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Objective To estimate the incidence of ectopic pregnancy (EP) associated with prescription contraceptive use. Study Design We performed a retrospective cohort study of women aged 15 to 44 years at Kaiser Permanente Northern and Southern California during 2010 to 2019. We identified EPs and prescription contraceptive use from diagnosis, procedural, and medication codes, and natural language processing of clinical notes from electronic health records. Contraceptive use categories included combined hormonal contraceptives, intrauterine devices, depot-medroxyprogesterone acetate (DMPA), progestin-only pills (POPs), implants, no method after recent discontinuation of a prescription contraceptive in the last 12 months, and no method after discontinuation of a prescription contraceptive more than 12 months ago or no use of prescription contraceptives during the study period. Contraceptive use was updated as women started, stopped, or changed methods. An EP was attributed to a contraceptive method if it occurred 14 days after starting and up to 42 days after stopping a method. Age-adjusted EP incidence and 95% confidence intervals (CI) were estimated per 10,000 woman-years overall and by contraceptive category. Results There were 11,436 EPs among 3,204,118 women with 11,909,842 woman-years of follow-up for an overall EP incidence of 9.5 per 10,000 woman-years (95%CI 9.3−9.6). The majority of EPs (9662; 84.5%) occurred during no prescription contraceptive use. EP incidence was lowest during DMPA (1.8 per 10,000 woman-years [95%CI 1.2−2.5]) or implant (2.0 per 10,000 woman-years [95%CI 1.2−3.3]) use, and higher during POP use at 15.2 (95%CI 12.2−19.6); however, incidence was highest after recent discontinuation of a prescription contraceptive (20.6 per 10,000 woman-years [95%CI 19.7-21.4]). Conclusions EP incidence is lower with prescription contraceptive use than with nonuse. Implications All prescription contraceptives, including POPs are protective of EP.

To explore to what extent intrauterine device (IUD) expulsion is associated with demographic and clinical risk factors.The APEX-IUD (Association of Perforation and Expulsion of IntraUterine Devices) study was a U.S. cohort study using electronic health records from three integrated health care systems (Kaiser Permanente Northern California, Southern California, and Washington) and a health care information exchange (Regenstrief Institute). These analyses included individuals aged 50 years or younger with IUD insertions from 2001 to 2018. Intrauterine device expulsion cumulative incidence and incidence rates were estimated. Using Cox regression models, hazard ratios with 95% CIs were estimated before and after adjustment for risk factors of interest (age, race and ethnicity, parity, body mass index [BMI], heavy menstrual bleeding, and dysmenorrhea) and potential confounders.In total, 228,834 individuals with IUD insertion and no delivery in the previous 52 weeks were identified (184,733 [80.7%] with levonorgestrel-releasing intrauterine system). Diagnosis of heavy menstrual bleeding-particularly a diagnosis in both recent and past periods-was the strongest risk factor for IUD expulsion. Categories with the highest risk of IUD expulsion within each risk factor included individuals diagnosed with overweight, obesity, and morbid obesity; those in younger age groups, especially among those aged 24 years or younger; and in those with parity of four or more. Non-Hispanic White individuals had the lowest incidence and risk, and after adjustment, Asian or Pacific Islander individuals had the highest risk. Dysmenorrhea was not independently associated with expulsion risk when adjusting for heavy menstrual bleeding.Most risk factors for expulsion identified in this study appear consistent with known physiologic factors that affect uterine anatomy and physiology (age, BMI, heavy menstrual bleeding, parity). The increased risk of IUD expulsion among individuals of color warrants further investigation. Intrauterine devices are an effective long-term contraceptive; expulsion is uncommon, but patients should be counseled accordingly.Bayer AG.EU PAS register, EUPAS33461.

