenotype of FASD is extremely challenging. In 2006 the Neurobehavioral Screening Tool (NST) was developed, which derived from a selection of 10 questions from the Child Behavior Checklist (CBCL) developed by Achenbach. The NST is an official screening tool in the FASD toolkit of the Public Health Agency of Canada, and has been shown to identify a phenotypical neurobehavioral pattern in children affected by FASD with high sensitivity and specificity. A challenge in the interpretation of screening results has been ascertaining the potential influence of maternal psychiatric morbidity. The most common psychiatric morbidity among mothers who consume alcohol in excess during pregnancy is depression. OBJECTIVE: The purpose of this study was to examine the influence of maternal depression, evidenced by clinical diagnosis, and use of antidepressant drugs, on the typical behavioural presentation displayed by children diagnosed with an FASD. METHODS: Endorsement rates of NST items among children diagnosed with an FASD reported in three previous studies (n=134) and the typically developing healthy control children from these studies (n=112) were compared with the prospectively collected results of children born to and reared by mothers suffering from clinical depression (n=49) and additional typyically developing healthy control children (n=22). RESULTS: In this study, none of the children born to the mothers suffering from clinical depression screened positive on the NST, however a significant number of these caregivers reported that their child was hyperactive. The mother's level of depression as indicated by her CES-D score was also shown to correlate with the child's conduct, namely, lying/cheating and disobedience at home. CONCLUSION: These results indicate that the sensitivity and specificity of the NST are not significantly affected by maternal depression, however endorsement rates of items measuring impulse control, oppositional behaviours and conduct may be influenced. Further studies are needed to examine the potential effects of other maternal psychopathologies on endorsement rates.

Validation of the facial photographic in fetal alcohol spectrum disorder screening and diagnosis.

OBJECTIVE: A prospective study to validate the computer-assisted method of measuring palpebral fissure length and philtrum smoothness using digital patient photographs. These are key diagnostic facial features of Fetal Alcohol Syndrome. PARTICIPANTS: Motherisk Program (including Breaking the Cycle), Hospital for Sick Children, Toronto - a clinical, research and teaching program dedicated to antenatal drug, chemical, and disease risk counseling. 40 children referred for FASD assessment, 21 under 4 years old, 19 were 4 years or older. METHODS/ MATERIALS: Facial measurements were obtained directly from the patient by physicians and compared to those obtained by computer software measurement of photographs of the same patient. OUTCOME MEASURES: Palpebral fissure length and philtrum smoothness. RESULTS: The photographic measurements showed shorter palpebral fissure length than the direct measurements when analyzing all children (25.4±2.3 vs .23.2±2.4mm; p<0.0001), and children under four (n=21, 24.7±2.4 vs. 21.6±1.6mm; p<0.0001). The difference for older children (n=19) did not reach statistical significance. The computer found four false positive cases and no false negative cases of clinically short palpebral fissure (sensitivity=100%, specificity=64%). Direct measurement scores for philtrum smoothness were different from the computer's measurements using the frontal view (p=0.0012) but not using the ¾ view. CONCLUSION: The method of computer-assisted measurement tends to underestimate the true length and, hence, over- diagnose short palpebral fissure, especially in children under four years old. This method may serve as a useful fetal alcohol syndrome screening tool.

Implications of serum creatinine measurements on GFR estimation and vancomycin dosing in children.

BACKGROUND: Different serum creatinine (sCr) assays may obtain different values in the same patient, causing discrepancies in estimated glomerular filtration rate (eGFR) and sCr-based vancomycin dosing calculations. OBJECTIVE: To identify potential discrepancies in sCr concentrations obtained by different assays, the compensated Jaffe (sCr-Jaffe) and the enzymatic (sCr-enz), and to compare between the eGFR and vancomycin daily dose, based on these sCr values. METHOD: sCr-Jaffe and, sCr-enz concentrations of 890 healthy children, aged 1-18 years, were available from the Canadian Laboratory Initiative in Pediatric Reference Intervals study in Ontario. For each subject, eGFR (eGFR-Jaffe, eGFR-enz) was calculated using the revised Schwartz equation, and vancomycin daily dose (Vdose-Jaffe, Vdose-enz) was calculated using a sCr-based pharmacokinetic model. RESULT: Significant, age-related differences were found in sCr concentrations, and in subsequent eGFR and Vdose, between the two assays. In children aged 1-5 years, mean sCr-Jaffe was higher than sCr-enz (44.0 ± 5.0 vs. 27.7 ± 7.3 µmol/L, P < 0.001), leading to lower eGFR-Jaffe (83.2 ± 9.0 vs. 137.9 ± 27.1 mL/min/1.73m2, P < 0.001) and lower Vdose-Jaffe (44.7 ± 2.5 vs. 53.5 ± 5.1 mg/kg/24 h, P < 0.001). CONCLUSION: Based on these findings, young children may be at risk for vancomycin under-treatment. Further research is needed to define the more accurate sCr assay in young children treated with renally excreted drugs.

Safety of treatment of obsessive compulsive disorder in pregnancy and puerperium.

QUESTION: My patient is 3 weeks postpartum and has experienced repetitive checking and washing of her newborn as a result of obsessive concerns with the newborn's safety. Should I refer her for a psychiatric assessment to rule out obsessive compulsive disorder (OCD) or should I reassure her that her behaviour is normal? ANSWER: Current data suggest that pregnancy and the postpartum period are times of high risk of OCD onset and exacerbation. The presenting symptoms of OCD overlap with normal concerns and behaviour during the perinatal period; however, an undiagnosed or untreated disorder could have adverse consequences for both the mother and her newborn. Therefore, it is strongly recommended that this patient undergo screening and psychiatric assessment in order to be appropriately managed.