Agreement Between Self-reports and Urine Toxicology Measures of Illicit Methamphetamine and Cocaine Use During Early Pregnancy.

OBJECTIVE: This study aimed to assess agreement between self-report and urine toxicology measures assessing use of 2 illicit simulants (methamphetamine and cocaine) during early pregnancy. METHODS: This cross-sectional study of 203,053 pregnancies from 169,709 individuals receiving prenatal care at Kaiser Permanente Northern California between January 1, 2011, and December 31, 2019, assessed agreement ( κ , sensitivity, and specificity) between self-reported frequency and urine toxicology measures of methamphetamine and cocaine early in pregnancy. RESULTS: Prenatal use of the illicit stimulants was rare according to toxicology (n = 244 [0.12%]) and self-report measures (n = 294 [0.14%]). Agreement between these measures was low ( κ < 0.20). Of the 498 positive pregnancies, 40 (8.03%) screened positive on both measures, 204 (40.96%) screened positive on toxicology tests only, and 254 (51.00%) screened positive by self-report only. Relative to toxicology tests, sensitivity of any self-reported use was poor with 16.39% (95% confidence interval [CI], 11.75%-21.04%) of pregnancies with a positive toxicology test self-reporting any use in pregnancy. Relative to self-report, sensitivity of toxicology tests was also poor with 13.61% (95% CI, 9.69%-17.52%) of pregnancies who self-reported any use having positive urine toxicology tests. The sensitivity improved slightly at higher frequencies of self-reported use: daily, 17.50% (95% CI, 5.72%-29.29%); weekly, 25.00% (95% CI, 11.58%-38.42%); and monthly or less, 11.06% (95% CI, 6.89%-15.23%). Specificity was high (>99%), reflecting the high negative rate of use. CONCLUSIONS: Findings suggest that using self-report and toxicology measures in combination likely provides the most accurate information on methamphetamine and cocaine use in early pregnancy. Findings also highlight the need to provide supportive nonstigmatizing environments in which pregnant individuals feel comfortable disclosing substance use without fear of punishment.

Patterns of Substance Use During Early Pregnancy and Associations With Behavioral Health Characteristics.

OBJECTIVES: The aims of the study are to identify patterns of early pregnancy substance use and to examine how these patterns relate to behavioral health conditions measured in early pregnancy. METHODS: We conducted a retrospective observational study (N= 265,274 pregnancies) screened for alcohol, cannabis, nicotine, pharmaceutical opioids, and stimulants during the first trimester via self-report and urine toxicology tests in Kaiser Permanente Northern California from January 1, 2012, to December 31, 2019. To identify patterns of prenatal substance use, we conducted latent class analysis. We then calculated the prevalence of depression, anxiety, intimate partner violence, and family drug use history for each prenatal substance use group and compared the prevalences by estimating prevalence ratios using modified Poisson regression, adjusting for sociodemographic characteristics. RESULTS: We identified the following 4 latent groups with different patterns of substance use: ( a ) predominantly alcohol and no other substances (9.30%), ( b ) predominantly cannabis and no other substances (4.88%), ( c ) predominantly nicotine and some pharmaceutical opioids (1.09%), and ( d ) high-polysubstance (alcohol, cannabis, nicotine, and stimulants; 0.36%); these pregnancies were compared with ( e ) no prenatal substance use (84.37%). The prevalence of all behavioral health conditions was elevated in all prenatal substance use groups compared with the no substance use group. Furthermore, the prevalence of depressive and anxiety disorders, intimate partner violence and family drug use history were greater in the high-polysubstance cluster than the alcohol and cannabis clusters. CONCLUSIONS: Results highlight the importance of screening and interventions for all types of substance use during early pregnancy and suggest a particularly high need to prioritize targeting early interventions to pregnant and reproductive age individuals with polysubstance use.

A systematic review of in utero cannabis exposure and risk for structural birth defects.