(s): To examine recent trends in preterm birth (PTB) and its clinical subtypes by maternal race/ethnicity among singleton births.Kaiser Permanente Southern California electronic health records (EHR) for all singleton births between 2009-2020 (n=427,698) were used to examine PTB trends and their subtypes (spontaneous [SPTB] and iatrogenic [IPTB]). Data on preterm labor triage extracted from EHRs using Natural Language Processing (NLP) were used to define PTB subtypes. Maternal race/ethnicity was categorized as non-Hispanic (NH) White, NH-Black, Hispanic, and NH-Asian/Pacific Islander. Multiple logistic regression was used to quantify the linear trend for PTB and its subtypes. Racial/ethnic trends were further examined by considering statistical interactions and stratifications.From 2009 to 2020, the overall PTB rate decreased by 9.12% (from 8.04% to 7.31%; p.001). Rates decreased by 19.29% among NH-Whites (from 7.23% to 5.83%, p.001), 6.15% among Hispanics (from 7.82% to 7.34%; p=.036), and 12.60% among NH-Asian/Pacific Islanders (from 8.90% to 7.78%; p.001) whereas a non-significantly increased PTB rate (8.45%) was observed among NH-Blacks (from 9.91% to 10.75%; p=.103). Between 2009 and 2020, overall SPTB rates decreased by 28.85% (from 5.75% to 4.09%; p.001). However, overall IPTB rates increased by 40.45% (from 2.29% to 3.22%; p.001). SPTB rates decreased by 34.73% among NH-Whites (from 5.44% to 3.55%, p.001), 19.75% among NH-Blacks (from 6.82% to 5.47%, p.001), 22.96% among Hispanics (from 5.55% to 4.28%, p.001), and 28.19% among NH-Asian/Pacific Islanders (from 6.50% to 4.67%, p.001). IPTB rates increased by 52.42% among NH-Whites (from 1.88% to 2.61%, p.001), 107.89% among NH-Blacks (from 3.18% to 6.13%, p.001), 46.88% among Hispanics (from 2.29% to 3.26%, p.001), and 42.21% among NH-Asian/Pacific Islanders (from 2.45% to 3.44%, p.001).The overall PTB rate decreased over time and was driven by a decrease in the SPTB rate. There is racial/ethnic variability in rates of SPTB and IPTB. The observed increase in IPTB among all racial and ethnic groups, especially NH-Blacks is disconcerting and needs further investigation.

BACKGROUND Migraine is a common neurological disorder characterized by repeated headaches of varying intensity, particularly during the postpartum period for women. However, due to lack of a validated instrument for uniform case ascertainment on postpartum migraine headache, there is uncertainty in the reported prevalence in the literature. OBJECTIVE To evaluate the completeness and accuracy of reporting postpartum migraine headache coding in health plan electronic health records (EHR) and compare the coding quality before and after implementation of the International Classification of Diseases-Clinical Modification [ICD]-10-CM coding and pharmacy records in EHR. METHODS Medical records of 200 pregnancies delivered in all Kaiser Permanente Southern California (KPSC) hospitals during two time periods: 1/1/2012 - 12/31/2014 (ICD-9-CM coding period) and 1/1/2017 - 12/31/2019 (ICD-10-CM coding period) were randomly selected from EHR for chart review, and postpartum migraine headache cases recorded within one year after delivery were identified. Abstracted clinical records for cases were compared with corresponding diagnosis and pharmacy prescription utilization records for both ICD-9-CM and ICD-10-CM coding periods through comparisons of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), as well as the summary statistics of F-score (F) and Youden’s J Statistic (J). Kappa statistic (K) for interrater reliability were calculated. RESULTS The overall interrater agreement among two chart abstractors for postpartum migraine headache was 100%. Diagnosis coding (F = 87.8%, J = 82.5%) did better than pharmacy records (F = 72.7%, J = 57.5%) when identifying cases, but combining both of these sources of data produced much greater accuracy identification of postpartum migraine cases (F = 96.9%, J = 99.7%). Results were similar across the ICD-9-CM and ICD-10-CM coding periods. CONCLUSIONS Neither diagnostic codes nor pharmacy records alone are sufficient for identifying postpartum migranie cases reliably, but when used together, they are quite reliable. The completeness of data remained similar after the implementation of the ICD-10-CM coding in the EHR system. CLINICALTRIAL Not Applicable.

