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CORK Bibliography: Prenatal Drug Exposure

73 citations. October 2010 to present

Prepared: September 2011

Accornero VH; Anthony JC; Morrow CE; Xue L; Mansoor E; Johnson AL et al. Estimated effect of prenatal cocaine exposure on examiner-rated behavior at age 7 years. Neurotoxicology and Teratology 33(3): 370-378, 2011. (69 refs.)

Prenatal cocaine exposure has been linked to increased child behavior difficulties in some studies but not others. Objective: The primary aim was to estimate the relationship between in utero cocaine exposure and child behavioral functioning at age 7 years with ratings made by blinded examiners during a structured testing session. A second aim was to examine whether caregiver drug use and psychological problems might mediate suspected relationships between prenatal cocaine exposure and aspects of examiner-rated behavior. Methods: 407 children (212 cocaine-exposed, 195 non-exposed) participating in the longitudinal Miami Prenatal Cocaine Study (MPCS) were rated with regard to their behavior during a neuropsychological assessment conducted at age 7 years. Raters were trained research psychometricians blinded to drug exposure status. Individual behavioral items were summarized and the cocaine-behavior relationship was estimated within the context of latent variable modeling, using Mplus software. Results: Two latent variables, Behavioral Regulation and Sociability, were derived via exploratory latent structure analysis with promax rotation. Prenatal cocaine exposure, statistically controlling for child sex, test age, and prenatal exposure to alcohol, tobacco, and marijuana, was associated with Behavioral Regulation (estimated slope beta = -0.25; 95% CI = -0.48. -0.02; p = 0.04) but not Sociability (estimated slope beta = 0.03; 95% Cl = -0.26, 0.20; p = 0.79). Neither postnatal drug use by caregivers nor the severity of their psychological problems at age 5 follow-up predicted levels of child Behavioral Regulation or Sociability at age 7 years (p>0.10). Conclusions: Examiner ratings of child behavior at age 7 revealed less optimal behavioral regulation for prenatally cocaine-exposed compared to non-exposed children, in contrast with what had been previously found from parent-report data. This evidence highlights the potential value of trained observers in assessing behavioral outcomes of children exposed in utero to drugs and other toxicants.

Adams EK; Melvin CL; Raskind-Hood C; Joski PJ; Galactionova E. Infant delivery costs related to maternal smoking: An update. Nicotine & Tobacco Research 13(8): 627-637, 2011. (45 refs.)

Introduction: Adverse maternal and infant health outcomes due to maternal smoking are well known. Previous estimates of health care costs for infants at delivery attributable to maternal smoking were $366 million, $704 per smoker, in 1996 dollars. Changes in antenatal and neonatal care, medical care inflation, and declines in the prevalence of maternal smoking call for an updated analysis. Methods: We used Pregnancy Risk Assessment Monitoring System for 2001/2002 to estimate the association of maternal smoking to Neonatal Intensive Care Unit (NICU) admission and, in turn, the length of stay for infants admitted/not admitted. Models are then used with 2003 natality files to derive predicted expenses as is and "as if" mothers did not smoke. The difference in these predicted expenses is smoking attributable expenses (SAEs). The updated analysis incorporated Hispanic ethnicity as an additional variable, data from 27 as opposed to 13 states, and updated (2004) NICU costs per night. Results: In contrast to earlier work, we find no significant association of maternal smoking and NICU admission but rather, a positive effect on the length of stay of exposed infants once admitted to the NICU. SAEs were estimated at $122 million (CI = -$29m to $285m) nationally and $279 (CI = -$76 to $653) per maternal smoker in 2004 dollars. Conclusions: Declines in maternal smoking prevalence between the mid-1990s and 2003 combined with a weaker relationship of maternal smoking to NICU admission offset medical care inflation such that infants' SAEs declined. Yet, these are significant in magnitude, incurred immediately and highly preventable.

Aliyu MH; Lynch O; Wilson RE; Alio AP; Kristensen S; Marty PJ et al. Association between tobacco use in pregnancy and placenta-associated syndromes: A population-based study. Archives of Gynecology and Obstetrics 283(4): 729-734, 2011. (33 refs.)

Cigarette smoking is an established risk factor for adverse perinatal outcomes. The purpose of this study is to examine the association between maternal smoking in pregnancy and the occurrence of placental-associated syndromes (PAS). We analyzed data from a population-based retrospective cohort of singleton deliveries that occurred in the state of Missouri from 1989 through 2005 (N = 1,224,133). The main outcome was PAS, a composite outcome defined as the occurrence of placental abruption, placenta previa, preeclampsia, small for gestational age, preterm or stillbirth. We used logistic regression models to generate adjusted odd ratios and their 95 percent confidence intervals. Non-smoking gravidas served as the referent category. The overall prevalence of prenatal smoking was 19.6%. Cigarette smoking in pregnancy was associated with the composite outcome of placental syndromes (odds ratio, 95% confidence interval = 1.59, 1.57-1.60). This association showed a dose-response relationship, with the risk of PAS increasing with increased quantity of cigarettes smoked. Similar results were observed between smoking in pregnancy and independent risks for abruption, previa, SGA, stillbirth, and preterm delivery. Maternal smoking in pregnancy is a risk factor for the development of placenta-associated syndrome. Smoking cessation interventions in pregnancy should continue to be encouraged in all maternity care settings.

Aranda JV; Beharry K; Valencia GB; Natarajan G; Davis J. Caffeine impact on neonatal morbidities. Journal of Maternal-Fetal & Neonatal Medicine 23(Supplement 3): 20-23, 2010. (30 refs.)

Caffeine is a silver bullet in neonatology. This ubiquitous trimethylxanthine, pervasively used in the human diet and beverages, significantly impacts on major acute neonatal morbidities including apnea of prematurity, bronchopulmonary dysplasia, patent ductus arteriousus with or without surgical ligation and post-operative apnea. Potential uses in respiratory distress syndrome as suggested by improved lung function in primate models is supported by the decreased time on mechanical ventilation and need for oxygen therapy. Improved later outcomes at 18 to 22 months include clinically significant decreases in cerebral palsy, cognitive impairment, and severe retinopathy of prematurity in those babies who received caffeine during the neonatal period compared to non-caffeine treated placebo neonates. Ongoing and future research studies focus on optimizing current dose regimens to determine whether benefits can be maximized while maintaining an impressive safety profile. Molecular pharmacologic studies focused on the molecular and the biochemical mechanisms underlying the protective effects of caffeine are also being done to optimize treatment regimes and to target potential molecular pathways leading to further decreases in acute and long term neonatal morbidities. Since its use in newborns three decades ago, caffeine is now one of the safest, most cost-beneficial and effective therapies in the newborn.

Ashford KB; Hahn E; Hall L; Rayens MK; Noland M; Ferguson JE. The effects of prenatal secondhand smoke exposure on preterm birth and neonatal outcomes. Journal of Obstetric, Gynecologic, and Neonatal Nursing 39(5): 525-535, 2010. (55 refs.)

Objective: To examine the relationship between prenatal secondhand smoke (SHS) exposure, preterm birth and immediate neonatal outcomes by measuring maternal hair nicotine. Design: Cross-sectional, observational design. Setting: A metropolitan Kentucky birthing center. Participants: Two hundred and ten (210) mother-baby couplets. Methods: Nicotine in maternal hair was used as the biomarker for prenatal SHS exposure collected within 48 hours of birth. Smoking status was confirmed by urine cotinine analysis. Results: Smoking status (nonsmoking, passive smoking, and smoking) strongly correlated with low, medium, and high hair nicotine tertiles (=.74; p <.001). Women exposed to prenatal SHS were more at risk for preterm birth (odds ratio [OR]=2.3; 95% Confidence Interval [CI] [.96, 5.96]), and their infants were more likely to have immediate newborn complications (OR=2.4; 95% CI [1.09, 5.33]) than nonexposed women. Infants of passive smoking mothers were at increased risk for respiratory distress syndrome (RDS) (OR=4.9; 95% CI [1.45, 10.5]) and admission to a Neonatal Intensive Care Unit (NICU) (OR=6.5; CI [1.29, 9.7]) when compared to infants of smoking mothers (OR=3.9; 95% CI [1.61, 14.9]; OR=3.5; 95% CI [2.09, 20.4], respectively). Passive smokers and/or women with hair nicotine levels greater than .35 ng/ml were more likely to deliver earlier (1 week), give birth to infants weighing less (decrease of 200-300 g), and deliver shorter infants (decrease of 1.1-1.7 cm). Conclusions: Prenatal SHS exposure places women at greater risk for preterm birth, and their newborns are more likely to have RDS, NICU admissions, and immediate newborn complications.

Bauer CR; Lambert BL; Bann CM; Lester BM; Shankaran S; Bada HS et al. Long-term impact of maternal substance use during pregnancy and extrauterine environmental adversity: Stress hormone levels of preadolescent children. Pediatric Research 70(2): 213-219, 2011. (33 refs.)

Prenatal cocaine exposure (PCE) is associated with blunted stress responsivity within the extrauterine environment. This study investigated the association between PCE and diurnal salivary cortisol levels in preadolescent children characterized by high biological and/or social risk (n = 725). Saliva samples were collected at their home. Analyses revealed no group differences in basal evening or morning cortisol levels; however, children with higher degrees of PCE exhibited blunted overnight increases in cortisol, controlling for additional risk factors. Race and caregiver depression were also associated with diurnal cortisol patterns. Although repeated PCE may contribute to alterations in the normal or expected stress response later in life, sociodemographic and environmental factors are likewise important in understanding hormone physiology, especially as more time elapses from the PCE. Anticipating the potential long-term medical, developmental, or behavioral effects of an altered ability to mount a normal protective cortisol stress response is essential in optimizing the outcomes of children with PCE.

Beyerlein A; Ruckinger S; Toschke AM; Rosario AS; von Kries R. Is low birth weight in the causal pathway of the association between maternal smoking in pregnancy and higher BMI in the offspring? European Journal of Epidemiology 26(5): 413-420, 2011. (57 refs.)

A number of cross-sectional and prospective studies suggested a priming effect of maternal smoking in pregnancy on offspring's obesity. It has been hypothesized that this association might be explained by low birth weight and subsequent catch-up growth in the causal pathway. We therefore examined the role of birth weight in children exposed versus not exposed to cigarette smoking in utero on later body mass index (BMI). Using data of 12,383 children and adolescents (3-17 years of age) recorded in a German population-based survey (KiGGS), we assessed mean body mass index standard deviation scores (BMI-SDS) in different birth weight SDS categories, stratified for children with smoking and non-smoking mothers. We calculated spline regression models with BMI-SDS as outcome variable, cubic splines of birth weight SDS, and potential confounding factors. Children whose mothers had been smoking during pregnancy had lower birth weight SDS and higher BMI-SDS at interview compared to children of non-smoking mothers. However, we observed a linear association between birth weight SDS and BMI-SDS in crude analyses for both groups. Similarly, almost linear effects were observed in adjusted spline regression analyses, except for children with very low birth weight. The respective 95% confidence bands did not preclude a linear effect for the whole birth weight SDS distribution. Our findings suggest that low birth weight is unlikely to be the main cause for the association between intrauterine nicotine exposure and higher BMI in later life. Alternative mechanisms, such as alterations in the noradrenergic system or increased food efficiency, have to be considered.

Bowen SE. Two serious and challenging medical complications associated with volatile substance misuse: Sudden sniffing death and fetal solvent syndrome. (review). Substance Use & Misuse 46(Supplement 1): 68-72, 2011. (40 refs.)

Volatile substance misuse is a prevalent and often overlooked behavior among adolescents, including reported use among young pregnant women. Several medical repercussions can arise from the improper use of volatile substances, yet they are often underappreciated among scientists and health professionals. This brief review reports on the recent advances made in the preclinical and clinical data about two serious medical complications surrounding volatile substance misuse: sudden sniffing death and fetal solvent syndrome. Suggestions for treatment interventions are discussed. The paper's limitations are noted.

Braillon A; Bewley S; Dubois G. Tobacco harm to the developing child. (editorial). European Journal of Pediatrics 169(12): 1565-1567, 2010. (13 refs.)

Braun JM; Daniels JL; Poole C; Olshan AF; Hornung R; Bernert JT et al. A prospective cohort study of biomarkers of prenatal tobacco smoke exposure: The correlation between serum and meconium and their association with infant birth weight. Environmental Health 9(e-53), 2010. (38 refs.)