Introduction: Cannabis use among pregnant women has increased over time. Therefore, there is a great public health need to understand the consequences of in utero cannabis exposure. While several meta-analyses and reviews have summarized the evidence of in utero cannabis exposure on adverse obstetric outcomes (e.g., low birth weight and preterm birth) and long-term offspring development, there has not been a focus on in utero cannabis exposure and risk for structural birth defects. Methods: We conducted a systematic review using PRISMA guidelines to evaluate the association between in utero cannabis exposure and structural birth defects. Results: We identified 20 articles to include in our review and focused on interpreting findings from the 12 that adjusted for potential confounders. We report findings by seven organ systems. Within the 12 articles, four reported on cardiac malformations, three reported on central nervous system malformations, one reported on eye malformations, three reported on gastrointestinal malformations, one reported on genitourinary malformations, one reported on musculoskeletal malformations, and two reported on orofacial malformations. Discussion: Findings on associations between in utero cannabis exposure and birth defects reported in more than two articles were mixed (i.e., findings for cardiac, gastrointestinal, central nervous system malformations). Findings for associations between in utero cannabis exposure and birth defects reported in two articles (i.e., orofacial malformations) or in a single article (eye, genitourinary, and musculoskeletal) suggested that cannabis exposure was not associated with these types of malformations, but strong conclusions cannot be drawn from such sparce research. We review the limitations and gaps in the existing literature and call for more research to rigorously evaluate associations between in utero cannabis exposure and structural birth defects. Systematic Review Registration: identifier CRD42022308130.

Racial and ethnic differences in perinatal depression and anxiety.

BACKGROUND: Findings on racial and ethnic differences in perinatal depression/anxiety are mixed. METHODS: We assessed racial and ethnic differences in depression, anxiety, and comorbid depression/anxiety diagnoses in the year before, during, and the year after pregnancy (n = 116,449) and depression severity during (n = 72,475) and in the year after (n = 71,243) pregnancy among patients in a large, integrated healthcare delivery system. RESULTS: Compared to Non-Hispanic White individuals, Asian individuals had lower risk of perinatal depression and anxiety (e.g., depression during pregnancy relative risk [RR] = 0.35, 95 % confidence interval [CI]:0.33-0.38) and postpartum moderate/severe (RR = 0.63, 95 % CI:0.60-0.67) and severe (RR = 0.66, 95 CI:0.61-0.71) depression but higher risk of moderate/severe depression during pregnancy (RR = 1.18, 95 % CI:1.11-1.25). Non-Hispanic Black individuals had higher risk of perinatal depression, comorbid depression/anxiety, and moderate/severe and severe depression (e.g., depression diagnoses during pregnancy RR = 1.35, 95 % CI:1.26-1.44). Hispanic individuals had lower risk of depression during pregnancy and perinatal anxiety (e.g., depression during pregnancy RR = 0.86, 95 % CI:0.82-0.90) but higher risk of postpartum depression (RR = 1.14, 95 % CI:1.09-1.20) and moderate/severe and severe depression during and after pregnancy (e.g., severe depression during pregnancy RR = 1.59, 95 % CI:1.45-1.75). LIMITATIONS: Information on depression severity was unavailable for some pregnancies. Findings may not generalize to individuals without insurance or outside of Northern California. CONCLUSIONS: Non-Hispanic Black individuals of reproductive age should be targeted with prevention and intervention efforts aimed at reducing and treating depression and anxiety. Asian and Hispanic individuals of reproductive age should be targeted with campaigns to destigmatize mental health disorders and demystify treatments and systematically screened for depression/anxiety.

Association of serum folate levels during pregnancy and prenatal depression.

OBJECTIVE: To evaluate the association between serum folate levels during pregnancy and prenatal depression and the extent to which obesity may modify this relationship. METHODS: This secondary data analysis leveraged data from a previous study of pregnant Kaiser Permanente Northern California participants who completed a survey and provided a serum sample between 2011 and 2013. Serum folate was assessed using the Center for Disease Control's Total Folate Serum/Whole Blood Microbiological Assay Method. A score of 15 or greater on the Center for Epidemiologic Studies Depression Scale was defined as prenatal depression. We used Poisson regression to estimate risk of prenatal depression given prenatal serum folate status (low/medium tertiles vs. high tertile) in the full sample and in subsamples of women with pre-pregnancy body mass index in the (a) normal range and (b) overweight/obese range. RESULTS: Of the sample, 13% had prenatal depression. Combined low/medium folate tertiles was associated with prenatal depression (adjusted relative risk [aRR] = 1.97, 95% confidence interval [CI]: 0.93-4.18), although results did not reach statistical significance. This relationship was stronger among women with overweight/obesity than women with normal weight (aRR: 2.61, 95% CI: 1.01-6.71 and aRR: 1.50, 95% CI: 0.34-6.66, respectively). CONCLUSION: Results suggest an association between lower pregnancy folate levels and prenatal depression that may be stronger among women with overweight or obesity. Future studies need to clarify the temporal sequence of these associations.

