Exogenous oxytocin administration during labor and autism spectrum disorder.

BACKGROUND: Oxytocin is a neuropeptide hormone that plays a key role in social behavior, stress regulation, and mental health. Synthetic oxytocin administration is a common obstetrical practice, and importantly, previous research has suggested that intrapartum exposure may increase the risk of neurodevelopmental disorders, such as autism spectrum disorder. OBJECTIVE: This study aimed to examine the association between synthetic oxytocin exposure during labor and autism spectrum disorder diagnosis in the child. STUDY DESIGN: This population-based retrospective cohort study compared 2 cohorts of children: (1) all children born in British Columbia, Canada between April 1, 2000 and December 31, 2014 (n=414,336 births), and (2) all children delivered at Soroka University Medical Center in Be'er-Sheva, Israel between January 1, 2011 and December 31, 2019 (n=82,892 births). Nine different exposure groups were examined. Cox proportional hazards models were used to estimate crude and adjusted hazard ratios of autism spectrum disorder in both cohorts on the basis of induction and/or augmentation exposure status. To further control for confounding by indication, we conducted sensitivity analyses among a cohort of healthy, uncomplicated deliveries and among a group that was induced only for postdates. In addition, we stratified our analyses by infant sex to assess for potential sex differences. RESULTS: In the British Columbia cohort, 170,013 of 414,336 deliveries (41.0%) were not induced or augmented, 107,543 (26.0%) were exposed to oxytocin, and 136,780 (33.0%) were induced or augmented but not exposed to oxytocin. In the Israel cohort, 51,790 of 82,892 deliveries (62.5%) were not induced or augmented, 28,852 (34.8%) were exposed to oxytocin, and 2250 (2.7%) were induced or augmented but not exposed to oxytocin. On adjusting for covariates in the main analysis, significant associations were observed in the Israel cohort, including adjusted hazard ratios of 1.51 (95% confidence interval, 1.20-1.90) for oxytocin-augmented births and 2.18 (95% confidence interval, 1.32-3.57) for those induced by means other than oxytocin and not augmented. However, oxytocin induction was not significantly associated with autism spectrum disorder in the Israel cohort. In the Canadian cohort, there were no statistically significant adjusted hazard ratios. Further, no significant sex differences were observed in the fully adjusted models. CONCLUSION: This study supports that induction of labor through oxytocin administration does not increase the risk of autism spectrum disorder in the child. Our international comparison of 2 countries with differences in clinical practice regarding oxytocin administration for induction and/or augmentation suggests that previous studies reporting a significant association were likely confounded by the underlying indication for the induction.

Association between prenatal antibiotic exposure and autism spectrum disorder among term births: A population-based cohort study.

BACKGROUND: Prenatal antibiotic exposure induces changes in the maternal microbiome, which could influence the development of the infant's microbiome-gut-brain axis. OBJECTIVES: We assessed whether prenatal antibiotic exposure is associated with an increased risk of autism spectrum disorder (ASD) in offspring born at term. METHODS: This population-based retrospective cohort study included everyone who delivered a live singleton-term infant in British Columbia, Canada between April 2000 and December 2014. Exposure was defined as filling antibiotic prescriptions during pregnancy. The outcome was an ASD diagnosis from the British Columbia Autism Assessment Network, with a follow-up to December 2016. To examine the association among pregnant individuals treated for the same indication, we studied a sub-cohort diagnosed with urinary tract infections. Cox proportional hazards models were used to estimate unadjusted and adjusted hazard ratios (HR). The analysis was stratified by sex, trimester, cumulative duration of exposure, class of antibiotic, and mode of delivery. We ran a conditional logistic regression of discordant sibling pairs to control for unmeasured environmental and genetic confounding. RESULTS: Of the 569,953 children included in the cohort, 8729 were diagnosed with ASD (1.5%) and 169,922 were exposed to prenatal antibiotics (29.8%). Prenatal antibiotic exposure was associated with an increased risk of ASD (HR 1.10, 95% confidence interval [CI] 1.05, 1.15), particularly for exposure during the first and second trimesters (HR 1.11, 95% CI 1.04, 1.18 and HR 1.09, 95% CI 1.03, 1.16, respectively), and exposure lasting ≥15 days (HR 1.13, 95% CI 1.04, 1.23). No sex differences were observed. The association was attenuated in the sibling analysis (adjusted odds ratio 1.04, 95% CI 0.92, 1.17). CONCLUSIONS: Prenatal antibiotic exposure was associated with a small increase in the risk of ASD in offspring. Given the possibility of residual confounding, these results should not influence clinical decisions regarding antibiotic use during pregnancy.