INTRODUCTION: Ectopic pregnancy leads to reproductive health morbidity, including greater risk of another ectopic pregnancy, infertility, and, in rare cases, mortality. Information on trends in the incidence of ectopic pregnancy in the last decade is limited. METHODS: A population-based cross-sectional study of women aged 15−44 years enrolled at Kaiser Permanente Northern and Southern California 2010−2019 was conducted. Electronic health records were used to identify ectopic pregnancies. The crude ectopic pregnancy incidence per 1000 pregnancies (live births, induced abortions, and ectopic pregnancies) and 95% confidence interval (CI) was estimated per study year, overall, and stratified by age group. The age-adjusted incidence and 95% CI was estimated per study year, overall, and stratified by race/ethnicity. Temporal trend was assessed using Poisson regression. RESULTS: There were 15,537 ectopic pregnancies among 979,027 pregnancies. The overall age-adjusted ectopic pregnancy incidence was 15.8 per 1000 pregnancies, 95% CI: 15.6, 16.1. The annual incidence increased from 15.2, 95% CI: 14.4, 16.1, in 2010 to 16.4, 95% CI: 15.6, 17.2, in 2019 (p < 0.001). The overall incidence was highest among women aged 40−44 years (24.2, 95% CI: 22.7, 25.6) and non-Hispanic Black women (21.9, 95% CI: 21.0, 22.8); compared to 30–34-year-old (16.2, 95% CI: 15.7, 16.6) and non-Hispanic White (14.6, 95% CI: 14.1, 15.0) women, respectively. DISCUSSION: The increase in ectopic pregnancy incidence during the studied period was largely driven by increasing incidence in younger women. However, disparities in the incidence by age and race/ethnicity persisted. CONCLUSION: Ectopic pregnancy remains a significant source of reproductive health morbidity, especially for older ( >40 years) and non-Hispanic Black women.

Objective This study aimed to examine whether severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection during pregnancy is associated with increased odds of perinatal complications and viral transmission to the infant. Study Design A retrospective cohort study of women who delivered at Kaiser Permanente Southern California hospitals (April 6, 2020–February 28, 2021) was performed using data extracted from electronic health records (EHRs). During this time polymerize chain reaction (PCR)-based tests for SARS-CoV-2 was universally offered to all pregnant women at labor and delivery admission, as well as earlier in the pregnancy, if they were displaying symptoms consistent with SARS-CoV-2 infection or a possible exposure to the virus. Adjusted odds ratio (aOR) was used to estimate the strength of associations between positive test results and adverse perinatal outcomes. Results Of 35,123 women with a singleton pregnancy, 2,203 (6%) tested positive for SARS-CoV-2 infection with 596 (27%) testing positive during the first or second trimester and 1,607 (73%) during the third trimester. Women testing positive were younger than those who tested negative (29.7 [5.4] vs. 31.1 [5.3] years; mean [standard deviation (SD)]; p Conclusion These findings suggest that prenatal SARS-CoV-2 infection increases the odds of some adverse perinatal outcomes. The likelihood of vertical transmission from the mother to the fetus was low (0.3%), suggesting that pregnancy complications resulting from SARS-CoV-2 infection pose more risk to the baby than transplacental viral transmission. Key Points