In-utero cannabis exposure and long-term psychiatric and neurodevelopmental outcomes: The limitations of existing literature and recommendations for future research.

Given increases in cannabis use in pregnancy and animal model research showing effects of in-utero cannabis exposure, high-quality information on long-term consequences of in-utero cannabis exposure in humans is needed. While reviews have summarized findings from observational studies with humans, reviews have not focused on limitations of these studies and recommendations for future research. Therefore, we critically reviewed observational research on in-utero cannabis exposure and psychiatric and neurodevelopmental outcomes measured at or after age 3 and provided recommendations for future research. We used Web of Science, Google Scholar, and work cited from relevant identified publications to identify 46 papers to include in our review. Our review includes two main sections. The first section highlights the extensive limitations of the existing research, which include small and nongeneralizable samples, reliance on self-reported data, lack of detail on timing and amount of exposure, inclusion of older exposure data only, not accounting for important confounders, inclusion of potential mediators as covariates, not including outcome severity measures, and not assessing for offspring sex differences. The second section provides recommendations for future research regarding exposure and outcome measures, sample selection, confounder adjustment, and other methodological considerations. For example, with regard to exposure definition, we recommend that studies quantify the amount of cannabis exposure, evaluate the influence of timing of exposure, and incorporate biological measures (e.g., urine toxicology measures). Given that high-quality information on long-term consequences of in-utero cannabis exposure in humans does not yet exit, it is crucial for future research to address the limitations we have identified.

Initiation of Opioid Prescription and Risk of Suicidal Behavior Among Youth and Young Adults.

BACKGROUND AND OBJECTIVES: Opioids are involved in an increasing proportion of suicide deaths. This study examined the association between opioid analgesic prescription initiation and suicidal behavior among young people. METHODS: We analyzed Swedish population-register data on 1 895 984 individuals ages 9 to 29 years without prior recorded opioid prescriptions. We identified prescriptions dispensed from January 2007 onward and diagnosed self-injurious behavior and death by suicide through December 2013. We first compared initiators with demographically matched noninitiators. To account for confounding, we applied an active comparator design, which examined suicidal behavior among opioid initiators relative to prescription nonsteroidal antiinflammatory drug (NSAID) initiators while inverse-probability-of-treatment weighting with individual and familial covariates. RESULTS: Among the cohort, 201 433 individuals initiated opioid prescription. Relative to demographically matched noninitiators, initiators (N = 180 808) had more than doubled risk of incident suicidal behavior (hazard ratio = 2.64; 95% confidence interval [CI], 2.47-2.81). However, in the active comparator design, opioid initiators (N = 86 635) had only 19% relatively greater risk of suicidal behavior compared with NSAID initiators (N = 255 096; hazard ratio = 1.19; 95% CI,: 1.11-1.28), corresponding to a weighted 5-year cumulative incidence of 2.2% (95% CI, 2.1-2.4) for opioid and 1.9% (95% CI, 1.9-2.0) for NSAID initiators. Most sensitivity analyses produced comparable results. CONCLUSIONS: Opioid initiation may make only a small contribution to the elevated risk of suicidal behavior among young people receiving pharmacologic pain management. In weighing benefits and harms of opioid initiation, our results suggest that increased risk of suicidal behavior may not be a major concern.

A Nation-Wide Swedish Cohort Study on Early Maternal Age at First Childbirth and Risk for Offspring Deaths, Accidents, and Suicide Attempts.

In a sample of over one million Swedish first-born offspring, we examined associations between early maternal age at first childbirth (MAFC; i.e., < 20 and 20-24 vs 25-29 years) and offspring non-accidental deaths, accidental deaths, deaths by suicide, non-fatal accidents, and suicide attempts. We included year of birth and several maternal and paternal characteristics as covariates and conducted maternal cousin comparisons to adjust for unmeasured confounding. Early MAFC (e.g., teenage childbearing) was associated with all outcomes, with the most pronounced risk elevation for accidental deaths [Hazard Ratio (HR) < 20 2.50, 95% confidence interval (CI) 2.23, 2.80], suicides (HR < 20 2.08, 95% CI 1.79, 2.41), and suicide attempts (HR < 20 2.85, 95% CI 2.71, 3.00). Adjusting for covariates and comparing cousins greatly attenuated associations (e.g., accidental deaths HR < 20 1.61, 95% CI 1.22, 2.11; suicides HR < 20 1.01, 95% CI 0.69, 1.47; and suicide attempts HR < 20 1.35, 95% CI 1.19, 1.52). A similar pattern emerged for non-accidental deaths and non-fatal accidents. Therefore, results indicated maternal background factors may be largely responsible for observed associations.