Autism Risk and Perinatal Antibiotic Use.

OBJECTIVES: Antibiotics are commonly administered during labor and delivery, and research has suggested that fetal exposure to antibiotics can increase risk for autism spectrum disorder (ASD). We assessed whether antibiotic exposure during labor and delivery increased the risk of ASD in the offspring. METHODS: This retrospective cohort study included everyone who delivered a live singleton-term infant in British Columbia, Canada, between April 1, 2000, and December 31, 2014. This cohort included 569 953 deliveries. To examine the association among pregnant individuals being treated for the same indication, we studied a subcohort of those who tested positive for group B Streptococcus. Cox proportional hazards models were used to estimate unadjusted and adjusted hazard ratios in both cohorts. A sensitivity analysis was conducted using length of first stage of labor as a proxy measure for dose to assess for a dose-response relationship. RESULTS: In this population-based study, antibiotic use during labor and delivery was not associated with an increased risk of ASD in offspring. The unadjusted and adjusted hazard ratios were 1.29 (95% confidence interval, 1.24-1.35) and 0.99 (0.94-1.04), respectively; and 1.07 (0.90-1.27) and 0.88 (0.74-1.05), respectively, in the group B Streptococcus-positive cohort. We observed no substantial difference in the association between antibiotic exposure and ASD depending on length of the first stage of labor. CONCLUSIONS: Our findings suggest that concern for ASD should not factor into the clinical decision on whether to administer antibiotics during labor and delivery. Future research is needed to examine longer durations of prenatal antibiotic exposure.

The association between prenatal greenspace exposure and Autism spectrum disorder, and the potentially mediating role of air pollution reduction: A population-based birth cohort study.

BACKGROUND: Autism spectrum disorder (ASD) incidence has increased in past decades. ASD etiology remains inconclusive, but research suggests genetic, epigenetic, and environmental contributing factors and likely prenatal origins. Few studies have examined modifiable environmental risk factors for ASD, and far fewer have examined protective exposures. Greenspace has been associated with positive child development, but very limited greenspace research has examined ASD risk or prenatal exposures. Only one ecological study in 2017 has evaluated the association between greenspace and ASD, observing protective benefits. Greenspace may have direct effects on ASD risk and indirect effects by reducing air pollution exposure, a growing suspected ASD risk factor. OBJECTIVES: To measure the association between prenatal greenspace exposure and ASD risk and examine if reduced air pollution levels in areas of higher greenspace mediate this association. METHODS: We linked a population-based birth cohort of all deliveries in Metro Vancouver, Canada, from 2004 to 2009, with follow-up to 2014. Diagnoses were based on Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised instruments. Greenspace was quantified as the average of the annual mean Normalized Difference Vegetation Index (NDVI) within a 250 m buffer of a residential postal code. Air pollutant exposures-particulate matter with a diameter less than 2.5 µm (PM2.5), nitric oxide (NO), and nitrogen dioxide (NO2)-were derived from previously developed and temporally adjusted land use regression models. We estimated air pollutant exposures as the mean concentration per month during pregnancy. We calculated odds ratios (ORs) using logistic regression per NDVI interquartile range (IQR) increase, adjusting for child sex, birth month and year, maternal age and birthplace, and neighborhood-level urbanicity and income. To estimate the health impact of greenspace on ASD at the population level, we used the logistic regression model and marginal standardization to derive risk differences (RDs). Lastly, to quantify the mediating effect of greenspace on ASD risk through air pollution reduction, we used marginal structural models and a potential outcomes framework to calculate marginal risk differences (RDs) to decompose the total effect of greenspace on ASD into natural direct and indirect effects. RESULTS: Of 129,222 births, 1,921 (1.5 %) children were diagnosed with ASD. The adjusted OR for ASD per NDVI IQR (0.12) increase was 0.96 (95 % CI: 0.90, 1.02) in 250 m buffer zones and 0.94 (95 % CI: 0.89, 1.00) in 100 m buffer zones. On the additive scale, the adjusted RDs were null. Natural direct, natural indirect, and total effect RDs were null for PM2.5, NO, and NO2 mediation models. CONCLUSION: Prenatal greenspace exposure was associated with reduced odds of ASD, but in the additive scale, this effect was null at the population level. No mediating effect was observed through reduced air pollution, suggesting that air pollution may act as a confounder rather than as a mediator.