Background: The evaluation of infant meconium as a cumulative matrix of prenatal toxicant exposure requires comparison to established biomarkers of prenatal exposure. Methods: We calculated the frequency of detection and concentration of tobacco smoke metabolites measured in meconium (nicotine, cotinine, and trans-3'-hydroxycotinine concentrations) and three serial serum cotinine concentrations taken during the latter two-thirds of pregnancy among 337 mother-infant dyads. We estimated the duration and intensity of prenatal tobacco smoke exposure using serial serum cotinine concentrations and calculated geometric mean meconium tobacco smoke metabolite concentrations according to prenatal exposure. We also compared the estimated associations between these prenatal biomarkers and infant birth weight using linear regression. Results: We detected nicotine (80%), cotinine (69%), and trans-3'-hydroxycotinine (57%) in most meconium samples. Meconium tobacco smoke metabolite concentrations were positively associated with serum cotinine concentrations and increased with the number of serum cotinine measurements consistent with secondhand or active tobacco smoke exposure. Like serum cotinine, meconium tobacco smoke metabolites were inversely associated with birth weight. Conclusions: Meconium is a useful biological matrix for measuring prenatal tobacco smoke exposure and could be used in epidemiological studies that enroll women and infants at birth. Meconium holds promise as a biological matrix for measuring the intensity and duration of environmental toxicant exposure and future studies should validate the utility of meconium using other environmental toxicants.

Broussard CS; Rasmussen SA; Reefhuis J; Friedman JM; Jann MW; Riehle-Colarusso T et al. Maternal treatment with opioid analgesics and risk for birth defects. American Journal of Obstetrics and Gynecology 204(4): article 314.e1, 2011. (40 refs.)

OBJECTIVE: We examined whether maternal opioid treatment between 1 month before pregnancy and the first trimester was associated with birth defects. STUDY DESIGN: The National Birth Defects Prevention Study (1997 through 2005) is an ongoing population-based case-control study. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIS) for birth defects categories with at least 200 case infants or at least 4 exposed case infants. RESULTS: Therapeutic opioid use was reported by 2.6% of 17,449 case mothers and 2.0% of 6701 control mothers. Treatment was statistically significantly associated with conoventricular septal defects (OR, 2.7; 95% CI, 1.1-6.3), atrioventricular septal defects (OR, 2.0; 95% CI, 1.2-3.6), hypoplastic left heart syndrome (OR, 2.4; 95% CI, 1.4-4.1), spina bifida (OR, 2.0; 95% CI, 1.3-3.2), or gastroschisis (OR, 1.8; 95% CI, 1.1-2.9) in infants. CONCLUSION: Consistent with some previous investigations, our study shows an association between early pregnancy maternal opioid analgesic treatment and certain birth defects. This information should be considered by women and their physicians who are making treatment decisions during pregnancy.

Browne ML; Hoyt AT; Feldkamp ML; Rasmussen SA; Marshall EG; Druschel CM et al. Maternal caffeine intake and risk of selected birth defects in the National Birth Defects Prevention Study. Birth Defects Research. Part A: Clinical and Molecular Teratology 91(2): 93-101, 2011. (29 refs.)

BACKGROUND: Caffeine intake is common during pregnancy, yet few epidemiologic studies have examined the association between maternal caffeine consumption and birth defects. Using data from the National Birth Defects Prevention Study (NBDPS), we examined the association between maternal caffeine consumption and anotia/microtia, esophageal atresia, small intestinal atresia, craniosynostosis, diaphragmatic hernia, omphalocele, and gastroschisis. METHODS: The NBDPS is a multi-site population-based case-control study. The present analysis included 3,346 case infants and 6,642 control infants born from October 1997 through December 2005. Maternal telephone interview reports of demographic characteristics and conditions and exposures before and during pregnancy were collected. Odds ratios and 95% confidence intervals, adjusted for relevant covariates, were calculated to estimate the associations between maternal dietary caffeine intake (coffee, tea, soda, and chocolate) and maternal use of caffeine-containing medications and each defect. RESULTS: We observed small, statistically significant elevations in adjusted odds ratios ranging from 1.3 to 1.8 for total maternal dietary caffeine intake or specific types of caffeinated beverages and anotia/microtia, esophageal atresia, small intestinal atresia, and craniosynostosis; however, dose-response patterns were absent. Periconceptional use of caffeine-containing medications was infrequent and estimates were imprecise. CONCLUSIONS: We did not find convincing evidence of an association between maternal caffeine intake and the birth defects included in this study. The increasing popularity of caffeine-containing energy drinks and other caffeinated products may result in higher caffeine intake among women of childbearing age. Future studies should consider more detailed evaluation of such products.

Bruin JE; Gerstein HC; Holloway AC. Long-term consequences of fetal and neonatal nicotine exposure: A critical review. (review). Toxicological Sciences 116(2): 364-374, 2010. (167 refs.)

Cigarette smoking during pregnancy is associated with numerous obstetrical, fetal, and developmental complications, as well as an increased risk of adverse health consequences in the adult offspring. Nicotine replacement therapy (NRT) has been developed as a pharmacotherapy for smoking cessation and is considered to be a safer alternative for women to smoking during pregnancy. The safety of NRT use during pregnancy has been evaluated in a limited number of short-term human trials, but there is currently no information on the long-term effects of developmental nicotine exposure in humans. However, animal studies suggest that nicotine alone may be a key chemical responsible for many of the long-term effects associated with maternal cigarette smoking on the offspring, such as impaired fertility, type 2 diabetes, obesity, hypertension, neurobehavioral defects, and respiratory dysfunction. This review will examine the long-term effects of fetal and neonatal nicotine exposure on postnatal health.

Burns L; Conroy E; Mattick RP. Infant mortality among women on a methadone program during pregnancy. Drug and Alcohol Review 29(5): 551-556, 2010. (20 refs.)

Introduction and Aims. The rate and correlates of infant death in those born to opioid-dependent women are unclear. This study aims to determine the infant mortality rate of infants born to women on a methadone program during pregnancy and to identify any modifiable risk factors. Design and Methods. A retrospective study of live births to all women in New South Wales, Australia during the period 1995-2002. Using record linkage four groups were compared: (i) live births to women on a methadone program during pregnancy who subsequently died during infancy; (ii) live births to women not on a methadone program who subsequently died during infancy; (iii) live births to women on a methadone program during pregnancy who did not die during infancy; and (iv) live births to women not on a methadone program who did not die during infancy. Results, Discussion and Conclusion. The infant mortality rate was higher among infants whose mothers were on methadone during pregnancy (24.3 per 1000 live born infants in group 1 and 4.0 per 1000 live born infants in group 2) compared with infants of all other mothers. The single main cause of death for all infants was Sudden Infant Death Syndrome. There was a higher rate of smoking among women on methadone. The findings suggest that methadone and non-methadone infant-mother pairs have different symptom profiles, diagnostic procedures and/or different patterns of access to care.

Burris HH; Collins JW; Wright RO. Racial/ethnic disparities in preterm birth: Clues from environmental exposures. (review). Current Opinion in Pediatrics 23(2): 227-232, 2011. (36 refs.)

Purpose of review: Despite advances in medical care, preterm birth and its associated racial/ethnic disparities remain major public health issues. Environmental exposures may contribute to racial disparities in preterm birth. Recent findings: Recent work in Iran demonstrated lead levels less than 10 mu g/dl to be associated with preterm birth and premature rupture of membranes. Data on air pollution are mixed. A study in California found exposure to nitric oxide species to be associated with preterm birth. However, results from large birth cohorts in the Netherlands found no association. Interestingly, a study in South Korea recently demonstrated that socioeconomic status modifies the association between air pollution and preterm birth. A recent promising study randomized minority pregnant women in Washington, District of Columbia, to cognitive behavioral therapy vs. usual care to decrease exposure to environmental tobacco smoke (ETS). The investigators reported reductions in ETS exposure and the risk of very preterm birth. Summary Clues about potential mechanisms underlying disparities in preterm birth can be gained from exploring differences in environmental exposures. Investigators should include environmental variables when studying birth outcomes. Such efforts should result in targeted interventions to decrease the incidence of preterm birth and its disparities.

Chiodo LM; da Costa DE; Hannigan JH; Covington CY; Sokol RJ; Janisse J et al. The impact of maternal age on the effects of prenatal alcohol exposure on attention. Alcoholism: Clinical and Experimental Research 34(10): 1813-1821, 2010. (76 refs.)

Background: Prenatal exposure to alcohol has a variety of morphologic and neurobehavioral consequences, yet more than 10% of women continue to drink during pregnancy, placing their offspring at risk for fetal alcohol spectrum disorders (FASD). Identification of at-risk pregnancies has been difficult, in part, because the presence and severity of FASD are influenced by factors beyond the pattern of alcohol consumption. Establishing maternal characteristics, such as maternal age, that increase the risk of FASD is critical for targeted pregnancy intervention. Methods: We examined the moderating effect of maternal age on measures of attention in 462 children from a longitudinal cohort born to women with known alcohol consumption levels (absolute ounces of alcohol per day at conception) who were recruited during pregnancy. Analyses examined the impact of binge drinking, as average ounces of absolute alcohol per drinking day. Smoking and use of cocaine, marijuana, and opiates were also assessed. At 7 years of age, the children completed the Continuous Performance Test, and their teachers completed the Achenbach Teacher Report Form. Results: After controlling for covariates, stepwise multiple regression analyses revealed a negative relation between levels of prenatal binge drinking and several measures of attention. The interaction between alcohol consumption and maternal age was also significant, indicating that the impact of maternal binge drinking during pregnancy on attention was greater among children born to older drinking mothers. Conclusion: These findings are consistent with previous findings that children born to older alcohol-using women have more deleterious effects of prenatal alcohol exposure on other neurobehavioral outcomes.

Cohen RT; Raby BA; Van Steen K; Fuhlbrigge AL; Celedon JC; Rosner BA et al. In utero smoke exposure and impaired response to inhaled corticosteroids in children with asthma. Journal of Allergy and Clinical Immunology 126(3): 491-497, 2010. (38 refs.)

Background: Few studies have examined the effects of in utero smoke exposure (IUS) on lung function in children with asthma, and there are no published data on the impact of IUS on treatment outcomes in children with asthma. Objectives: To explore whether IUS exposure is associated with increased airway responsiveness among children with asthma and whether IUS modifies the response to treatment with inhaled corticosteroids (ICSs). Methods: To assess the impact of parent-reported IUS exposure on airway responsiveness in childhood asthma, we performed a repeated-measures analysis of methacholine PC20 data from the Childhood Asthma Management Program, a 4-year, multicenter, randomized, double-masked, placebo-controlled trial of 1041 children age 5 to 12 years comparing the long-term efficacy of ICS with mast cell stabilizing agents or placebo. Results: Although improvement was seen in both groups, children with asthma and IUS exposure had on average 26% less of an improvement in airway responsiveness over time compared with unexposed children (P = .01). Moreover, while children who were not exposed to IUS who received budesonide experienced substantial improvement in PC20 compared with untreated children (1.25-fold increase; 95% CI, 1.03-1.50; P = .02), the beneficial effects of budesonide were attenuated among children with a history of IUS exposure (1.04-fold increase, 95% CI, 0.65-1.68; P = .88). Conclusion: In utero smoke exposure reduces age-related improvements in airway responsiveness among children with asthma. Moreover, IUS appears to blunt the beneficial effects of ICS use on airways responsiveness. These results emphasize the importance of preventing this exposure through smoking cessation counseling efforts with pregnant women.

Coker I; Colak A; Hasturk AG; Yildiz O; Turkon H; Halicioglu O. Maternal and cord blood homocysteine and folic acid levels in smoking and nonsmoking pregnant women. Gynecologic and Obstetric Investigation 71(4): 245-249, 2011. (28 refs.)

Introduction: The homocysteine level in blood is affected by gender, diet, smoking, folic acid and B-complex vitamins. It is known that higher than normal homocysteine levels in plasma may cause vascular endothelium dysfunction, resulting in the promotion of thrombus formation. In our study, we aimed to assess the effects of smoking during pregnancy on the homocysteine and folic acid levels of the mother and baby. Methods: The study included 58 pregnant women who had completed their 37th week of gestation: 30 women were nonsmokers (NONSM) and 28 were smokers (SM). The measurement of homocysteine and folic acid levels in all samples were performed with an Immulite 2000 analyzer, using the chemiluminescence method. Results: Maternal blood folic acid levels were significantly lower in SM (p = 0.041) than in NONSM. In SM, homocysteine levels in the umbilical cord blood were found to be significantly higher than those in NONSM (p = 0.006). Conclusion: High homocysteine levels in umbilical cord blood of smoking mothers, and the probable continuation of passive smoking for the babies after birth, make us think that the baby may have a predisposition towards vascular diseases at later periods in life.

Crane JMG; Keough M; Murphy P; Burrage L; Hutchens D. Effects of environmental tobacco smoke on perinatal outcomes: A retrospective cohort study. International Journal of Obstetrics and Gynaecology 118(7): 865- 871, 2011. (19 refs.)