A Clinical Trial of a Program for Pain Management and Opioid Reduction During Pregnancy.

A substantial proportion of pregnant women use prescription opioids. However, the lack of efficacy of chronic prescription opioid use for pain, combined with an increased risk of these medications in general and during pregnancy, suggests that the risks of these medications may outweigh the benefits of continued use. Though research has not evaluated non-pharmacological approaches to treat chronic pain during pregnancy, research conducted with the general population outside of pregnancy suggests that cognitive behavioral therapy (CBT) is an effective, non-pharmacological treatment. Therefore, the purpose of this study was to evaluate the effectiveness of CBT for chronic pain paired with shared decision-making for prescription opioid dose reduction among pregnant women with prescription opioid misuse. The study was an open-label, 8-week clinical trial of CBT for chronic pain and shared decision-making for prescription opioid dose reduction. Participants included a clinical sample of 20 pregnant women between the ages of 18 and 45 years who were misusing opioids but did not meet DSM-IV criteria for an opioid use disorder or other substance use disorder. Compared to baseline, at 8 weeks, participants had significant reductions in average prescription opioid morphine equivalent dose, prescription opioid misuse, worst pain ratings, and pain interference in general activity and at work. They did not report improvement in other pain ratings or areas of functioning. This study provides valuable information regarding the preliminary efficacy of CBT for chronic pain paired with shared decision-making among pregnant women misusing prescription opioids. ClinicalTrials.gov: NCT02804152.

A nation-wide Swedish study of opioid analgesic prescribing patterns during pregnancy and associated preexisting mental health conditions.

INTRODUCTION: Research has consistently shown individuals with mental health conditions are more likely to be prescribed opioid analgesic medications and to engage in heavier utilization. However, it is unclear whether these findings apply to pregnant women. STUDY DESIGN: We explored opioid analgesic prescription in 689,400 pregnancies occurring in Sweden between 2007 and 2013. We investigated prescription patterns across time and type of source clinic for any opioid analgesic and for strong and weak opioid analgesics. We further evaluated the extent to which receipt of opioid analgesic medications was associated with previous mental health diagnoses and prescriptions of other psychoactive medications. RESULTS: The prevalence of pregnant women who filled prescriptions for opioid analgesics (4.5%) was relatively stable across the assessed years. However, among pregnant women who filled opioid analgesic prescriptions, there was a large increase in strong opioid analgesic prescriptions-from 6.1% in 2007 to 17.1% in 2013. The main source of opioid analgesic prescriptions were primary care and obstetrics and gynecology clinics-38.7% of all filled prescriptions originated from primary care providers and 25.3% from obstetrics and gynecology practitioners. Compared to pregnant women who did not fill any opioid analgesic prescriptions, those who did were more likely to have a wide range of preexisting mental health diagnoses (e.g. anxiety disorder odds ratio [OR] = 3.13, 95% confidence interval [CI]:2.98,3.29) and to utilize a wide range of other psychoactive medications (e.g. benzodiazepines OR = 4.26, 95% CI:4.10,4.43). Similarly, those who received strong opioids were more likely to have a wide range of mental health diagnoses and be prescribed a wide range of psychoactive medications compared to those who received weak opioids. CONCLUSIONS: These results highlight the need for physicians treating pregnant women and women of childbearing age for painful conditions to obtain detailed histories of mental health problems, screen for symptoms of mental health problems, and facilitate integrated care and evidence-based mental health interventions if needed.

Risk factors and child outcomes associated with short and long interpregnancy intervals.

Previous research assessing consequences of interpregnancy intervals (IPIs) on child development is mixed. Utilizing a population-based US sample (n=5,339), we first estimated the associations between background characteristics (e.g., sociodemographic and maternal characteristics) and short (≤ 1 year) and long (> 3 years) IPI. Then, we estimated associations between IPI and birth outcomes, infant temperament, cognitive ability, and externalizing symptoms. Several background characteristics, such as maternal age at childbearing and previous pregnancy loss, were associated with IPI, indicating research on the putative effects of IPI must account for background characteristics. After covariate adjustment, short IPI was associated with poorer fetal growth and long IPI was associated with lower infant activity level; however, associations between short and long IPI and the other outcomes were neither large nor statistically significant. These findings indicate that rather than intervening to modify IPI, at-risk families may benefit from interventions aimed at other modifiable risk factors.