Appraising the need for audiological assessment before autism spectrum disorder referral.

Objectives: Mandatory audiological testing before autism spectrum disorder (ASD) assessment is common practice. Hearing impairment (HI) in the general paediatric population is estimated at 3%; however, hearing impairment prevalence among children with ASD is poorly established. Our objective was to determine which children referred for ASD assessment require preliminary audiological assessment. Methods: Retrospective chart review of children (n=4,173; 0 to 19 years) referred to British Columbia's Autism Assessment Network (2010 to 2014). We analyzed HI rate, risk factors, and timing of HI diagnosis relative to ASD referral. Results: ASD was diagnosed in 53.4%. HI rates among ASD referrals was 3.3% and not significantly higher in children with ASD (ASD+; 3.5%) versus No-ASD (3.0%). No significant differences in HI severity or type were found, but more ASD+ females (5.5%) than ASD+ males (3.1%) had HI (P<0.05). Six HI risk factors were significant (problems with intellect, language, vision/eye, ear, genetic abnormalities, and prematurity) and HI was associated with more risk factors (P<0.01). Only 12 children (8.9%) were diagnosed with HI after ASD referral; all males 6 years or younger and only one had no risk factors. ASD+ children with HI were older at ASD referral than No-ASD (P<0.05). Conclusions: Children with ASD have similar hearing impairment rates to those without ASD. HI may delay referral for ASD assessment. As most children were diagnosed with HI before ASD referral or had at least one risk factor, we suggest that routine testing for HI among ASD referrals should only be required for children with risk factors.

Association of Epidural Analgesia During Labor and Delivery With Autism Spectrum Disorder in Offspring.