Objective: To evaluate the effects of environmental tobacco smoke (ETS) on perinatal outcomes. Design: Retrospective cohort study. Setting: Newfoundland and Labrador, Canada. Population: Nonsmoking women with singleton gestations who delivered 1 April 2001-31 March 2009, identified through the Newfoundland and Labrador Provincial Perinatal Database. Methods: Women who self-reported exposure to ETS were compared with those who reported no exposure. Univariate analyses and multivariate linear and logistic regression analyses (adjusting for maternal age, parity, partnered status, work status, level of education, body mass index, alcohol use, illicit drug use and gestational age) were performed and odds ratios(OR; or adjusted differences) with 95% confidence intervals were calculated. Main outcome measures: Birthweight, birth length, head circumference and stillbirth. Secondary outcomes included gestational age at delivery, preterm birth < 37 and < 34 weeks of gestation, prelabour rupture of membranes, Apgar score, endotracheal intubation for resuscitation, neonatal intensive care unit admission, congenital anomalies, respiratory distress syndrome, intraventricular haemorrhage, neonatal bacterial sepsis, jaundice and neonatal metabolic abnormalities. Results: A total of 11 852 women were included: 1202(11.1%) exposed to ETS and 10 650 (89.9%) not exposed. Exposure to ETS was an independent risk factor for lower mean birthweight (-53.7 g, 95% CI -98.4 to -8.9 g), smaller head circumference (-0.24 cm, 95% CI -0.39 to -0.08 cm), shorter birth length (-0.29 cm, 95% CI -0.51 to -0.07 cm), stillbirth (OR 3.35, 95% CI 1.16-9.72, P = 0.026), and trends towards preterm birth < 34 weeks (OR 1.87, 95% CI 1.00-3.53, P = 0.05) and neonatal sepsis (OR 2.96, 95% CI 0.99-8.86). Conclusions: Exposure of nonsmoking pregnant women to ETS is associated with a number of adverse perinatal outcomes including lower birthweight, smaller head circumference and stillbirth, as well as shorter birth length. This information is important for women, their families and healthcare providers, and reinforces the continued need for increased public policy and education on prevention of exposure to ETS.

Durmus B; Ay L; Hokken-Koelega ACS; Raat H; Hofman A; Steegers EAP et al. Maternal smoking during pregnancy and subcutaneous fat mass in early childhood. The Generation R Study. European Journal of Epidemiology 26(4): 295- 304, 2011. (46 refs.)

Maternal smoking during pregnancy increases the risk of obesity in the offspring. Not much is known about the associations with other measures of body composition. We assessed the associations of maternal smoking during pregnancy with the development of subcutaneous fat mass measured as peripheral and central skinfold thickness measurements in early childhood, in a population-based prospective cohort study from early fetal life onward in the city of Rotterdam, The Netherlands. The study was performed in 907 mothers and their children at the ages of 1.5, 6 and 24 months. As compared to non-smoking mothers, mothers who continued smoking during pregnancy were more likely to have a younger age and a lower educational level. Their children had a lower birth weight, higher risk of small size for gestational age and were breastfed for a shorter duration (P-values < 0.01). We did not observe differences in peripheral, central and total subcutaneous fat mass between the offspring of non-smoking mothers, mothers who smoked in first trimester only and mothers who continued smoking during pregnancy (P > 0.05). Also, the reported number of cigarettes smoked by mothers in both first and third trimester of pregnancy were not associated with peripheral, central and total subcutaneous fat mass in the offspring at the ages of 1.5, 6 and 24 months. Our findings suggest that fetal exposure to cigarette smoke during pregnancy does not influence subcutaneous fat mass in early childhood. Follow-up studies are needed in children at older ages and to identify associations of maternal smoking during pregnancy with other measures of body composition.

Durmus B; Kruithof CJ; Gillman MH; Willemsen SP; Hofman A; Raat H et al. Parental smoking during pregnancy, early growth, and risk of obesity in preschool children: The Generation R Study. American Journal of Clinical Nutrition 94(1): 164-171, 2011. (47 refs.)

Background: Maternal smoking during pregnancy seems to be associated with obesity in offspring. Not much is known about the specific critical exposure periods or underlying mechanisms for this association. Objective: We assessed the associations of active maternal and paternal smoking during pregnancy with early growth characteristics and risks of overweight and obesity in preschool children. Design: This study was a population-based, prospective cohort study from early fetal life until the age of 4 y in 5342 mothers and fathers and their children. Growth characteristics [head circumference, length, weight, and body mass index (BMI; in kg/m(2))] and overweight and obesity were repeatedly measured at the ages of 1, 2, 3, and 4 y. Results: In comparison with children from nonsmoking mothers, children from mothers who continued smoking during pregnancy had persistently smaller head circumferences and heights until the age of 4 y, whereas their weights were lower only until the age of 3 mo. This smaller length and normal to higher weight led to an increased BMI [SD score difference: 0.11; 95% CI: 0.02, 0.20; P < 0.05)] and an increased risk of obesity (odds ratio: 1.61; 95% CI: 1.03, 2.53; P < 0.05) at the age of 4 y. In nonsmoking mothers, paternal smoking was not associated with postnatal growth characteristics or risk of obesity in offspring. Maternal smoking during pregnancy was associated with a higher BMI at the age of 4 y in children with a normal birth weight and in those who were small for gestational age at birth. Conclusion: Our findings suggest that direct intrauterine exposure to smoke until late pregnancy leads to different height and weight growth adaptations and increased risks of overweight and obesity in preschool children.

Eiden RD; Granger DA; Schuetze P; Veira Y. Child behavior problems among cocaine-exposed toddlers: Indirect and interactive effects. Development and Psychopathology 23(2): 539- 550, 2011. (71 refs.)

This study examined the role of maternal psychopathology and maternal warmth as mediators of the association between prenatal cocaine and other substance exposure and toddler behavior problems. It was also hypothesized that infant cortisol reactivity and environmental risk may moderate these associations. Participants were 220 caregiver-infant dyads (119 cocaine exposed, 101 not cocaine exposed; 49% boys). Mother-infant dyads were recruited at delivery with assessments at 4-8 weeks and 7, 13, and 18 months of child ages. Results yielded no direct associations between prenatal cocaine/other substance exposure and toddler behavior problems, but significant indirect associations between prenatal cigarette/alcohol exposure and toddler behavior problems at 18 months. With regard to moderation, results indicated an indirect association between prenatal cocaine exposure and toddler behavior problems via lower maternal warmth for children with higher, but not lower, cortisol reactivity at 7 months. Results suggest potential pathways to toddler behavior problems among children at high biological risk.

Eiden RD; Schuetze P; Colder CR; Veira Y. Maternal cocaine use and mother-toddler aggression. Neurotoxicology and Teratology 33(3): 360-369, 2011. (84 refs.)

This study examined the direct and indirect associations between maternal cocaine use during pregnancy and mother-toddler aggression in an interactive context at 2 years of child age. We hypothesized that in addition to direct effects of cocaine exposure on maternal and child aggression, the association between maternal cocaine use and mother-toddler aggression may be indirect via higher maternal psychiatric symptoms, negative affect, or poor infant autonomic regulation at 13 months. Participants consisted of 220 (119 cocaine exposed, 101 non-cocaine exposed) mother-toddler dyads participating in an ongoing longitudinal study of prenatal cocaine exposure. Results indicated that mothers who used cocaine during pregnancy displayed higher levels of aggression toward their toddlers compared to mothers in the control group. Results from model testing indicated significant indirect associations between maternal cocaine use and maternal aggression via higher maternal negative affect as well as lower infant autonomic regulation at 13 months. Although there were no direct associations between cocaine exposure and toddler aggression, there was a significant indirect effect via lower infant autonomic regulation at 13 months. Results highlight the importance of including maternal aggression in predictive models of prenatal cocaine exposure examining child aggression. Results also emphasize the important role of infant regulation as a mechanism partially explaining associations between cocaine exposure and mother-toddler aggression.

Ekblad M; Gissler M; Lehtonen L; Korkeila J. Prenatal smoking exposure and the risk of psychiatric morbidity into young adulthood. Archives of General Psychiatry 67(8): 841-849, 2010. (44 refs.)

Context: Prenatal smoking exposure modulates brain development, which may deviate mental development of the offspring. Objective: To study the effects of prenatal smoking exposure on psychiatric morbidity and mortality among Finnish young adults by means of population-based longitudinal register data. Design: Information on maternal smoking as reported by the mothers (0, <10, or >10 cigarettes a day) and other background factors (maternal age and parity and child's sex, gestational age, birth weight, and 5-minute Apgar score) was derived from the Finnish Medical Birth Register. Information on children's psychiatric diagnoses related to outpatient visits (1998-2007), children's inpatient care (1987-2007), and mothers' psychiatric inpatient care (1969-1989) was derived from the Finnish Hospital Discharge Register. Information on deaths and their causes for the children (1987-2007) was received from the Cause-of-Death Register. Setting: Population-based study of all singletons born in Finland from 1987 to 1989 with information on prenatal smoking exposure. Patients: The source population included all singleton births in Finland from January 1, 1987, through December 31, 1989 (n=175 869), excluding children with major congenital anomalies (3.1%) and children who died during the first week of life (0.3%). Main Outcome Measures: Psychiatric morbidity and mortality. Results: The prevalence of maternal smoking was 15.3%. The risk of psychiatric morbidity was significantly higher in the exposed children than in the unexposed children. Among the offspring of mothers who smoked fewer than 10 cigarettes a day, 21.0% had any psychiatric diagnoses (adjusted odds ratio [OR], 1.53 [95% confidence interval (CI), 1.47-1.60]) compared with 24.7% among those of mothers who smoked more than 10 cigarettes a day (1.85 [1.74-1.96]) and 13.7% in the unexposed children (the reference group). The risk was significantly increased for most of the psychiatric diagnoses. The strongest effects were in psychiatric disorders due to psychoactive substance use and in behavioral and emotional disorders. The risk of mortality was significantly higher in children exposed to more than 10 cigarettes a day (OR, 1.69 [95% CI, 1.31-2.19]) compared with unexposed children. Conclusion: Prenatal smoking exposure is associated with an increased risk of psychiatric morbidity, whereas prenatal exposure to more than 10 cigarettes a day increases the risk of mortality in childhood, adolescence, and young adulthood.

Espy KA; Fang H; Johnson C; Stopp C; Wiebe SA; Respass J. Prenatal tobacco exposure: Developmental outcomes in the neonatal period. Developmental Psychology 47(1): 153-169, 2011. (94 refs.)

Smoking during pregnancy is a persistent public health problem that has been linked to later adverse outcomes. The neonatal period-the first month of life-carries substantial developmental change in regulatory skills and is the period when tobacco metabolites are cleared physiologically. Studies to date mostly have used cross-sectional designs that limit characterizing potential impacts of prenatal tobacco exposure on the development of key self-regulatory processes and cannot disentangle short-term withdrawal effects from residual exposure-related impacts. In this study, pregnant participants (N = 304) were recruited prospectively during pregnancy, and smoking was measured at multiple time points, with both self-report and biochemical measures. Neonatal attention, irritable reactivity, and stress dysregulation were examined longitudinally at three time points during the first month of life, and physical growth indices were measured at birth. Tobacco-exposed infants showed significantly poorer attention skills after birth, and the magnitude of the difference between exposed and nonexposed groups attenuated across the neonatal period. In contrast, exposure-related differences in irritable reactivity largely were not evident across the 1st month of life, differing marginally at 4 weeks of age only. Third-trimester smoking was associated with pervasive, deleterious, dose response impacts on physical growth measured at birth, whereas nearly all smoking indicators throughout pregnancy predicted level and growth rates of early attention. The observed neonatal pattern is consistent with the neurobiology of tobacco on the developing nervous system and fits with developmental vulnerabilities observed later in life.

Fakhfakh R; Jellouli M; Klouz A; Ben Hamida M; Lakhal M; Belkahia C et al. Smoking during pregnancy and postpartum among Tunisian women. Journal of Maternal-Fetal & Neonatal Medicine 24(6): 859- 862, 2011. (34 refs.)

Methods. Cross-sectional analysis of data on self-reported smoking and urinary cotinine among a sample of 398 pregnant women and recently pregnant, mothers of infants under the age of 2 months, who came to the Family Planning Clinic in Tunis urban area for either prenatal or newborn care. We used quantitative colorimetric urine test based on the koonig reaction, in which pink-red chromophores formed from nicotine and its metabolites condensation with barbituric acid were extracted into acetate buffer. Results. The smoking prevalence among Tunisian pregnant women or mothers of newborn infants was 4%. The validity of self-reported daily smoking was relatively low. Among women reporting no smoking at the interview 16% misreported active smoking. According to urinary cotinine values, the smoking prevalence was 18.8%. Conclusions. These results substantiate the unreliability of self-report on smoking status among women in prenatal and postnatal period and have implications in clinical and education practice.