A population-based study of concurrent prescriptions of opioid analgesic and selective serotonin reuptake inhibitor medications during pregnancy and risk for adverse birth outcomes.

BACKGROUND: Pregnant women with painful conditions often have mental health problems, including depression and anxiety. Co-morbid conditions may cause pregnant women to use multiple medications, although safety of such practice is poorly understood. OBJECTIVES: We investigated the influence of combined prescriptions of opioid analgesics and selective serotonin reuptake inhibitors (SSRIs) during pregnancy on two adverse birth outcomes. METHODS: We analysed Swedish population-based births (n = 688 914) between 2007 and 2013. Using national registers, we obtained data on filled medication prescriptions, birth outcomes, and a wide range of parental characteristics. We estimated preterm birth and small-for-gestational-age risk following independent or combined prescriptions of the two medications compared with no filled prescriptions for either medication. We adjusted for confounders using inverse probability of treatment weights. RESULTS: After adjusting for confounders, preterm birth risk was higher among women with opioid analgesic prescriptions only (5.9%; risk ratio [RR] 1.27, 95% confidence interval [CI] 1.22, 1.33), SSRIs only (6.2%; RR 1.34, 95% CI 1.27, 1.42), and both medications (7.8%; RR 1.70, 95% CI 1.47, 1.96) compared with unexposed women (4.6%). The interaction between the medications on preterm birth was small (risk difference [RD] 0.4%, 95% CI -0.8%, 1.6%); relative excess risk due to interaction [RERI] 0.09, 95% CI -0.17, 0.34; RR 1.00, 95% CI 0.85, 1.17). For small for gestational age, risk was approximately 2% across all groups, and there was no interaction between the medications (RD 0.3%, 95% CI -0.4%, 1.1%); RERI 0.15, 95% CI -0.16, 0.47; RR 1.15, 95% CI 0.87, 1.52). CONCLUSIONS: Compared with unexposed pregnancies, those with either medication alone had a small increased risk for preterm birth but no increased risk for small for gestational age. The magnitude of associations with combined exposure to both medications were not greater than the sum of the associations with each medication considered individually.

Antiseizure medication use during pregnancy and risk of ASD and ADHD in children.

OBJECTIVE: To determine whether children born to women who use antiseizure medications (ASMs) during pregnancy have higher risk of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) independent of confounding factors. METHODS: We used Swedish register data (n = 14,614 children born 1996-2011 and followed up through 2013) to examine associations in children of women with epilepsy, using the largest sample to date and adjusting for a range of measured confounders. We examined maternal-reported first-trimester use of any ASM (22.7%) and the 3 most commonly reported individual drugs (valproic acid 4.8%, lamotrigine 6.8%, and carbamazepine 9.7%). We identified ASD with ICD-10 diagnoses and ADHD with ICD-10 diagnoses or filled prescriptions of ADHD medication. RESULTS: Examination of individual drugs revealed that after adjustment for confounding, use of valproic acid was associated with ASD (hazard ratio [HR] 2.30, 95% confidence interval [CI] 1.53-3.47) and ADHD (HR 1.74, 95% CI 1.28-2.38). Whereas a small, nonstatistically significant association with ASD (HR 1.25, 95% CI = 0.88-1.79) and ADHD (HR 1.18, 95% CI 0.91-1.52) remained for reported use of carbamazepine, confounding explained all of the associations with lamotrigine (HRASD 0.86, 95% CI 0.67-1.53; HRADHD 1.01, 95% CI 0.67-1.53). CONCLUSIONS: We found no evidence of risk related to exposure to lamotrigine, whereas we observed elevated risk of ASD and ADHD related to maternal use of valproic acid. Associations with carbamazepine were weak and not statistically significant. Our findings add to a growing body of evidence that suggests that certain ASMs may be safer than others in pregnancy.

Association of Opioid Prescription Initiation During Adolescence and Young Adulthood With Subsequent Substance-Related Morbidity.