This study aimed to determine if hypothyroidism prior to, or during, pregnancy increases the risk of attention-deficit hyperactivity disorder (ADHD) in the child and how the association may be modified by preterm birth, sex of the child, and race-ethnicity.Data were abstracted from linked maternal-child medical records. Incidence rate differences (IRDs), adjusted hazard ratios (aHRs), and their 95% confidence intervals (CIs) were estimated to evaluate the association of maternal hypothyroidism with childhood ADHD risk. Stratified analyses were used to evaluate whether the association is affected by timing of first diagnosis, gestational age at birth (term vs. preterm), sex, and race-ethnicity.Hypothyroidism diagnosed prior to (IRD = 1.30), or during (IRD = 0.59) pregnancy increases the risk of ADHD in the children (aHR = 1.27; 95% CI: 1.15, 1.41, and 1.17; 95% CI: 1.00, 1.38). The association was strongest when diagnosed during the first trimester (IRD = 0.97 and aHR = 1.28; 95% CI: 1.04, 1.58). For children born preterm, there was significantly increased risk of ADHD if their mothers were diagnosed prior to (IRD = 3.06 and aHR = 1.43; 95% CI: 1.09, 1.88), but not during pregnancy. The effect of maternal hypothyroidism on increased risk of ADHD was stronger for boys (IRD = 1.84 and aHR = 1.26; 95% CI: 1.14, 1.40) than it was for girls (IRD = 0.48 and aHR = 1.19; 95% CI: 1.01, 1.40) and for Hispanic children (IRD = 1.60 and aHR = 1.45; 95% CI: 1.25, 1.68) compared with other race ethnicities.Exposure to maternal hypothyroidism during the periconceptual period significantly increases the risk of ADHD and that the association varies with gestational age at delivery, child sex, and race-ethnicity.· Maternal hypothyroidism increases the risk of ADHD diagnosis in the offspring.. · The association of maternal hypothyroidism with childhood ADHD was influenced by timing of diagnosis.. · Strength of the association was strongest in preterm born infants, boys, and Hispanic children..

Objective The coronavirus disease 2019 (COVID-19) pandemic has created a need for data regarding the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnant women. After implementing universal screening for COVID-19 in women admitted for delivery, we sought to describe the characteristics of COVID-19 in this large cohort of women. Study Design An observational study of women admitted to labor and delivery units in Kaiser Permanente Southern California (KPSC) hospitals between April 6 and May 11, 2020 who were universally offered testing for SARS-CoV-2 infection ( n = 3,963). Hospital inpatient and outpatient physician encounter, and laboratory records were used to ascertain universal testing levels, test results, and medical and obstetrical histories. The prevalence of SARS-CoV-2 infection was estimated from the number of women who tested positive during labor per 100 women delivered. Results Of women delivered during the study period, 3,923 (99.0%) underwent SARS-CoV-2 testing. A total of 17 (0.43%; 95% confidence interval: 0.23–0.63%) women tested positive, and none of them were symptomatic on admission. There was no difference in terms of characteristics between SARS-CoV-2 positive and negative tested women. One woman developed a headache attributed to COVID-19 3 days postpartum. No neonates had a positive test at 24 hours of life. Conclusion The findings suggest that in pregnant women admitted for delivery between April 6 and May 11, 2020 in this large integrated health care system in Southern California, prevalence of SARS-CoV-2 test positive was very low and all patients were asymptomatic on admission. Key Points The prevalence of SARS-CoV-2 infection in a large diverse cohort of term pregnant women was 0.43%. 99% of women accepted SARS-CoV-2 screening on admission to labor and delivery. All women with positive test results were asymptomatic at the time of testing.

As prenatal vaccinations become more prevalent, it is important to assess potential safety events. In a retrospective cohort study of Kaiser Permanente Southern California (Pasadena, California) mother-child pairs with birth dates during January 1, 2011–December 31, 2014, we investigated the association between prenatal tetanus, diphtheria, and acellular pertussis (Tdap) vaccination and risk of attention-deficit/hyperactivity disorder (ADHD) in offspring. Information on Tdap vaccination during pregnancy was obtained from electronic medical records. ADHD was defined by International Classification of Diseases codes (Ninth or Tenth Revision) and dispensed ADHD medication after age 3 years. Children were followed to the date of their first ADHD diagnosis, the end of Kaiser Permanente membership, or the end of follow-up (December 31, 2018). In Cox proportional hazards models, we estimated unadjusted and adjusted hazard ratios for the association between maternal Tdap vaccination and ADHD, with inverse probability of treatment weighting (IPTW) used to adjust for confounding. Of 128,756 eligible mother-child pairs, 85,607 were included in the final sample. The ADHD incidence rate was 3.41 per 1,000 person-years in the Tdap-vaccinated women and 3.93 per 1,000 person-years in the unvaccinated (hazard ratio = 1.01, 95% confidence interval: 0.88, 1.16). The IPTW-adjusted analyses showed no association between prenatal Tdap vaccination and ADHD in offspring (hazard ratio = 1.00, 95% confidence interval: 0.88, 1.14). In this study, prenatal Tdap vaccination was not associated with ADHD risk in offspring, supporting recommendations to vaccinate pregnant women.