Fokina VM; Patrikeeva SL; Zharikova OL; Nanovskaya TN; Hankins GVD; Ahmed MS. Transplacental transfer and metabolism of buprenorphine in preterm human placenta. American Journal of Perinatology 28(1I): 25-32, 2011. (27 refs.)

We sought to determine whether gestational age affects the transplacental transfer and metabolism of buprenorphine (BUP). Transfer of BUP (10 ng/mL) and its [ 3 H]isotope was determined across placentas of 30 to 34 weeks of gestation utilizing the technique of dual perfusion of placental lobule. Concentration of the drug in trophoblast tissue and in maternal and fetal circuits was determined by liquid scintillation spectrometry. Microsomes prepared from placentas of 17 to 37 weeks of gestation were divided into three groups: late second, early third, and late third trimesters. Antibodies raised against human cytochrome P450 (CYP) isoforms were utilized to identify the enzyme(s) catalyzing BUP biotransformation by preterm placental microsomes. The amount of norbuprenorphine formed was determined by liquid chromatography-mass spectrometry (LC-MS). BUP transfer across the placentas of 30 to 34 weeks of gestation was similar to those at term. CYP19 antibodies caused 60% inhibition of BUP metabolism by microsomes of late second and early third trimesters and 85% by microsomes of late third trimester. The developmental changes occurring in human placenta between 30 weeks of gestation through term do not affect the transfer of BUP across human placenta. CYP19 is the major enzyme responsible for biotransformation of BUP beginning at 17 weeks of gestation until term.

Gianicolo EAL; Cresci M; Ait-Ali L; Foffa I; Andreassi MG. Smoking and congenital heart disease: The epidemiological and biological link. (review). Current Pharmaceutical Design 16(23): 2572-2577, 2010. (52 refs.)

Cigarette smoking is a powerful human germ cell mutagen and teratogen. Congenital heart defects (CHD) are the most prevalent of all birth defects and leading cause of death in the first year of life. The purpose of this article is to review the epidemiology of the impact of cigarette smoking on CHD risk as well as to discuss the potential biological mechanisms of smoking-mediated abnormal cardiac development. Although epidemiological studies of association between parental smoking and CHD are limited, biological evidence supports the concept that cigarette smoking may substantially contribute to the aetiology of CHD through induction of either male and female germ-cell mutation or interference with epigenetic pathways. Further research is needed to better define the relationship between parental smoking and the risk of heart defects as well as to assess parental-fetal gene-smoking interactions.

Goel N; Beasley D; Rajkumar V; Banerjee S. Perinatal outcome of illicit substance use in pregnancy: Comparative and contemporary socio-clinical profile in the UK. European Journal of Pediatrics 170(2): 199-205, 2011. (23 refs.)

The aim of the study was to determine the contemporary socio-clinical profile and perinatal outcome of illicit substance use in pregnancy in a large UK city and compare with published literature. Cases were identified retrospectively from the 'cause for concern' referrals over 5 years (2003-2007). Data was collected on mother-infant pair from medical notes and laboratory records. Chi-square and Mann-Whitney U tests were used where appropriate for statistical analysis. One hundred sixty-eight women were identified as using illicit substance in pregnancy. Smoking (97.4%), unemployment (85.4%) and single status (42.3%) were frequent. Besides controlled use of methadone, heroin, cannabis and benzodiazepines were the most commonly used drugs. Hepatitis C prevalence was high (29.9%) despite low antenatal screening rates (57.7%). Neonatal morbidity was related to prematurity (22.9%), small for dates (28.6%) and neonatal abstinence syndrome (NAS; 58.9%). By day 5 of life, 95.1% of the babies developing NAS and 96.1% of those requiring pharmacological treatment were symptomatic. Of the infants developing NAS, 31.7% required pharmacological treatment. A total of 82.5% babies went home with their mother, and 21.2% were placed on the Child Protection Register. Only 14.3% were breast feeding at discharge. Illicit substance use in pregnancy continues to be associated with significant maternal and neonatal morbidity, and the socio-clinical profile in this decade appears unchanged in the UK. Hepatitis C prevalence is high, and detection should be improved through targeted antenatal screening. Where facility in the community is unavailable, 5 days of hospital stay is sufficient to safely identify babies at risk of developing NAS. Most babies were discharged home with their mother.

Goldman GD; Ryan SD. Direct and modifying influences of selected risk factors on children's pre-adoption functioning and post-adoption adjustment. Children and Youth Services Review 33(2): 291-300, 2011. (83 refs.)

Child adoption outcomes are influenced by child's behavior and parents' expectations (Haugaard & Hazan, 2003). Pre-adoption risk factors, such as prenatal alcohol, tobacco and/or other drug (ATOD) exposure, male sex, sexual abuse, and multiple out-of-home placements have been linked to increased externalizing (acting out) behaviors that are difficult to manage and are most closely associated with adoption disruption (Barth, 1991, 2001 Rosenthal & Groze, 1991; Smith & Howard, 1999). However, adoption researchers have found that positive outcomes (fewer externalizing behaviors) are possible for children who have been exposed to pre-adoption risk factors, suggesting that adoptive families provide protective environments that allow healing (Barth, 1991, 1993; Barth & Brooks, 2000). The current study sought to increase understanding of the influence of these pre-adoption risk factors on adoption outcome with attention to the influence of prenatal alcohol, tobacco, and/or other drug (ATOD) exposure. Results indicated that pre-adoption functioning was significantly influenced by prenatal ATOD exposure, but post-adoption adjustment was not. Structural equation modeling then was used to analyze both the direct and moderating influences of the identified risk factors on the relationship between the child's pre-adoption functioning and post-adoption adjustment. Negative influences of the risk factors on the child's externalizing behavior, individually and additively, in both direct effects and moderation analyses, were not found, with one exception. The only model to have a statistically significant effect was the moderation analysis containing the interaction of all four risk factors. Child development, child welfare, addiction professionals, and adoptive families will find this information to be of value in their quest to facilitate successful adoptions and growth of healthy children and families.

Good MM; Solt I; Acuna JG; Rotmensch S; Kim MJ. Methamphetamine use during pregnancy maternal and neonatal implications. Obstetrics and Gynecology 116(2, Part 1): 330-334, 2010. (32 refs.)

OBJECTIVE: To report the demographic characteristics and clinical morbidity of methamphetamine-exposed pregnancies compared with control patients in a tertiary care, urban, academic medical center. METHODS: A single-site chart review from 2000 to 2006 was conducted. International Classification of Diseases, 9th Revision code 648.3x was used to identify potential study participants. Specific inclusion criteria required either a positive urine drug screen for methamphetamine use or by patient statement of methamphetamine use during pregnancy. Data from 276 identified patients were then compared with the 34,055 in the general obstetric population during the same period for various demographic factors and perinatal outcomes. RESULTS: Two hundred seventy-six patients responsible for 273 live births were identified between 2000 and 2006. Factors that were significantly associated with methamphetamine use were age younger than 20 years (9% methamphetamine compared with 16% control patients), non-Hispanic white ethnicity (55% compared with 71%), married (12% compared with 46%), preterm delivery (52% compared with 17%), low Apgar scores (6% compared with 1-2%), cesarean delivery (29% compared with 23%), and neonatal mortality (4% compared with 1%). Additionally, the maternal demographic characteristics suggested that these women were more likely to be unemployed, use other abusive substances, and have higher rates of domestic violence and adoption when compared with the control population. CONCLUSION: Methamphetamine use in pregnancy is complicated by more morbid maternal and neonatal outcomes when compared with the general obstetric population. Because the patients in this study were in a variety of ways demographically distinct, attempts to identify these patients early and intervene in an effort to improve pregnancy-related outcomes appears possible and warranted.

Gouin K; Murphy K; Shah PS. Effects of cocaine use during pregnancy on low birthweight and preterm birth: systematic review and metaanalyses. (review). American Journal of Obstetrics and Gynecology 204(4): article 340.e1, 2011. (44 refs.)

OBJECTIVE: To review systematically maternal antenatal cocaine exposure and adverse perinatal outcomes. STUDY DESIGN: Medline, Embase, CINAHL and secondary references in relevant studies were searched. English language studies of antenatal cocaine exposure and pregnancy outcomes published from 1966 to July 2009 were included. Metaanalyses were performed using the random effects model. RESULTS: Thirty-one studies were included. Cocaine use during pregnancy was associated with significantly higher odds of preterm birth (odds ratio [OR], 3.38; 95% confidence interval [CI], 2.72-4.21), low birthweight (OR, 3.66; 95% CI, 2.90-4.63), and small for gestational age infants (OR, 3.23; 95% CI, 2.43-4.30), as well as shorter gestational age at delivery (-1.47 week; 95% CI, -1.97 to -0.98 week) and reduced birthweight (-492 g; 95% CI, -562 to -421 g). CONCLUSION: Prenatal cocaine exposure is significantly associated with preterm birth, low birthweight, and small for gestational age infants.

Gurol A; Capik C; Apay SE; Kockar C. Relationship between parental smoking and respiratory illness in infants. Healthmed 5(3): 633- 638, 2011. (27 refs.)

Objective: Aim of the study was to determine relationship between parental smoking and respiratory illness in infants. Methods: This questionnaire-based study was conducted between February and May 2008 at a hospital with pediatric clinics in Erzurum in the north-east of Turkey and it included 150 infants with respiratory disease and their mothers. Results: The infants' the mean age was 8.08 +/- 2.62 months. It's found that infants exposed to passive smoking came more times to hospitals for bronchopneumonia and pneumonia diseases than infants not exposed to passive smoking and the differences between them have statistically significant. Conclusion: Health professionals need to inform parents about the relationship between parental smoking and respiratory illness in infants.

Habek D; Kovacevic M. Adverse pregnancy outcomes and long-term morbidity after early fetal hypokinesia in maternal smoking pregnancies. Archives of Gynecology and Obstetrics 283(3): 491-495, 2011. (33 refs.)

The aim of this study is to evaluate perinatal outcome and subsequent morbidity and neurodevelopment in 10-year-old children with fetal hypokinesia intrauterinely verified by ultrasonography in early pregnancy as a pattern of abnormal fetal behavior due to maternal chronic smoking. This study revealed significant global fetal hypokinesia as well as head and arm hypokinesia in early pregnancy in mothers' chronic smokers (group 3-more than 20 cigarettes a day). This retrospective study was performed in mothers and their 10-year-old children included in the study of the effect of cigarette smoking on fetal movements in early pregnancy. Perinatal outcome was assessed according to maternal data, course, and outcome of pregnancy and delivery. Data on the long-term (10 years) development and morbidity from infancy during childhood until age 10 years were obtained from the children's medical histories and medical rehabilitation records, maternal, and paternal histories. The psycholinguistic development was estimated. In group 3, there was a poor overall perinatal outcome and high rate of the bronchoconstrictive syndrome and recurrent infections, while one case of the sudden infant death syndrome. Poor school performance was recorded in five children, attention-deficit/hyperactivity disorder in four, and autism, dystonia syndrome, social maladaptation, and minimally cerebral disfunction in one child each. Retarded psycholinguistic development was found in seven children, only three of them attending speech therapy (P < 0.05). Fetal hypokinesia in early pregnancy related with maternal smoking was found to correlate with poor perinatal outcome, subsequent morbidity, and developmental impairments in 10-year-old children born to mothers smoking more than 20 cigarettes a day.

Hayashi K; Matsuda Y; Kawamichi Y; Shiozaki A; Saito S. Smoking during pregnancy increases risks of various obstetric complications: A case-cohort study of the Japan Perinatal Registry Network Database. Journal of Epidemiology 21(1): 61-66, 2011. (26 refs.)