Importance: Concerns about adverse outcomes associated with opioid analgesic prescription have led to major guideline and policy changes. Substantial uncertainty remains, however, regarding the association between opioid prescription initiation and increased risk of subsequent substance-related morbidity. Objective: To examine the association of opioid initiation among adolescents and young adults with subsequent broadly defined substance-related morbidity. Design, Setting, and Participants: This cohort study analyzed population-register data from January 1, 2007, to December 31, 2013, on Swedish individuals aged 13 to 29 years by January 1, 2013, who were naive to opioid prescription. To account for confounding, the analysis compared opioid prescription recipients with recipients of nonsteroidal anti-inflammatory drugs as an active comparator, compared opioid-recipient twins and other multiple birth individuals with their nonrecipient co-multiple birth offspring (co-twin control), examined dental prescription as a specific indication, and included individual, parental, and socioeconomic covariates. Data were analyzed from March 30, 2019, to January 22, 2020. Exposures: Opioid prescription initiation, defined as first dispensed opioid analgesic prescription. Main Outcomes and Measures: Substance-related morbidity, assessed as clinically diagnosed substance use disorder or overdose identified from inpatient or outpatient specialist records, substance use disorder or overdose cause of death, dispensed pharmacotherapy for alcohol use disorder, or conviction for substance-related crime. Results: Among the included cohort (n = 1 541 862; 793 933 male [51.5%]), 193 922 individuals initiated opioid therapy by December 31, 2013 (median age at initiation, 20.9 years [interquartile range, 18.2-23.6 years]). The active comparator design included 77 143 opioid recipients without preexisting substance-related morbidity and 229 461 nonsteroidal anti-inflammatory drug recipients. The adjusted cumulative incidence of substance-related morbidity within 5 years was 6.2% (95% CI, 5.9%-6.5%) for opioid recipients and 4.9% (95% CI, 4.8%-5.1%) for nonsteroidal anti-inflammatory drug recipients (hazard ratio, 1.29; 95% CI, 1.23-1.35). The co-twin control design produced comparable results (3013 opioid recipients and 3107 nonrecipients; adjusted hazard ratio, 1.43; 95% CI, 1.02-2.01), as did restriction to analgesics prescribed for dental indications and additional sensitivity analyses. Conclusions and Relevance: Among adolescents and young adults analyzed in this study, initial opioid prescription receipt was associated with an approximately 30% to 40% relative increase in risk of subsequent substance-related morbidity in multiple designs that adjusted for confounding. These findings suggest that this increase may be smaller than previously estimated in some other studies.

Associations of Prescribed ADHD Medication in Pregnancy with Pregnancy-Related and Offspring Outcomes: A Systematic Review.

BACKGROUND: Increasing numbers of reproductive-aged women are using attention-deficit/hyperactivity disorder (ADHD) medications. Findings from studies exploring the safety of these medications during pregnancy are mixed, and it is unclear whether associations reflect causal effects or could be partially or fully explained by other factors that differ between exposed and unexposed offspring. OBJECTIVES: The aim of this systematic review was to evaluate the adverse pregnancy-related and offspring outcomes associated with exposure to prescribed ADHD medication during pregnancy with a focus on how studies to date have handled the influence of confounding. METHODS: We searched PubMed, Embase, PsycINFO, and Web of Science up to 1 July 2019 without any restrictions on language or date of publication. We included all observational studies (e.g., cohort studies, case-control studies, case-crossover studies, cross-sectional studies, and registry-based studies) with pregnant women of any age or from any setting who were prescribed ADHD medications and evaluated any outcome, including both short- and long-term maternal and offspring outcomes. Two independent authors then used the Newcastle-Ottawa Scale to rate the quality of the included studies. RESULTS: Eight cohort studies that estimated adverse pregnancy-related and offspring outcomes associated with exposure to ADHD medication during pregnancy were included in the qualitative review. The included studies had substantial methodological differences in data sources, type of medications examined, definitions of studied pregnancy-related and offspring outcomes, types of control groups, and confounding adjustment. There was no convincing evidence for teratogenic effects according to the relative risk of pregnancy-related and offspring outcomes, and the observed differences in absolute risks were overall small in magnitude. Adjustment for confounding was inadequate in most studies, and none of the included studies adjusted for ADHD severity in the mothers. CONCLUSION: The current evidence does not suggest that the use of ADHD medication during pregnancy results in significant adverse consequences for mother or offspring. However, the data are too limited to make an unequivocal recommendation. Therefore, physicians should consider whether the advantages of using ADHD medication outweigh the potential risks for the developing fetus according to each woman's specific circumstances. Future research should attempt to triangulate research findings based on a combination of different designs that differ in their underlying strengths and limitations and should investigate specific confounding factors, the potential impact of timing of exposure, and potential long-term outcomes in the offspring.