Intrauterine devices are effective instruments for contraception, and 1 levonorgestrel-releasing device is also indicated for the treatment of heavy menstrual bleeding (menorrhagia).To compare the incidence of intrauterine device expulsion and uterine perforation in women with and without a diagnosis of menorrhagia within the first 12 months before device insertion STUDY DESIGN: This was a retrospective cohort study conducted in 3 integrated healthcare systems (Kaiser Permanente Northern California, Southern California, and Washington) and a healthcare information exchange (Regenstrief Institute) in the United States using electronic health records. Nonpostpartum women aged ≤50 years with intrauterine device (eg, levonorgestrel or copper) insertions from 2001 to 2018 and without a delivery in the previous 12 months were studied in this analysis. Recent menorrhagia diagnosis (ie, recorded ≤12 months before insertion) was ascertained from the International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification codes. The study outcomes, viz, device expulsion and device-related uterine perforation (complete or partial), were ascertained from electronic medical records and validated in the data sources. The cumulative incidence and crude incidence rates with 95% confidence intervals were estimated. Cox proportional hazards models estimated the crude and adjusted hazard ratios using propensity score overlap weighting (13-16 variables) and 95% confidence intervals.Among 228,834 nonpostpartum women, the mean age was 33.1 years, 44.4% of them were White, and 31,600 (13.8%) had a recent menorrhagia diagnosis. Most women had a levonorgestrel-releasing device (96.4% of those with and 78.2% of those without a menorrhagia diagnosis). Women with a menorrhagia diagnosis were likely to be older, obese, and have dysmenorrhea or fibroids. Women with a menorrhagia diagnosis had a higher intrauterine device-expulsion rate (40.01 vs 10.92 per 1000 person-years) than those without, especially evident in the first few months after insertion. Women with a menorrhagia diagnosis had a higher cumulative incidence (95% confidence interval) of expulsion (7.00% [6.70-7.32] at 1 year and 12.03% [11.52-12.55] at 5 years) vs those without (1.77% [1.70-1.84] at 1 year and 3.69% [3.56-3.83] at 5 years). The risk of expulsion was increased for women with a menorrhagia diagnosis vs for those without (adjusted hazard ratio, 2.84 [95% confidence interval, 2.66-3.03]). The perforation rate was low overall (1/1000 person-years) but higher in women with a diagnosis of menorrhagia vs in those without (0.98 vs 0.63 per 1000 person-years). The cumulative incidence (95% confidence interval) of uterine perforation was slightly higher for women with a menorrhagia diagnosis (0.09% [0.06-0.14] at 1 year and 0.39% [0.29-0.53] at 5 years) than those without it (0.07% [0.06-0.08] at 1 year and 0.28% [0.24-0.33] at 5 years). The risk of perforation was slightly increased in women with a menorrhagia diagnosis vs in those without (adjusted hazard ratio, 1.53; 95% confidence interval, 1.10-2.13).The risk of expulsion is significantly higher in women with a recent diagnosis of menorrhagia. Patient education and counseling regarding the potential expulsion risk is recommended at insertion. The absolute risk of perforation for women with a recent diagnosis of menorrhagia is very low. The increased expulsion and perforation rates observed are likely because of causal factors of menorrhagia.