Importance: Evidence from studies investigating the association of epidural analgesia use during labor and delivery with risk of autism spectrum disorder (ASD) in offspring is conflicting. Objective: To assess the association of maternal use of epidural analgesia during labor and delivery with ASD in offspring using a large population-based data set with clinical data on ASD case status. Design, Setting, and Participants: This population-based retrospective cohort study included term singleton children born in British Columbia, Canada, between April 1, 2000, and December 31, 2014. Stillbirths and cesarean deliveries were excluded. Clinical ASD diagnostic data were obtained from the British Columbia Autism Assessment Network and the British Columbia Ministry of Education. All children were followed up until clinical diagnosis of ASD, death, or the study end date of December 31, 2016. Exposures: Use of epidural analgesia during labor and delivery. Main Outcomes and Measures: A clinical diagnosis of ASD made by pediatricians, psychiatrists, and psychologists with specialty training to assess ASD. Cox proportional hazards models were used to estimate the hazard ratio of epidural analgesia use and ASD. Models were adjusted for maternal sociodemographics; maternal conditions during pregnancy; labor, delivery, and antenatal care characteristics; infant sex; gestational age; and status of small or large for gestational age. A conditional logistic regression model matching women with 2 births or more and discordance in ASD status of the offspring also was performed. Results: Of the 388 254 children included in the cohort (49.8% female; mean gestational age, 39.2 [SD, 1.2] weeks; mean follow-up, 9.05 [SD, 4.3] years), 5192 were diagnosed with ASD (1.34%) and 111 480 (28.7%) were exposed to epidural analgesia. A diagnosis of ASD was made for 1710 children (1.53%) among the 111 480 deliveries exposed to epidural analgesia (94 157 women) vs a diagnosis of ASD in 3482 children (1.26%) among the 276 774 deliveries not exposed to epidural analgesia (192 510 women) (absolute risk difference, 0.28% [95% CI, 0.19%-0.36%]). The unadjusted hazard ratio was 1.32 (95% CI, 1.24-1.40) and the fully adjusted hazard ratio was 1.09 (95% CI, 1.00-1.15). There was no statistically significant association of epidural analgesia use during labor and delivery with ASD in the within-woman matched conditional logistic regression (839/1659 [50.6%] in the exposed group vs 1905/4587 [41.5%] in the unexposed group; fully adjusted hazard ratio, 1.07 [95% CI, 0.87-1.30]). Conclusions and Relevance: In this population-based study, maternal epidural analgesia use during labor and delivery was associated with a small increase in the risk of autism spectrum disorder in offspring that met the threshold for statistical significance. However, given the likelihood of residual confounding that may account for the results, these findings do not provide strong supporting evidence for this association.

Baclofen Toxicity in Children With Acute Kidney Injury: Case Reports and Review of the Literature.

Baclofen is a medication used for tone management in cerebral palsy. Although it acts mainly at the spinal cord level, it can cause central nervous system adverse reactions at higher doses. Baclofen is mainly eliminated by renal excretion and there have been reports on adverse events when used in adults with renal impairment; however, there are no consensus guidelines as to the dose adjustments required due to renal impairment. The authors describe 2 children with acute kidney injury (AKI) and systemic side effects with initiation of oral baclofen, which was started for treatment of dystonia/spasticity in the recovery phase of their kidney injury. Following the initiation of the drug, they both had decreased level of consciousness and respiratory difficulties, which warranted discontinuation of the drug. These cases highlight the need for reduced initial dose, slow titration, and close monitoring when initiating baclofen treatment in children with AKI.

Identification of Pediatric Autism Spectrum Disorder Cases Using Health Administrative Data.

Administrative data are frequently used to identify Autism Spectrum Disorder (ASD) cases in epidemiological studies. However, validation studies on this mode of case ascertainment have lacked access to high-quality clinical diagnostic data and have not followed published reporting guidelines. We report on the diagnostic accuracy of using readily available health administrative data for pediatric ASD case ascertainment. The validation cohort included almost all the ASD-positive children born in British Columbia, Canada from April 1, 2000 to December 31, 2009 and consisted of 8,670 children in total. 4,079 ASD-positive and 2,787 ASD-negative children were identified using Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADI-R) assessments done through the British Columbia Autism Assessment Network (BCAAN). An additional 1,804 ADOS/ADI-R assessed ASD-positive children were identified using Ministry of Education records. This prospectively collected clinical data (the diagnostic gold standard) was then linked to each child's physician billing and hospital discharge data. The diagnostic accuracy of 11 algorithms that used the administrative data to assign ASD case status was assessed. For all algorithms, high positive predictive values (PPVs) were observed alongside low values for other measures of diagnostic accuracy illustrating that PPVs alone are not an adequate measure of diagnostic accuracy. We show that British Columbia's health administrative data cannot reliably be used to discriminate between children with ASD and children with other developmental disorders. Utilizing these data may result in misclassification bias. Methodologically sound, region-specific validation studies are needed to support the use of administrative data for ASD case ascertainment. Autism Res 2020, 13: 456-463. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Health administrative data are frequently used to identify Autism Spectrum Disorder (ASD) cases for research purposes. However, previous validation studies on this sort of case identification have lacked access to high-quality clinical diagnostic data and have not followed published reporting guidelines. We show that British Columbia's health administrative data cannot reliably be used to discriminate between children with ASD and children with other developmental disorders.