Maternal prescribed opioid analgesic use during pregnancy and associations with adverse birth outcomes: A population-based study.

BACKGROUND: Published research on prescribed opioid analgesic (POA) use during pregnancy and birth outcomes is limited in scope and has not adequately adjusted for potential confounding factors. To help address these gaps, we estimated associations between maternal POAs during pregnancy and two adverse birth outcomes using a large population-based dataset, multiple definitions of POA exposure, and several methods to evaluate the influence of both measured and unmeasured confounding factors. METHODS AND FINDINGS: We obtained data by linking information from several Swedish registers and conducted a retrospective cohort study on a population-based sample of 620,458 Swedish births occurring between 2007 and 2013 (48.6% female; 44.4% firstborn). We evaluated associations between prenatal POA exposure and risk for preterm birth (PTB; <37 gestational weeks) and small for gestational age (SGA; birth weight 2 standard deviations below the expected weight for gestational age or lower). We evaluated the influence of confounding by adjusting for a wide range of measured covariates while comparing exposed and unexposed infants. Additionally, we adjusted for unmeasured confounding factors by using several advanced epidemiological designs. Infants exposed to POAs anytime during pregnancy were at increased risk for PTB compared with unexposed infants (6.4% exposed versus 4.4% unexposed; adjusted odds ratio [OR] = 1.38, 95% confidence interval [CI] 1.31-1.45, p < 0.001). This association was attenuated when we compared POA-exposed infants with acetaminophen-exposed infants (OR = 1.18, 95% CI 1.07-1.30, p < 0.001), infants born to women who used POAs before pregnancy only (OR = 1.05, 95% CI 0.96-1.14, p = 0.27), and unexposed siblings (OR = 0.99, 95% CI 0.85-1.14, p = 0.92). We also evaluated associations with short-term versus persistent POA use during pregnancy and observed a similar pattern of results, although the magnitudes of associations with persistent exposure were larger than associations with any use or short-term use. Although short-term use was not associated with SGA (adjusted ORsingle-trimester = 0.95, 95% CI 0.87-1.04, p = 0.29), persistent use was associated with increased risk for SGA (adjusted ORmultiple-trimester = 1.40, 95% CI 1.17-1.67, p < 0.001) compared with unexposed infants. The association with persistent exposure was attenuated when we used alternative comparison groups (e.g., sibling comparison OR = 1.22, 95% CI 0.60-2.48, p = 0.58). Of note, our study had limitations, including potential bias from exposure misclassification, an inability to adjust for all sources of confounding, and uncertainty regarding generalizability to countries outside of Sweden. CONCLUSIONS: Our results suggested that observed associations between POA use during pregnancy and risk of PTB and SGA were largely due to unmeasured confounding factors, although we could not rule out small independent associations, particularly for persistent POA use during pregnancy.

Annual Research Review: Maternal antidepressant use during pregnancy and offspring neurodevelopmental problems - a critical review and recommendations for future research.

Children of women treated with antidepressants during pregnancy are more likely to develop neurodevelopmental problems than are unexposed children. Associations between prenatal antidepressant exposure and neurodevelopmental problems could reflect a causal effect or could be partially or fully explained by other factors that differ between exposed and unexposed offspring, including having mothers with conditions requiring antidepressant treatment (e.g. depression), environmental risk factors, and/or genetic risk factors shared across disorders. This translational review aims to provide a brief overview of findings from rodent experiments and critically evaluate observational studies in humans to assess the extent to which associations between prenatal antidepressant exposure and neurodevelopmental problems are due to causal mechanisms versus other influences. We focus our review on two important neurodevelopmental outcomes - autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). In general, rodent studies have reported adverse effects of perinatal antidepressant exposure on neurodevelopment. Between-species differences raise questions about the generalizability of these findings to humans. Indeed, converging evidence from studies using multiple designs and approaches suggest that observed associations between prenatal antidepressant exposure and neurodevelopmental problems in humans are largely due to confounding factors. We also provide specific recommendations for future research. Animal research should explicitly evaluate the impact of timing of exposure and dosage of medications, as well as better map outcome measures in rodents to human neurodevelopmental problems. Observational studies should investigate specific confounding factors, specific antidepressant drugs and classes, the potential impact of timing of exposure, and a wider range of other potential offspring outcomes. The findings summarized in this review may help women and their doctors make informed decisions about antidepressant use during pregnancy by providing reassurance that use of these medications during pregnancy is unlikely to substantially increase the risk of ASD and ADHD.