Mary S Anthony,1 Mary Anne Armstrong,2 Darios Getahun,3 Delia Scholes,4 Jennifer Gatz,5 Renate Schulze-Rath,6 Debbie Postlethwaite,2 Maqdooda Merchant,2 Amy L Alabaster,2 Giulia Chillemi,2 Tina Raine-Bennett,2 Fagen Xie,3 Vicki Y Chiu,3 Theresa M Im,3 Harpreet S Takhar,3 Michael Fassett,3 Jane Grafton,4 David Cronkite,4 Laura Ichikawa,4 Susan D Reed,4,7 Siu Lui Hui,5 Mary E Ritchey,1 Catherine W Saltus,8 Elizabeth B Andrews,1 Kenneth J Rothman,8 Alex Asiimwe,6 Richard Lynen,9 Juliane Schoendorf101RTI Health Solutions, Research Triangle Park, NC, USA; 2Kaiser Permanente Northern California, Oakland, CA, USA; 3Kaiser Permanente Southern California, Pasadena, CA, USA; 4Kaiser Permanente Washington, Seattle, WA, USA; 5Regenstrief Institute, Indianapolis, IN, USA; 6Bayer AG, Berlin, Germany; 7University of Washington, Seattle, WA, USA; 8RTI Health Solutions, Waltham, MA, USA; 9Bayer HealthCare, Whippany, NJ, USA; 10Bayer OY, Espoo, FinlandObjective: To validate algorithms identifying uterine perforations and intrauterine device (IUD) expulsions and to ascertain availability of breastfeeding status at the time of IUD insertion.Study design and setting: Four health care systems with electronic health records (EHRs) participated: Kaiser Permanente Northern California (KPNC), Kaiser Permanente Southern California (KPSC), Kaiser Permanente Washington (KPWA), and Regenstrief Institute (RI). The study included women ≤50 years of age with an IUD insertion. Site-specific algorithms using structured and unstructured data were developed and a sample validated by EHR review. Positive predictive values (PPVs) of the algorithms were calculated. Breastfeeding status was assessed in a random sample of 125 women at each research site with IUD placement within 52 weeks postpartum.Results: The study population included 282,028 women with 325,582 IUD insertions. The PPVs for uterine perforation were KPNC 77%, KPSC 81%, KPWA 82%, and RI 47%; PPVs for IUD expulsion were KPNC 77%, KPSC 87%, KPWA 68%, and RI 37%. Across all research sites, breastfeeding status at the time of IUD insertion was determined for 94% of those sampled.Conclusions: Algorithms with a high PPV for uterine perforation and IUD expulsion were developed at 3 of the 4 research sites. Breastfeeding status at the time of IUD insertion could be determined at all research sites. Our findings suggest that a study to evaluate the associations of breastfeeding and postpartum IUD insertions with risk of uterine perforation and IUD expulsion can be successfully conducted retrospectively; however, automated application of algorithms must be supplemented with chart review for some outcomes at one research site due to low PPV.Keywords: electronic health records, intrauterine device, breastfeeding, validation study, algorithm, postpartum