Background: The adverse effects of maternal smoking on the health of pregnant women have been examined mostly on a disease-by-disease basis. The aims of this study were to evaluate simultaneously the effects of smoking during pregnancy on various obstetric complications, using data from a large medical database, and to investigate the expediency of using a case-cohort design for such an analysis. Methods: A case-cohort study was conducted within the Japan Perinatal Registry Network database. Perinatal information on infant deliveries was entered into the database at 125 medical centers in Japan. The base population of the study was 180 855 pregnant women registered in the database from 2001 through 2005. The outcome measures were the incidences of 11 different obstetric complications. Logistic regression models were used to estimate age-adjusted risk ratios (aRRs) and relative excess incidence proportions (REIs). Results: The overall prevalence of smoking during pregnancy was 5.8% in the base cohort, and the prevalence was higher among younger women. A comparison of the cases and control cohort showed that smokers during pregnancy had statistically significant higher risks for preterm rupture of the membrane (aRR: 1.67, 95% confidence interval [CI]: 1.43-1.96; REI: 40.2%, 95% CI: 29.9%-49.1%), chorioamnionitis (1.65, 1.36-2.00; 39.4%, 26.4%-50.0%), incompetent cervix (1.63, 1.35-1.96; 38.5%, 25.8%-49.1%), threatened premature delivery (1.38, 1.17-1.64; 27.7%, 14.5%-38.9%), placental abruption (1.37, 1.10-1.72; 27.1%, 8.8%-41.7%), and pregnancy-induced hypertension (1.20, 1.01-1.41; 16.4%, 1.2%-29.3%). Conclusions: Maternal smoking was associated with a number of obstetric complications. This highlights the importance of smoking cessation during pregnancy. In addition, case-cohort analysis proved useful in estimating RRs for multiple outcomes in a large database.

Huijbregts SCJ; van Berkel SR; Swaab-Barneveld H; van Goozen SHM. Neurobiological and behavioral stress reactivity in children prenatally exposed to tobacco. Psychoneuroendocrinology 36(6): 913-918, 2011. (23 refs.)

This study examined neurobiological and behavioral stress reactivity in children who had been prenatally exposed to tobacco. Neurobiological stress reactivity was measured using salivary cortisol and alpha-amylase levels at five different time points throughout a stressful neuropsychological test session, which involved a competition against a videotaped opponent. Participants (mean age: 10.6 years, SD 1.3) were 14 prenatally exposed (PE) children, 9 children with disruptive behavior problems (DBD), and 15 normal controls (NC). For cortisol responses, no significant differences between the three groups were observed. Normal controls, however, had significantly higher alpha-amylase levels than PE-children throughout the test session, and their alpha-amylase levels also increased throughout the session, whereas these remained low and stable for PE-children. Alpha-amylase levels and trajectory of PE-children were similar to those observed for DBD-children. PE-children also showed significantly increased behavioral stress reactivity compared to NC-children, and neurobiological and behavioral stress reactivity were inversely related in PE-children, again similar to what was observed for DBD-children. These results support the hypothesis that prenatal smoking may lead to long-lasting neurobiological and behavioral changes in exposed offspring.

Hwa HL. Intrauterine illicit substance exposure. (editorial). Pediatrics and Neonatology 51(5): 253-254, 2010. (28 refs.)

Isemann B; Meinzen-Derr J; Akinbi H. Maternal and neonatal factors impacting response to methadone therapy in infants treated for neonatal abstinence syndrome. Journal of Perinatology 31(1): 25-29, 2011. (27 refs.)

Objective: To identify maternal and neonatal factors that impact response to methadone therapy for neonatal abstinence syndrome. Study Design: This is a retrospective review of 128 infants that received pharmacotherapy for opiate withdrawal to identify factors associated with favorable response to methadone therapy. Maternal and neonatal data were analyzed with univariate statistics and multivariate logistic regression. Result: Maternal methadone maintenance dose during pregnancy correlated with length of stay (P=0.009). There was an inverse correlation between the amount of mother's breast milk ingested and length of stay (beta=-0.03, P=0.02). Methadone was initiated later, tapered more rapidly and was more successful as monotherapy in preterm infants. Five percent of infants were admitted to hospital again for rebound withdrawal following reduction of breast milk intake. Conclusion: Severity of neonatal abstinence syndrome may be mitigated by titrating methadone to the lowest effective dose during pregnancy and by encouraging breast milk feeds, which should be weaned gradually.

Jansson LM; DiPietro JA; Velez M; Elko A; Williams E; Milio L et al. Fetal neurobehavioral effects of exposure to methadone or buprenorphine. Neurotoxicology and Teratology 33(2): 240- 243, 2011. (24 refs.)

As part of a double-blind study of medication treatment for opioid dependence during pregnancy, 17 opioid-dependent pregnant women maintained on either buprenorphine or methadone underwent fetal monitoring at 24, 28, 32, and 36 weeks gestation. Maternal demographic information and infant outcomes did not significantly differ by medication group. Earlier in gestation (24 and 28 weeks), buprenorphine-exposed fetuses had higher levels of fetal heart rate variability, more accelerations in fetal heart rate and greater coupling between fetal heart rate and fetal movement than the methadone-exposed group (all ps<.05). Later in gestation (32 and 36 weeks), buprenorphine-exposed fetuses displayed less suppression of motor activity and longer duration of movements than the methadone-exposed group (all ps<.05). These results may have implications for the optimal treatment of the opioid-dependent pregnant woman.

Jones HE. Commentary on Kraft, et al. (2011): Treatment of neonatal abstinence syndrome - morphine, buprenorphine and beyond. (editorial). Addiction 106(3): 581-582, 2011

Koshy G; Delpisheh A; Brabin BJ. Dose response association of pregnancy cigarette smoke exposure, childhood stature, overweight and obesity. European Journal of Public Health 21(3): 286-291, 2011. (36 refs.)

Background: The combined dose response effects of pregnancy cigarette smoke exposure on childhood overweight, obesity and short stature have not been reported. Method: A community based cross-sectional survey of 3038 children aged 5-11 years from 15 primary schools in Merseyside, UK. Self-completed parental questionnaires were used for family characteristics, socio-economic status and parental smoking practices. Children were measured for height and weight and z-scores calculated for parental smoking categories. Results: Of 689 (34.0%) mothers who smoked during pregnancy 50.5% smoked ten or more cigarettes daily (heavy smokers). Children of maternal non-smokers had prevalence estimates for overweight, obesity and short stature of 25, 9.6 and 3.2%, respectively. Prevalence estimates were higher in children of mothers who were heavy smokers during pregnancy, 31.5% (P = 0.001), 15.6% (P < 0.001) and 5.5% (P = 0.001), respectively. Mean height for age z-scores was lower among heavy maternal (P < 0.001) and paternal smokers (P < 0.01) compared to non-smokers. Childhood overweight, obesity or short stature were all associated with heavy maternal smoking during pregnancy (all P < 0.001). Mean body mass index (BMI) z-scores were higher in boys of mothers who smoked (P = 0.043). The adjusted odds ratio for short stature in children of heavy maternal smokers was 2.76 (95% CI 1.21-6.33) and 4.28 (1.37-13.37) if both parents were heavy smokers. The adjusted OR for obesity in children of maternal smokers was 1.61(1.19-2.18). The population attributable risk for short stature was 8.8% (1.1-22.7) for heavy maternal smokers. Conclusion: A dose-response association was observed between pregnancy smoking exposure, short stature and obesity.

Lavezzi AM; Corna MF; Matturri L. Ependymal alterations in sudden intrauterine unexplained death and sudden infant death syndrome: Possible primary consequence of prenatal exposure to cigarette smoking. Neural Development 5(article 17), 2010. (45 refs.)

Background: The ependyma, the lining providing a protective barrier and filtration system separating brain parenchyma from cerebrospinal fluid, is still inadequately understood in humans. In this study we aimed to define, by morphological and immunohistochemical methods, the sequence of developmental steps of the human ependyma in the brainstem (ventricular ependyma) and thoracic spinal cord (central canal ependyma) of a large sample of fetal and infant death victims, aged from 17 gestational weeks to 8 postnatal months. Additionally, we investigated a possible link between alterations of this structure, sudden unexplained fetal and infant death and maternal smoking. Results: Our results demonstrate that in early fetal life the human ependyma shows a pseudostratified cytoarchitecture including many tanycytes and ciliated cells together with numerous apoptotic and reactive astrocytes in the subependymal layer. The ependyma is fully differentiated, with a monolayer of uniform cells, after 32 to 34 gestational weeks. We observed a wide spectrum of ependymal pathological changes in sudden death victims, such as desquamation, clusters of ependymal cells in the subventricular zone, radial glial cells, and the unusual presence of neurons within and over the ependymal lining. These alterations were significantly related to maternal smoking in pregnancy. Conclusions: We conclude that in smoking mothers, nicotine and its derivatives easily reach the cerebrospinal fluid in the fetus, immediately causing ependymal damage. Consequently, we suggest that the ependyma should be examined in-depth first in victims of sudden fetal or infant death with mothers who smoke.

Lee BE; Hong YC; Park H; Ha M; Kim JH; Chang N et al. Secondhand smoke exposure during pregnancy and infantile neurodevelopment. Environmental Research 111(4): 539- 544, 2011. (59 refs.)

During prenatal development, the nervous system may be more susceptible to environmental toxicants, such as secondhand smoke. The authors assessed the effects of prenatal and postnatal secondhand smoke exposure on the neurodevelopment of 6-month infants. The subjects were 414 mother and infant pairs with no medical problems, taken from the Mothers' and Children's Environmental Health study. Prenatal and postnatal exposures to secondhand smoke were determined using maternal self-reports. Examiners, unaware of exposure history, assessed the infants at 6 months of age using the Bayley Scales of Infant Development. Bayley scores were compared for secondhand smoke exposed and unexposed groups after adjusting for potential confounders. Multiple logistic regression analysis was carried out to estimate the risk of developmental delay posed by SHS exposure. The multivariate model included residential area, maternal age, pre-pregnancy body mass index, education, income, infant sex, parity, birth weight, and type of feeding. After adjusting for covariates, secondhand smoke exposure during pregnancy was found to be related to a decrease in mental developmental index score, but not to a decrease in psychomotor developmental index score. In addition, secondhand smoke exposure during pregnancy was found to increase the risk of developmental delay (mental developmental index score 5 85) at 6 months. This study suggests that the infants of non-smoking women exposed to secondhand smoke are at risk of neurodevelopmental delay.

Leonardi-Bee J; Britton J; Venn A. Secondhand smoke and adverse fetal outcomes in nonsmoking pregnant women: A meta-analysis. Pediatrics 127(4): 734-741, 2011. (50 refs.)

OBJECTIVE: To determine the risk of adverse fetal outcomes of secondhand smoke exposure in nonsmoking pregnant women. METHODS: This was a systematic review and meta-analysis in accordance with Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. We searched Medline and Embase (to March 2009) and reference lists for eligible studies; no language restrictions were imposed. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated by using random-effect models. Our search was for epidemiologic studies of maternal exposure to secondhand smoke during pregnancy in nonsmoking pregnant women. The main outcome measures were spontaneous abortion, perinatal and neonatal death, stillbirth, and congenital malformations. RESULTS: We identified 19 studies that assessed the effects of secondhand smoke exposure in nonsmoking pregnant women. We found no evidence of a statistically significant effect of secondhand smoke exposure on the risk of spontaneous abortion (OR: 1.17 [95% CI: 0.88-1.54]; 6 studies). However, secondhand smoke exposure significantly increased the risk of stillbirth (OR: 1.23 [95% CI: 1.09-1.38]; 4 studies) and congenital malformation (OR: 1.13 [95% CI: 1.01-1.26]; 7 studies), although none of the associations with specific congenital abnormalities were individually significant. Secondhand smoke exposure had no significant effect on perinatal or neonatal death. CONCLUSIONS: Pregnant women who are exposed to secondhand smoke are estimated to be 23% more likely to experience stillbirth and 13% more likely give birth to a child with a congenital malformation. Because the timing and mechanism of this effect is not clear, it is important to prevent secondhand smoke exposure in women before and during pregnancy.

Maccani MA; Avissar-Whiting M; Banister CE; McGonnigal B; Padbury JF; Marsit CJ. Maternal cigarette smoking during pregnancy is associated with downregulation of miR-16, miR-21 and miR-146a in the placenta. Epigenetics 5(7): 583-589, 2010. (52 refs.)

Maternal cigarette smoking during pregnancy is associated with poor fetal outcome and aberrant miRNA expression is associated with adverse pregnancy outcomes. In 25 human placentas, we analyzed the expression of four candidate miRNA previously implicated in growth and developmental processes: miR-16, miR-21, miR-146a and miR-182, and used three immortalized placental cell lines to identify if specific components of cigarette smoke were responsible for alterations to miRNA expression. miR-16, miR-21 and miR-146a were significantly downregulated in cigarette smoke-exposed placentas compared to controls. TCL-1 cells exposed to both nicotine and benzo(a)pyrene exhibited significant, dose-dependent downregulation of miR-146a. These results suggest that miR-146a is particularly responsive to exposures, and that smoking may elicit some of its downstream effects through alteration of miRNA expression.

Maisonet M; Christensen KY; Rubin C; Holmes A; Flanders WD; Heron J et al. Role of prenatal characteristics and early growth on pubertal attainment of British girls. Pediatrics 126(3): E591-E600, 2010. (43 refs.)