Outcome-dependent associations between short interpregnancy interval and offspring psychological and educational problems: a population-based quasi-experimental study.

Background: Causal interpretation of associations between short interpregnancy interval (the duration from the preceeding birth to the conception of the next-born index child) and the offspring's psychological and educational problems may be influenced by a failure to account for unmeasured confounding. Methods: Using population-based Swedish data from 1973-2009, we estimated the association between interpregnancy interval and outcomes [autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), severe mental illness, suicide attempt, criminality, substance-use problem and failing grades] while controlling for measured covariates. We then used cousin comparisons, post-birth intervals (the interval between the second- and third-born siblings to predict second-born outcomes) and sibling comparisons to assess the influence of unmeasured confounding. We included an exploratory analysis of long interpregnancy interval. Results: Interpregnancy intervals of 0-5 and 6-11 months were associated with higher odds of outcomes in cohort analyses. Magnitudes of association were attenuated following adjustment for measured covariates. Associations were eliminated for ADHD, severe mental illness and failing grades, but maintained magnitude for ASD, suicide attempt, criminality and substance-use problem in cousin comparisons. Post-birth interpregnancy interval and sibling comparisons suggested some familial confounding. Associations did not persist across models of long interpregnancy interval. Conclusions: Attenuation of the association in cousin comparisons and comparable post-birth interval associations suggests that familial genetic or environmental confounding accounts for a majority of the association for ADHD, severe mental illness and failing grades. Modest associations appear independently of covariates for ASD, suicide attempt, criminality and substance-use problem. Post-birth analyses and sibling comparisons, however, show some confounding in these associations.

Within-Family Analysis of Interpregnancy Interval and Adverse Birth Outcomes.

OBJECTIVE: To examine associations among interpregnancy interval, the duration from the preceding birth to the conception of the next-born index child, and adverse birth outcomes using designs that adjust for measured and unmeasured factors. METHODS: In this prospective cohort study, we used population-based Swedish registries from 1973 to 2009 to estimate the associations between interpregnancy interval (referent 18-23 months) and adverse birth outcomes (ie, preterm birth [less than 37 weeks of gestation], low birth weight [LBW; less than 2,500 g], small for gestational age [SGA; greater than 2 SDs below average weight for gestational age]). Analyses included cousin and sibling comparisons and postbirth intervals (ie, the interval between secondborn and thirdborn offspring predicting secondborn outcomes) to address unmeasured familial confounding. RESULTS: Traditional cohort-wide analyses showed higher odds of preterm birth (adjusted odds ratio [OR] 1.51, 99% CI 1.39-1.63, 5.99% preterm births]) and LBW (adjusted OR 1.25, 99% CI 1.13-1.39, 3.32% LBW) after a short interpregnancy interval (0-5 months) compared with offspring born after an interpregnancy interval of 18-23 months (3.21% preterm births, 1.92% LBW). Except for preterm birth (adjusted OR 1.72, 99% CI 1.26-2.35), associations were attenuated in cousin comparisons. A small association between a short interpregnancy interval and preterm birth remained in sibling comparisons (adjusted OR 1.22, 99% CI 1.11-1.35), but associations with LBW (adjusted OR 0.83, 99% CI 0.74-0.94) and SGA (adjusted OR 0.74, 99% CI 0.64-0.85) reversed direction. For pregnancy intervals of 60 months or more, odds of preterm birth (adjusted OR 1.51, 99% CI 1.43-1.60, 5.07% preterm births), LBW (adjusted OR 1.61, 99% CI 1.50-1.73, 3.43% low-birth-weight births), and SGA (adjusted OR 1.54, 99% CI 1.42-1.66, 2.49% SGA births) were also higher when compared with the reference interval (1.53% SGA). Associations between long interpregnancy interval and adverse birth outcomes remained through cousin and sibling comparisons. Postbirth interval analyses showed familial confounding is present for short interpregnancy intervals, but supported independent associations for long interpregnancy intervals. CONCLUSION: Familial confounding explains most of the association between a short interpregnancy interval and adverse birth outcomes, whereas associations with long interpregnancy intervals were independent of measured and unmeasured factors.