Association of Prenatal Exposure to Air Pollution With Autism Spectrum Disorder.

Importance: The etiology of autism spectrum disorder (ASD) is poorly understood, but prior studies suggest associations with airborne pollutants. Objective: To evaluate the association between prenatal exposures to airborne pollutants and ASD in a large population-based cohort. Design, Setting, and Participants: This population-based cohort encompassed nearly all births in Metro Vancouver, British Columbia, Canada, from 2004 through 2009, with follow-up through 2014. Children were diagnosed with ASD using a standardized assessment with the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. Monthly mean exposures to particulate matter with a diameter less than 2.5 µm (PM2.5), nitric oxide (NO), and nitrogen dioxide (NO2) at the maternal residence during pregnancy were estimated with temporally adjusted, high-resolution land use regression models. The association between prenatal air pollution exposures and the odds of developing ASD was evaluated using logistic regression adjusted for child sex, birth month, birth year, maternal age, maternal birthplace, and neighborhood-level urbanicity and income band. Data analysis occurred from June 2016 to May 2018. Exposures: Mean monthly concentrations of ambient PM2.5, NO, and NO2 at the maternal residence during pregnancy, calculated retrospectively using temporally adjusted, high-resolution land use regression models. Main Outcomes and Measures: Autism spectrum disorder diagnoses based on standardized assessment of the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. The hypothesis being tested was formulated during data collection. Results: In a cohort of 132 256 births, 1307 children (1.0%) were diagnosed with ASD by the age of 5 years. The final sample size for the PM2.5-adjusted model was 129 439 children, and for NO and NO2, it was 129 436 children; of these, 1276 (1.0%) were diagnosed with ASD. Adjusted odds ratios for ASD per interquartile range (IQR) were not significant for exposure to PM2.5 during pregnancy (1.04 [95% CI, 0.98-1.10] per 1.5 µg/m3 increase [IQR] in PM2.5) or NO2 (1.06 [95% CI, 0.99-1.12] per 4.8 ppb [IQR] increase in NO2) but the odds ratio was significant for NO (1.07 [95% CI, 1.01-1.13] per 10.7 ppb [IQR] increase in NO). Odds ratios for male children were 1.04 (95% CI, 0.98-1.10) for PM2.5; 1.09 (95% CI, 1.02-1.15) for NO; and 1.07 (95% CI, 1.00-1.13) for NO2. For female children, they were for 1.03 (95% CI, 0.90-1.18) for PM2.5; 0.98 (95% CI, 0.83-1.13) for NO; and 1.00 (95% CI, 0.86-1.16) for NO2. Conclusions and Relevance: In a population-based birth cohort, we detected an association between exposure to NO and ASD but no significant association with PM2.5 and NO2.

Parental responses to infant crying and colic: the effect on breastfeeding duration.