OBJECTIVES: The objective of this study was to explore the influence of maternal prenatal characteristics and behaviors and of weight and BMI gain during early childhood on the timing of various puberty outcomes in girls who were enrolled in the Avon Longitudinal Study of Parents and Children. METHODS: Repeated self-assessments of pubertal development were obtained from similar to 4000 girls between the ages of 8 and 14. Data on prenatal characteristics and weight at birth and 2, 9, and 20 months of age were obtained from questionnaires, birth records, and clinic visits. Infants' weights were converted to weight-for-age and BMI SD scores (SDSs; z scores), and change values were obtained for the 0- to 20-month and other intervals within that age range. We used parametric survival models to estimate associations with age of entry into Tanner stages of breast and pubic hair and menarche. RESULTS: Maternal initiation of menarche at age <12, smoking during pregnancy, and primiparity were associated with earlier puberty. A 1-unit increase in the weight SDS change values for the 0- to 20-month age interval was associated with earlier ages of entry into pubertal outcomes (0.19-0.31 years). Increases in the BMI SDS change values were also associated with earlier entry into pubertal outcomes (0.07-0.11 years). CONCLUSIONS: Many of the maternal prenatal characteristics and weight and BMI gain during infancy seemed to have similar influences across different puberty outcomes. Either such early factors have comparable influences on each of the hormonal processes involved in puberty, or processes are linked and awakening of 1 aspect triggers the others.

Maritz GS; Harding R. Life-long programming implications of exposure to tobacco smoking and nicotine before and soon after birth: Evidence for altered lung development. International Journal of Environmental Research and Public Health 8(3): 875-898, 2011. (134 refs.)

Tobacco smoking during pregnancy remains common, especially in indigenous communities, and likely contributes to respiratory illness in exposed offspring. It is now well established that components of tobacco smoke, notably nicotine, can affect multiple organs in the fetus and newborn, potentially with life-long consequences. Recent studies have shown that nicotine can permanently affect the developing lung such that its final structure and function are adversely affected; these changes can increase the risk of respiratory illness and accelerate the decline in lung function with age. In this review we discuss the impact of maternal smoking on the lungs and consider the evidence that smoking can have life-long, programming consequences for exposed offspring. Exposure to maternal tobacco smoking and nicotine intake during pregnancy and lactation changes the genetic program that controls the development and aging of the lungs of the offspring. Changes in the conducting airways and alveoli reduce lung function in exposed offspring, rendering the lungs more susceptible to obstructive lung disease and accelerating lung aging. Although it is generally accepted that prevention of maternal smoking during pregnancy and lactation is essential, current knowledge of the effects of nicotine on lung development does not support the use of nicotine replacement therapy in this group.

Menzies D. The case for a worldwide ban on smoking in public places. Current Opinion In Pulmonary Medicine 17(2): 116-122, 2011. (49 refs.)

Purpose of review: Second-hand smoke (SHS) is a major cause of morbidity and mortality on a global scale. Governments have increasingly sought to mitigate the effects of SHS by introducing legislation that restricts tobacco consumption in public places. There is emerging evidence that such legislation leads to direct and indirect health benefits. Recent findings: Exposure to SHS is now shown to be associated with development of cardiovascular disease, and poorer health outcomes in patients with established chronic obstructive pulmonary disease. Childhood (including in-utero) exposure to SHS has recently been linked with increased risk of cleft palate, demonstrable signs of atherosclerosis, and the development of emphysema and lung cancer in adulthood. Comprehensive bans on smoking in public lead to a reduction in overall exposure to SHS for both adults and children and have also been shown to immediately attenuate the incidence of myocardial infarction and paediatric hospital attendances with acute asthma. Summary: Banning smoking in public places is an effective tool for reducing tobacco-related morbidity across a multiplicity of diseases. Countries that have not already done so should introduce legislation to enforce effective legislation that prohibits smoking in public places.

Motlagh MG; Katsovich L; Thompson N; Lin HQ; Kim YS; Scahill L et al. Severe psychosocial stress and heavy cigarette smoking during pregnancy: An examination of the pre- and perinatal risk factors associated with ADHD and Tourette syndrome. European Journal of Epidemiology 19(10): 755-764, 2010. (62 refs.)

Attention-deficit/hyperactivity disorder (ADHD) is frequently diagnosed in children with Tourette syndrome (TS). The basis for this co-occurrence is uncertain. This study aimed to determine if specific pre- and perinatal risk factors, including heavy maternal smoking and severe psychosocial stress during pregnancy, were associated with one or both disorders, or neither. We compared maternal report data on pre- and perinatal risk factors on 222 children between the ages of 7 and 18 years including 45 individuals with TS alone, 52 individuals with ADHD alone, 60 individuals with condition of comorbid TS + ADHD, and 65 unaffected control children. Pre- and perinatal histories as well as psychiatric assessments were performed using standardized questionnaires and semi-structured interviews with the mothers and children. Logistic regression was used to determine the odds ratio for each variable of interest. Compared to the mothers of unaffected control children, the mothers of children with ADHD alone reported higher rates of heavy smoking (> 10 cigarettes per day) during pregnancy and higher levels of severe psychosocial stress during pregnancy (OR = 13.5, p < 0.01 and OR = 6.8, p < 0.002, respectively). The TS + ADHD and the TS alone patients also had higher rates heavy maternal smoking and high levels of psychosocial stress compared to the control children, but these differences failed to reach statistical significance (heavy smoking: OR = 8.5, p < 0.052, OR = 4.6, p < 0.19, respectively; severe psychosocial stress: OR = 3.1, p < 0.07, OR = 2.6, p < 0.11, respectively). Heavy maternal smoking and severe levels psychosocial stress during pregnancy were independently associated with a diagnosis of ADHD. TS patients also had higher rates of these risk factors, but the ORs failed to reach statistical significance. Efforts are needed to reduce the frequency of these risk factors in high-risk populations. Future studies, using genetically sensitive designs, are also needed to sort out the causal pathways.

Mulder EJH; Tegaldo L; Bruschettini P; Visser GHA. Foetal response to maternal coffee intake: Role of habitual versus non-habitual caffeine consumption. Journal of Psychopharmacology 24(11): 1641-1648, 2010. (35 refs.)

Little is known about the effect on the human foetus of long-term and acute exposure to caffeine. We studied the organisation of foetal sleep-wake states in 13 healthy near-term foetuses over a wide range of maternal plasma caffeine concentrations (0-13 mu g/mL) reflecting normal lifestyle conditions (day 0) and again following intake of two cups of regular coffee (similar to 300 mg of caffeine) intermitted by 50 h of abstinence (day 2; acute effects). On either day, 2 h simultaneous recordings were made of foetal heart rate, general- , eye-, and breathing-movements. The recordings were analysed for the presence of each of four foetal behavioural states: quiet-and active-sleep, quiet-and active-wakefulness. There was a linear relationship between maternal caffeine content and the incidence of foetal general movements during active sleep on day 0 (R = 0.74; P < 0.02). After coffee loading on day 2, foetuses of non-or low-caffeine consumers showed increases in active wakefulness (P < 0.001), general movements (P < 0.05) and heart rate variation (P < 0.01) but lower basal heart rate (P < 0.01) compared with their day 0 values. The changes in foetal heart rate (variation) and behaviour occurred between 90 and 180 min post-consumption. In contrast, foetuses of habitual caffeine consumers remained unaffected suggestive of foetal tolerance to caffeine. The results indicate differential performance between foetuses regularly exposed to caffeine and those caffeine-naive, both under normal maternal lifestyle conditions and in response to maternal coffee ingestion.

Nkansah-Amankra S. Neighborhood contextual factors, maternal smoking, and birth outcomes: Multilevel analysis of the South Carolina PRAMS Survey, 2000-2003. Journal of Women's Health 19(8): 1543-1552, 2010. (52 refs.)

Background: Previous studies investigating relationships among neighborhood contexts, maternal smoking behaviors, and birth outcomes (low birth weight [LBW] or preterm births) have produced mixed results. Methods: We evaluated independent effects of neighborhood contexts on maternal smoking behaviors and risks of LBW or preterm birth outcomes among mothers participating in the South Carolina Pregnancy Risk Assessment and Monitoring System (PRAMS) survey, 2000-2003. The PRAMS data were geocoded to 2000 U. S. Census data to create a multilevel data structure. We used a multilevel regression analysis (SAS PROC GLIMMIX) to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI). Results: In multivariable logistic regression models, high poverty, predominantly African American neighborhoods, upper quartiles of low education, and second quartile of neighborhood household crowding were significantly associated with LBW. However, only mothers resident in predominantly African American Census tract areas were statistically significantly at an increased risk of delivering preterm (OR 2.2, 95% CI 1.29-3.78). In addition, mothers resident in medium poverty neighborhoods remained modestly associated with smoking after adjustment for maternal-level covariates. The results also indicated that maternal smoking has more consistent effects on LBW than preterm births, particularly for mothers living in deprived neighborhoods. Conclusions: Interventions seeking to improve maternal and child health by reducing smoking during pregnancy need to engage specific community factors that encourage maternal quitting behaviors and reduce smoking relapse rates. Inclusion of maternal-level covariates in neighborhood models without careful consideration of the causal pathway might produce misleading interpretation of the results.

Nomura Y; Marks DJ; Halperin JM. Prenatal exposure to maternal and paternal smoking on attention deficit hyperactivity disorders symptoms and diagnosis in offspring. Journal of Nervous and Mental Disease (9): 672-678, 2010. (52 refs.)

The study examined the effect of maternal and paternal smoking during pregnancy on the child's inattention and hyperactivity/impulsivity symptoms, and the risk for attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD). Generalized estimating equations, incorporating data from multiple informants (parents and teachers), was used to evaluate levels of ADHD as a function of parental smoking. The risk for ADHD, ODD, and comorbid ADHD and ODD was evaluated using polytomous logistic regression. We found that maternal, but not paternal, smoking was significantly associated with elevated inattention, hyperactivity/impulsivity, and total ADHD symptoms in children. Children of smoking, relative to nonsmoking, mothers had a significant increased risk for comorbid ADHD and ODD and ADHD, but not ODD. Although father's smoking was not associated with an increased risk, as it strongly influenced mothers' smoking, intervention for both parents may be most effective in preventing the pathway to ADHD-related problems in the children.

Obel C; Olsen J; Henriksen TB; Rodriguez A; Jarvelin MR; Moilanen I et al. Is maternal smoking during pregnancy a risk factor for Hyperkinetic disorder?-findings from a sibling design. International Journal of Epidemiology 40(2): 338-345, 2011. (24 refs.)

Background: Studies have consistently shown that pregnancy smoking is associated with twice the risk of hyperactivity/inattention problems in the offspring. An association of this magnitude may indicate behavioural difficulties as one of the most important health effects related to smoking during pregnancy. However, social and genetic confounders may fully or partially account for these findings. Methods: A cohort including all singletons born in Finland from 1 January 1987 through 31 December 2001 was followed until 1 January 2006 based on linkage of national registers. Data were available for 97% (N = 868 449) of the population. We followed singleton children of smoking and non-smoking mothers until they had an International Classification of Diseases, 10th revision, diagnosis of hyperkinetic disorder (HKD) or to the end of the observation period. We used sibling-matched Cox regression analyses to control for social and genetic confounding. Results We found a much smaller association between exposure to maternal smoking during pregnancy and risk of HKD in children using the sibling-matched analysis [hazards ratio (HR) = 1.20, 95% confidence interval (CI) 0.97-1.49] than was observed in the entire cohort (HR 2.01, 95% CI 1.90-2.12). Conclusions: Our findings suggest that the strong association found in previous studies may be due to time-stable familial factors, such as environmental and genetic factors. If smoking is a causal factor, the effect is small and less important than what the previous studies indicate.

Oral R. Perinatal illicit drug use and fetal exposure: Consequences and management with a public health approach. Drug Testing and Analysis 1(2): 59-64, 2009. (51 refs.)

Perinatal illicit drug use and in utero exposure to illicit drugs have been significant public health issues affecting reproductiveage women and children because of the associated medical, social, psychological, and legal consequences. Surveys have shown that among pregnant women aged 15 to 44 years, 4% reported using illicit drugs in the past month in 2005-2006 and 11.8% reported current alcohol use. With a 4,169,000 live births occurred in 2006-2007 in the USA, this suggests approximately 180,000 women might have used illicit drugs, with or without alcohol, and thus a similar number of newborns might have been exposed to illicit drugs during pregnancy. This article discusses the consequences of prenatal drug exposure, the impact of intervention and the related cost/benefits. The implications for medical practice are noted, including the need for screening and testing. It discusses the need for policy development and the controversies involved in some policy proposals.

Parikh R; Hussain T; Holder G; Bhoyar A; Ewert AK. Maternal methadone therapy increases QTc interval in newborn infants. Archives of Disease in Childhood. Fetal and Neonatal Edition 96(2): F141-F143, 2011. (19 refs.)

Introduction Prolongation of the QT interval is a risk factor for sudden death. Methadone treatment is a well-recognised cause of QT interval lengthening in adults. The effect of maternal methadone treatment on the QT interval of the newborn infant is not known. This is the first prospective study of corrected QT (QTc) interval in infants born to mothers receiving methadone. Aim To compare QTc interval in infants born to mothers receiving methadone therapy with healthy controls. Method Twenty-six term infants (median gestation 38 weeks, range 37-40) born to mothers on methadone therapy had ECG recordings on days 1, 2, 4 and 7. The QTc interval was calculated using the Bazzett formula. Results for days 1 and 2 were compared with healthy matched control infants born to mothers who were not receiving methadone. Results for days 4 and 7 were compared with published normal values. Results In the methadone group, the QTc interval was significantly prolonged on days 1 and 2 of life. On days 4 and 7, this increase was no longer present. None of the infants in either group had any evidence of significant cardiac rhythm disturbance. Conclusion Maternal methadone therapy can cause transient prolongation of the QTc interval in newborn infants in the first 2 days of life. Newborns exposed to methadone are at risk of cardiac rhythm disturbances. Bradycardia, tachycardia or an irregular heart rate in an infant born to a mother on methadone treatment should prompt investigation with a 12-lead ECG.

Peck JD; Leviton A; Cowan LD. A review of the epidemiologic evidence concerning the reproductive health effects of caffeine consumption: A 2000-2009 update. (review). Food and Chemical Toxicology 48(10): 2549-2576, 2010. (149 refs.)

This review of human studies of caffeine and reproductive health published between January 2000 and December 2009 serves to update the comprehensive review published by Leviton and Cowan (2002). The adverse reproductive outcomes addressed in this review include: (1) measures of subfecundity; (2) spontaneous abortion; (3) fetal death; (4) preterm birth; (5) congenital malformations; and (6) fetal growth restriction. Methodologic challenges and considerations relevant to investigations of each reproductive endpoint are summarized, followed by a brief critical review of each study. The evidence for an effect of caffeine on reproductive health and fetal development is limited by the inability to rule out plausible alternative explanations for the observed associations, namely confounding by pregnancy symptoms and smoking, and by exposure measurement error. Because of these limitations, the weight of evidence does not support a positive relationship between caffeine consumption and adverse reproductive or perinatal outcomes.

Power C; Atherton K; Thomas C. Maternal smoking in pregnancy, adult adiposity and other risk factors for cardiovascular disease. Atherosclerosis 211(2): 643-648, 2010. (30 refs.)

Objective: To establish whether maternal smoking in pregnancy is associated with risk factors for cardiovascular disease (CVD) in mid-adulthood and whether associations are explained by postnatal influences. Methods: Participants were 8815 men and women in the 1958 British birth cohort, with data on CVD risk factors measured at 45 y. Maternal smoking was recorded at birth. Results: Offspring of smokers had a higher adult BMI, waist circumference, blood pressure, HbA1c and triglycerides on average than offspring of non-smokers; females had lower HDL cholesterol levels. Total cholesterol was unrelated to maternal smoking. Associations were abolished after adjustment for postnatal influences across life, except for BMI and waist circumference: offspring of smokers had a BMI greater by 0.83 kg/m(2) on average than offspring of non-smokers and a 1.8cm larger waist circumference. Mean BMI and waist circumference increased with number of cigarettes that the mother smoked, but were not elevated in offspring whose mother had quit smoking before or early in pregnancy. Conclusions: Adults exposed to tobacco in utero had a more adverse CVD risk profile in mid-adulthood which appeared to reflect a lifetime accumulation of postnatal influences; whereas their higher BMI and central adiposity may be due in part to intrauterine mechanisms.

Pueyo V; Guerri N; Oros D; Valle S; Tuquet H; Gonzalez I et al. Effects of smoking during pregnancy on the optic nerve neurodevelopment. Early Human Development 87(5): 331- 334, 2011. (23 refs.)

Background: Tobacco smoking during pregnancy alters neurodevelopment. Optical coherence tomography (OCT) provides precise measurements of the retinal nerve fiber layer (RNFL), which forms part of the central nervous system. Aims: To assess using the OCT how smoking during pregnancy would affect optic nerve development as detected in human offspring. Study design: Visual examination and OCT were performed on a group of children (n = 70; 4.15-13.50 years of age), classified as being exposed or not to maternal smoking during gestational period. The association between smoking during pregnancy and RNFL thickness was assessed by a linear regression analysis adjusted for possible confounding factors. Results: Although visual outcomes did not differ between groups, a significant decrease in the RNFL thickness was found in the group of infants exposed to smoke (105.3 vs 95.6; p=0.002), even when adjusting for gestational age, birth weight or gender. Conclusions: OCT measurements show that intrautero exposure to tobacco smoke interferes with the development of the optic nerve.

Rahu K; Rahu M; Pullmann H; Allik J. Effect of birth weight, maternal education and prenatal smoking on offspring intelligence at school age. Early Human Development 86(8): 493-497, 2010. (53 refs.)

To examine the combined effect of birth weight, mothers' education and prenatal smoking on psychometrically measured intelligence at school age 1,822 children born in 1992-1999 and attending the first six grades from 45 schools representing all of the fifteen Estonian counties with information on birth weight, gestational age and mother's age, marital status, education, parity and smoking in pregnancy, and intelligence tests were studied. The scores of Raven's Standard Progressive Matrices were related to the birth weight: in the normal range of birth weight (>= 2500 g) every 500 g increase in birth weight was accompanied by around 0.7-point increase in IQ scores. A strong association between birth weight and IQ remained even if gestational age and mother's age, marital status, education, place of residence, parity and smoking during pregnancy have been taken into account. Maternal prenatal smoking was accompanied by a 3.3-point deficit in children's intellectual abilities. Marriage and mother's education had an independent positive correlation with offspring intelligence. We concluded that the statistical effect of birth weight, maternal education and smoking in pregnancy on offspring's IQ scores was remarkable and remained even if other factors have been taken into account.

Raith W; Kutschera J; Muller W; Urlesberger B. Active ear acupuncture points in neonates with neonatal abstinence syndrome (NAS). American Journal of Chinese Medicine 39(1): 29-37, 2011. (28 refs.)

The aim of the study was to determine the presence of acupuncture ear points in neonates with Neonatal Abstinence Syndrome (NAS). NAS occurs in the first days of life in neonates whose mothers have a history of drug abuse, and may also occur in neonates whose mothers are currently following substitution therapy. The patients are neonates with NAS admitted over one year to the Division of Neonatology at the University Hospital Graz. The examination took place on the third day after delivery (mean value 70.3 hours) and was performed by a neuronal pen (PS 3 (c) Silberbauer, Vienna, Austria). An integrated sound and optical signal detected the active ear points that were then placed on an ear map. We investigated six neonates (four male, two female). All investigated neonates showed the presence of active ear acupuncture points. The psychovegetative rim was the most common organic area of the children, following by a few organic points. This corresponds with the results found in healthy neonates. In all neonates with NAS, we found the presence of psychic ear points. The identified psychic ear points are the frustration-point, R-point and the psychotropic area nasal from the incisura intertragica. In all neonates with NAS, active organic and psychic ear points were detectable in both ears. In the future, it could be possible to use active ear points for diagnostic and therapeutic purposes.

Rose-Jacobs R; Soenksen S; Appugliese DP; Cabral HJ; Richardson MA; Beeghly M et al. Early adolescent executive functioning, intrauterine exposures and own drug use. Neurotoxicology and Teratology 33(3): 379-392, 2011. (116 refs.)

Individual differences in adolescents' executive functioning are often attributed either to intrauterine substance exposure or to adolescents' own substance use, but both predictors typically have not been evaluated simultaneously in the same study. This prospective study evaluated whether intrauterine drug exposures, the adolescents' own substance use, and/or their potential interactions are related to poorer executive functioning after controlling for important contextual variables. Analyses were based on data collected on a sample of 137 predominantly African-American/African Caribbean adolescents from low-income urban backgrounds who were followed since their term birth. Intrauterine substance exposures (cocaine, marijuana, alcohol, and cigarettes) and adolescents' substance use were documented using a combination of biological assays and maternal and adolescent self-report. At 12-14 years of age, examiners masked to intrauterine exposures and current substance use assessed the adolescents using the Delis Kaplan Executive Function System (D-KEFS), an age-referenced instrument evaluating multiple dimensions of executive functioning (EF). Results. of covariate-controlled analyses in this study suggest that when intrauterine substance exposures and young adolescents' substance use variables were in the same analysis models, subtle differences in specific EF outcomes were identifiable in this non-referred sample. While further study with larger samples is indicated, these findings suggest that 1) research on adolescent substance use and intrauterine exposure research should evaluate both predictors simultaneously, 2) subtle neurocognitive effects associated with specific intrauterine drug exposures can be identified during early adolescence, and 3) intrauterine substance exposure effects may differ from those associated with adolescents' own drug use.

Seligman NS; Almario CV; Hayes EJ; Dysart KC; Berghella V; Baxter JK. Relationship between maternal methadone dose at delivery and neonatal abstinence syndrome. Journal of Pediatrics (3): 428-U112, 2010. (53 refs.)

Objective: To estimate the relationship between maternal methadone dose and the incidence of neonatal abstinence syndrome (NAS). Study design: We performed a retrospective cohort study of pregnant women treated with methadone for opiate addiction who delivered live-born neonates between 1996 and 2006. Four dose groups, on the basis of total daily methadone dose, were compared (<= 80 mg/d, 81-120 mg/d, 121-160 mg/d, and >160 mg/d). The primary outcome was treatment for NAS. Symptoms of NAS were objectively measured with the Finnegan scoring system, and treatment was initiated for a score >24 during the prior 24 hours. Results: A total of 330 women treated with methadone and their 388 offspring were included. Average methadone dose at delivery was 117 +/- 50 mg/d (range, 20-340 mg/d). Overall, 68% of infants were treated for NAS. Of infants exposed to methadone doses <= 80 mg/d, 81-120 mg/d, 121-160 mg/d, and >160 mg/d, treatment for NAS was initiated for 68%, 63%, 70%, and 73% of neonates, respectively (P = .48). The rate of maternal illicit opiate abuse at delivery was 26%, 28%, 19%, and 11%, respectively (P = .04). Conclusion: No correlation was found between maternal methadone dose and rate of NAS. However, higher doses of methadone were associated with decreased illicit opiate abuse at delivery.

Sommer A; Blanton SH; Weymouth K; Alvarez C; Richards BS; Barnes D et al. Smoking, the xenobiotic pathway, and clubfoot. Birth Defects Research. Part A: Clinical and Molecular Teratology 91(1): 20-28, 2011. (85 refs.)

BACKGROUND: Isolated clubfoot is a common orthopedic birth defect that affects approximately 135,000 newborns worldwide. It is characterized by ankle equinus, hindfoot varus, and forefoot adductus. Although numerous studies suggest a multifactorial etiology, the specific genetic and environmental components have yet to be delineated. Maternal smoking during pregnancy is the only common environmental factor consistently shown to increase the risk for clubfoot. Moreover, a positive family history of clubfoot, in conjunction with maternal smoking, increases the risk 20-fold. These findings suggest that genetic variation in smoking metabolism (xenobiotic) genes may increase susceptibility to clubfoot. Based on this reasoning, we interrogated eight candidate genes from the xenobiotic metabolism. METHODS: Twenty-two single-nucleotide polymorphisms and two null alleles in these genes (CYP1A1, CYP1A2, CYP1B1, CYP2A6, EPHX1, NAT2, GSTM1, and GSTT1) were genotyped in a dataset composed of non-Hispanic white and Hispanic multiplex and simplex families. RESULTS: Only rs1048943/CYP1A1 had significantly altered transmission in the aggregate and multiplex non-Hispanic white datasets (p = 0.003 and p = 0.009, respectively). Perturbation of CYP1A1 can cause an increase in harmful, adduct-forming metabolic intermediates. A significant interaction between EPHX1 and NAT2 was also found (p = 0.007). Importantly, for CYP1A2, significant maternal (p = 0.03; relative risk [RR] = 1.24; 95% confidence interval [CI], 1.04-1.44) and fetal (p = 0.01; RR = 1.33; 95% CI, 1.13-1.54) genotypic effects were identified, suggesting that both maternal and fetal genotypes can negatively impact limb development. No association was found between maternal smoking status and variation in xenobiotic metabolism genes. CONCLUSION: Together, these results suggest that xenobiotic metabolism genes are unlikely to play a major role in clubfoot; however, perturbation of this pathway may still play a contributory role.