CONTEXT: Infant crying can cause parental distress, and colic is associated with low maternal self-efficacy and heightened risk for depression. Breastfeeding is recognized as an effective method of calming infants, but the relationship of colic and the use of breastfeeding to remedy infant crying have not been tested for any effects on breastfeeding duration. OBJECTIVE: To evaluate the effects of infant colic (colic analysis) and breastfeeding as a method of infant calming (calming analysis) on breastfeeding duration. DESIGN: The authors followed 700 healthy breastfeeding mother-baby dyads from birth to 1 year. Maternal interviews were conducted postpartum, and at 2, 5, 10, 16, 24, 38, and 52 weeks to ascertain demographic factors, infant crying patterns, comforting practices, physician-diagnosed colic, and breastfeeding behaviors. Cox survival analyses were used to evaluate the independent effects of: (a) physician diagnosed colic; and (b) breastfeeding as a comforting practice on breastfeeding duration. Data from all 700 breastfeeding dyads were used in the colic analyses. In the calming analyses, to assure that breastfeeding was appropriately established, data were used from the 617 couplets that had breastfed for at least 2 weeks. Using a stepwise process, models, adjusted for typical predictors of breastfeeding duration, were developed for exclusive, full and partial breastfeeding duration. Variables of interest (i.e., colic diagnosis, breastfeeding for comfort) were then forced into the baseline models to determine any independent effects. RESULTS: In the first 16 weeks, parents found that holding (87%), breastfeeding (82%), walking (67%), and rocking (63%) were highly effective calming practices. Mothers who rated breastfeeding as highly effective had a higher frequency of breastfeeding at all contacts (p < 0.05). In adjusted analyses the use of breastfeeding to comfort infants was a significant predictor of longer partial (overall) ([hazard ratio] HR = 0.6, 95% CI 0.4 to 0.9; p = 0.02) but not exclusive or full breastfeeding duration. By 6 months, 44 mothers (6.3%) reported a diagnosis of colic. Mothers of infants with a diagnosis of colic were less likely to report breastfeeding as effective method of infant comforting (p = 0.03). In adjusted analyses the authors found that a diagnosis of colic predicted shorter full breastfeeding duration (HR = 2.4, 95% CI 1.4 to 4.2; p = 0.001) but not exclusive or partial duration. CONCLUSIONS: Breastfeeding to comfort a crying infant is a strong predictor of partial (overall) duration and is rated as a highly effective calming method by parents. These data suggest that parents may benefit from education about normal infant crying patterns and effective methods of infant comforting, including breastfeeding. However, mothers of infants diagnosed with colic are at risk for shortened duration of full breastfeeding. Although the reasons for this are unclear, it may be helpful to specifically address the subject of colic and infant feeding and encourage mothers to fully breastfeed for the recommended 6 months.

Pediatric faculty members' attitudes about part-time faculty positions and policies to support part-time faculty: a study at one medical center.

PURPOSE: To examine pediatric faculty members' attitudes about part-time faculty positions and policies to support part-time faculty. METHOD: In 2001, an anonymous 26-item questionnaire assessing attitudes about part-time faculty was mailed to all 441 faculty members of Cincinnati Children's Hospital Medical Center. Multivariable analyses were used to determine faculty characteristics associated with specific attitudes, and qualitative methods were used to analyze responses to an open-ended item assessing beliefs about facilitating part-time careers. RESULTS: Three hundred (68%) faculty members completed questionnaires. Twenty-nine (10%) worked part-time and an additional 88 (33%) had considered part-time work, primarily because of dependent children. Although 177 (59%) believed that part-time faculty were perceived as being less committed to their careers and the institution, 207 (69%) believed part-time faculty should be eligible for all academic tracks and 219 (73%) that they should be allowed extension of time to obtain tenure. Most reported that policy changes to support part-time faculty would enhance diversity (N = 234, 78%) and improve recruitment, retention, and promotion of female faculty. Multivariable analysis demonstrated that women and respondents with dependent children were more likely to be concerned about perceived commitment and more likely to endorse policies to support part-time faculty. Participants suggested that part-time careers for faculty would be facilitated by clarifying productivity expectations, expanding resources, and modifying existing policies. CONCLUSIONS: Although women and respondents with dependent children were concerned about perceived commitment of part-time faculty and were most supportive of policies that would support part-time faculty, pediatric faculty generally supported such policies.

Rubinstein-Taybi syndrome medical guidelines.

Children and adults with Rubinstein-Taybi Syndrome have specific medical conditions that occur with greater frequency than the general population. Based on the available information from the literature and clinical experience, recommendations for specific surveillance and interventions are made to guide those clinicians caring for individuals with Rubinstein-Taybi Syndrome. This is a first attempt at medical guidelines for individuals with RTS in the United States. On-going research is needed in many areas to guide decisions in medical care and allow for refinement of these medical guidelines.