Stephan-Blanchard E; Chardon K; Telliez F; Arnould JP; Leke A; Ammari M et al. Are benzo[a]pyrene-DNA adducts an accurate biomarker of long-term in utero exposure to smoking? Therapeutic Drug Monitoring 33(3): 329- 335, 2011. (38 refs.)

Background: Maternal smoking during pregnancy is associated with adverse perinatal outcomes. In view of concerns about under-reporting, benzo[a] pyrene (B[a]P)-DNA adducts could be used to provide information about long-term in utero exposure to smoking but have not previously been used with samples from neonates. This study aimed to verify whether B[a] P-DNA adducts could accurately assess tobacco smoke exposure during fetal life. The objectives were to correlate B[a] P-DNA adduct levels with active maternal and passive smoking and to determine the sensitivity and specificity of smoking and nonsmoking status by comparing neonatal B[a] P-DNA adduct levels with those of maternal self-reports. Materials and Methods: B[a] P-DNA adducts in neonatal buccal cell samples were determined by a competitive immunoassay. Three groups of neonates were constituted according to maternal self-reported smoking status during pregnancy: nonsmokers (n = 25; control group), <10 cigarettes per day (n = 18; S- group), or >10 cigarettes per day (n = 21; S+ group). Results: The mean B[a] P-DNA adduct level rose significantly when comparing the controls with the S- and S+ groups. Maternal active smoking had the strongest effect on B[a] P-DNA adduct levels in neonates. A crossanalysis between B[a] P-DNA adduct levels and maternal self-reported levels revealed high sensitivity and specificity. Conclusions: This preliminary study suggests that B[a] P-DNA adducts are reliable biomarkers for the screening of long-term in utero exposure to smoking and are accurate when compared with maternal self-reported levels of active smoking. Detection of B[a] P-DNA adducts in neonates could provide a useful, noninvasive tool in clinical risk assessment studies but would benefit from further confirmation with another validated biomarker.

Suarez L; Ramadhani T; Felkner M; Canfield MA; Brender JD; Romitti PA et al. Maternal smoking, passive tobacco smoke, and neural tube defects. Birth Defects Research. Part A-Clinical and Molecular Teratology 91(1): 29-33, 2011. (34 refs.)

BACKGROUND: Although cigarette smoke is a well-established toxin and harmful to the developing embryo, the evidence for an independent effect on the occurrence of neural tube defects (NTDs) is mixed. In this study, we examined the relation between NTDs and maternal exposures to cigarette smoke, including passive smoke exposure. METHODS: We used cases and controls from the large, multistate, population-based National Birth Defects Prevention Study. A total of 1041 NTD cases and 5862 live birth controls, delivered during 1997 to 2004, were available for analyses. Mothers were interviewed by telephone between 6 weeks and 24 months after delivery. Participation rates were 71% for NTD case mothers and 69% for control mothers. RESULTS: Compared with nonsmokers (and also not exposed to passive cigarette smoke), mothers exposed only to passive smoke had an increased NTD odds ratio (OR, 1.7; 95% confidence interval [CI], 1.4-2.0), adjusted for race-ethnicity, and study center. There was no increased OR for mothers who actively smoked 24 or fewer cigarettes per day. Mothers who smoked 25 or more cigarettes per day had an elevated OR (OR, 1.6; 95% CI, 0.9-3.0), but the OR adjusted for race-ethnicity, and center was compatible with the null. CONCLUSION: Results suggest that maternal exposure to passive smoke is associated with NTDs. Women who plan on becoming pregnant should minimize their exposure to passive smoke and refrain from smoking.

Sullivan KM; Bottorff J; Reid C. Does mother's smoking influence girls' smoking more than boys' smoking? A 20-year review of the literature using a sex- and gender-based analysis. (review). Substance Use & Misuse 46(5): 656-668, 2011. (72 refs.)

A systematic literature review was conducted to examine whether mother's smoking influences girls' smoking more than boys' smoking. Fifty-seven studies, published between 1989 and 2009, were analyzed using a sex and gender lens. Results indicate that mother's prenatal and postnatal smoking influences girls' smoking more than boys' smoking. Despite evidence that sex and gender are important determinants of smoking among adolescents when examined in relation to mother's smoking, the theoretical understanding of why girls are more likely to smoke if prenatally and postnatally exposed to mother's smoking remains unclear. Implications for future research are discussed.

Terplan M; Wright T. The effects of cocaine and amphetamine use during pregnancy on the newborn: Myth versus reality. (editorial). Journal of Addictive Diseases 30(1): 1-5, 2011. (45 refs.)

Twomey JE; Caldwell D; Soave R; Fontaine LA; Lester BM. Vulnerable infants program of Rhode Island: Promoting permanency for substance-exposed infants. Child Welfare 89(3): 121-U4, 2010. (40 refs.)

The Vulnerable Infants Program of Rhode Island is a care coordination program to promote permanency for substance-exposed infants by addressing parental needs and increasing collaboration among social service agencies. Over the first four years of the program, there was a decrease in time spent in the newborn nursery beyond medical necessity and identification of permanent placements by 12 months for 84% of infants, with the majority of infants (78%) placed with biological parents or relatives.

Voigt M; Zels K; Guthmann F; Hesse V; Gorlich Y; Straube S. Somatic classification of neonates based on birth weight, length, and head circumference: quantification of the effects of maternal BMI and smoking. Journal of Perinatal Medicine 39(3): 291- 297, 2011. (30 refs.)

We defined neonates as small, appropriate, or large for gestational age (SGA, AGA, LGA) based on birth weight, length, and head circumference. We analyzed the effects on the somatic classification of maternal body mass index (BMI) (< 18.5, 18.5-24.99, 25.0-29.99, >= 30) and smoking during pregnancy (0, 1-7, 8-14, >= 15 cigarettes daily). Data were from the German Perinatal Survey (1998-2000; 433,669 cases). The following refers to the classification by birth weight. In the normal maternal weight population SGA rates increased with cigarette consumption: 9.8%, 17.8%, 21.6%, and 25.4% for non-smokers, and smokers of 1-7, 8-14, and >= 15 cigarettes daily, respectively. In non-smoking underweight women the SGA rate was 17.4%. In underweight smokers of >= 15 cigarettes daily the SGA rate was 38.5% [odds ratio 5.77, 95% confidence interval 5.10-6.53, compared with normal weight non-smokers]. In the normal maternal weight population, LGA rates were 9.9%, 5.3%, 4.6%, and 3.5% for non-smokers, and smokers of 1-7, 8-14, and >= 15 cigarettes daily, respectively. In the obese, LGA rates were 20.9% (non-smokers) and 11.4% (>= 15 cigarettes). Similar findings were obtained for the somatic classifications based on birth length and head circumference. Results for the various combinations of maternal BMI and smoking status in the three classification systems are described. Our findings may assist in individualized risk assessment for SGA and LGA births.

Wehby GL; Fletcher JM; Lehrer SF; Moreno LM; Murray JC; Wilcox A; Lie RT. A genetics instrumental variables analysis of the effects of prenatal smoking on birth weight: Evidence from two samples. Biodemography and Social Biology 57(1, special issue): 3- 32, 2011. (73 refs.)

There is a large literature showing the detrimental effects of prenatal smoking on birth and childhood health outcomes. It is somewhat unclear, though, whether these effects are causal or reflect other characteristics and choices by mothers who choose to smoke that may also affect child health outcomes or biased reporting of smoking. In this paper, we use genetic markers that predict smoking behaviors as instruments to address the endogeneity of smoking choices in the production of birth and childhood health outcomes. Our results indicate that prenatal smoking produces more dramatic declines in birth weight than estimates that ignore the endogeneity of prenatal smoking, which is consistent with previous studies with non-genetic instruments. We use data from two distinct samples from Norway and the United States with different measured instruments and find nearly identical results. The study provides a novel application that can be extended to study several behavioral impacts on health and social and economic outcomes.

Wen XZ; Triche EW; Hogan JW; Shenassa ED; Buka SL. Birth weight and adult hypercholesterolemia subgroups of small-for-gestational-age based on maternal smoking status during pregnancy. Epidemiology 21(6): 786-790, 2010. (20 refs.)

Background: Being born small-for-gestational-age (SGA) is associated with hypercholesterolemia in later life. It is possible that only certain subgroups of SGA are at elevated risk for hypercholesterolemia. We examined the associations between SGA subgroups based on levels of maternal smoking during pregnancy and adult hypercholesterolemia. Methods: A subsample of 1625 adult offspring from the Collaborative Perinatal Project were followed at mean age 39 years. Subjects were classified by recorded fetal growth and maternal smoking status during pregnancy. Clinical diagnosis of hypercholesterolemia was obtained in interviews. Results: Compared with the appropriate-for-gestational-age subgroup without maternal smoking during pregnancy, only SGA subgroups with maternal smoking during pregnancy had higher risk of hypercholesterolemia: for heavy smoking, adjusted hazard ratio = 2.5 (95% confidence interval = 1.4- 4.3); moderate smoking, 1.7 (1.0-2.8); nonsmoking, 1.1 (0.5-2.1). Conclusion: Only SGA infants whose mothers smoked during pregnancy had elevated risk of hypercholesterolemia in adulthood.

Wikstrom AK; Cnattingius S; Stephansson O. Maternal use of Swedish snuff (Snus) and risk of stillbirth. Epidemiology 21(6): 772-778, 2010. (32 refs.)

Background: Swedish snuff has been discussed internationally as a safer alternative to tobacco smoking. International cigarette manufacturers are promoting new snuff products, and the use of Swedish snuff is increasing, especially among women of childbearing age. The effect of Swedish snuff on pregnancy complications is unknown. Methods: In this population-based cohort study, we estimated the risk of stillbirth in snuff users (n = 7629), light smokers (1-9 cigarettes/day; n = 41,488), and heavy smokers (>= 10 cigarettes/day; n = 17,014), using nontobacco users (n = 504,531) as reference. Results: Compared with nontobacco users, snuff users had an increased risk of stillbirth (adjusted odds ratio = 1.6 [95% confidence interval = 1.1-2.3]); the risk was higher for preterm (<37 weeks) stillbirth (2.1 [1.3-3.4]). For light smokers, the adjusted odds ratio of stillbirth was 1.4 (1.2-1.7) and the corresponding risk for heavy smokers was 2.4 (2.0-3.0). When we excluded women with preeclampsia or antenatal bleeding and infants who were small for gestational age, the smoking-related risks of stillbirth was markedly attenuated; the elevated risk for snuff users remained the same level. Conclusions: Use of Swedish snuff during pregnancy was associated with a higher risk of stillbirth. The mechanism behind this increased risk seems to differ from the underlying mechanism in smokers. Swedish snuff does not appear to be a safe alternative to cigarette smoking during pregnancy.

Yalcin SS; Orun E; Mutlu B; Madendag Y; Sinici I; Dursun A et al. Why are they having infant colic? A nested case-control study. Paediatric and Perinatal Epidemiology 24(6): 584-596, 2010. (48 refs.)

We aimed to analyse infant (birth characteristics, feeding type, faecal enzyme activities) and environmental (maternal smoking, nutrition and psychological status, mother-child bonding, family structure, support for the mother, familial atopy) risk factors for infant colic and to follow infants with respect to physical growth, sleeping status up to 8 months of age in a nested case-control study. 660 mothers who delivered at Dr Zekai Tahir Burak Maternity Hospital, were enrolled within 3-72 h post delivery. Each infant with inconsolable persistent crying and four matched infants with no crying episodes were invited by phone to Hacettepe University Ihsan Doramaci Children's Hospital at 30-45 days post partum. At 40-55 days, we examined the infants and gave mothers a questionnaire, including crying characteristics of the infants; 47 infants were diagnosed with colic and 142 as non-colic. When the infants were 7-8 months old, another interview was done. The colic group had higher proportions of less-educated (< 8 years) and smoking mothers, extended family and families with domestic violence than the non-colic group. The colic group of mothers had significantly higher rates of 'impaired bonding' in the Postpartum Bonding Questionnaire, higher scores on the Edinburgh Postnatal Depression Scale, higher scores for hostility subscales of the Brief Symptom Inventory and a more irregular sleep pattern than the non-colic group. No differences were revealed for faecal enzyme activities. At 7-8 months, the colic group was shorter than the non-colic group. Colic was associated with various perinatal factors (maternal education, smoking habits, cheese consumption, hostility scores and domestic violence) and having colic in infancy negatively affected the sleeping pattern and the height of the infant.