Reports of perforation risk related to intrauterine devices (IUDs) inserted immediately post partum and among non-post-partum individuals are scarce, and previous studies with only 12-month follow-ups underestimate the risk. Breastfeeding at IUD insertion and insertion within 36 weeks post partum have been associated with increased risk of uterine perforation. The aim of these analyses was to compare the incidence and risks of IUD-related uterine perforations by non-post-partum and post-partum intervals at IUD insertion, and among post-partum individuals, to assess the impact of breastfeeding on these outcomes.We did a multisite cohort study in the USA, using electronic health records (EHR). Study sites were three health-care systems and a site that used data from a health-care information exchange. The study population included individuals who were aged 50 years or younger and had an IUD insertion between Jan 1, 2001, and April 30, 2018. Individuals were excluded if they had not been in the health-care system for at least 12 months before IUD insertion. The primary outcome for this analysis was any IUD-related uterine perforation diagnosis for the first IUD insertion in this time period. Both complete and partial IUD-related perforations were identified. Chart abstraction was done to validate EHR-based algorithms or confirm perforations. The crude rate and cumulative incidence of uterine perforation were evaluated by non-post-partum and post-partum intervals at IUD insertion in the full cohort, and by breastfeeding status in a subcohort of post-partum individuals. Cox models estimated crude and adjusted hazard ratios (aHRs).Data from 326 658 individuals in the full cohort and 94 817 individuals in the post-partum subcohort were analysed. In the full cohort, we identified 1008 uterine perforations (51·2% complete), with the 5-year cumulative incidence being the lowest in the non-post-partum group (0·29%, 95% CI 0·26-0·34). The aHR for the post-partum interval relative to non-post partum ranged from 2·73 (95% CI 1·33-5·63; 0 to 3 days post partum) to 6·71 (4·80-9·38; 4 days to ≤6 weeks post partum). The post-partum subcohort of individuals with breastfeeding information had 673 uterine perforations (62% complete), with a 5-year cumulative incidence of 1·37% (95% CI 1·24-1·52) and an increased risk with breastfeeding (aHR 1·37, 95% CI 1·12-1·66).Although the risk for uterine perforation with IUD insertion 4 days to 6 weeks or less post partum is nearly seven times that of insertion non-post partum, perforation remains an incredibly rare event for all clinical time points. Despite a slight increased risk of perforation with breastfeeding at IUD insertion, the benefits of breastfeeding and effective contraception generally outweigh risks and should have little clinical impact. Therefore, IUD insertion timing should be based on individual desire for IUD contraception and patient convenience to assure an IUD insertion can occur. Careful follow-up of individuals at higher risk of uterine perforation is warranted.Bayer AG.

Objective The study aimed to examine the association between neonatal sepsis and autism risk among children and whether the risk varied with the timing of exposure, child's sex, and race/ethnicity. Study Design We conducted a retrospective cohort study using electronic health records (EHR) extracted from Kaiser Permanente Southern California Health Care System. Mother–child dyads were constructed by linking records of children born to member mothers and continuing to receive care through the system during the follow-up period with those of their biological mothers (n = 469,789). Clinical health records were used to define neonatal sepsis. Diagnosis of autism was made by medical specialists. Potential confounders included maternal sociodemographic factors, obstetrical history, child's age, sex, race/ethnicity, and maternal and child medical history. Incident rates and adjusted hazard ratios (aHR) were used to estimate the associations. Results Compared with children without the diagnosis of autism, children with the condition were more likely to be from Asian/Pacific Islander descent and male sex. Exposed children showed higher rates of autism as compared with unexposed children (3.43 vs. 1.73 per 1,000 person-years, aHR: 1.67–95% confidence interval [CI]: 1.39–2.00). Both preterm (aHR: 1.47; 95% CI: 1.09–1.98) and term (aHR: 1.63; 95% CI: 1.29–2.06) births were associated with increased risk for autism. Although the magnitude of the HRs and incidence ratios for neonatal sepsis to increase autism risk varied between race ethnicities, neonatal sepsis was associated with significantly increased likelihood of autism diagnosis for all race-ethic groups except for Asian/Pacific Islanders. Although neonatal sepsis was associated with significantly increased autism risk for both boys and girls, incident rates and HR point estimates suggested that the effect may be stronger in girls. Conclusion Neonatal sepsis is associated with increased risk of autism diagnosis in preterm- and term-born children. The association was significant for both girls and boys and all race ethnicities except for Asian-Pacific Islanders. Key Points

Intrauterine devices, including levonorgestrel-releasing and copper devices, are highly effective long-acting reversible contraceptives. The potential risks associated with intrauterine devices are low and include uterine perforation and device expulsion.This study aimed to evaluate the risk of perforation and expulsion associated with levonorgestrel-releasing devices vs copper devices in clinical practice in the United States.The Association of Perforation and Expulsion of Intrauterine Device study was a retrospective cohort study of women aged ≤50 years with an intrauterine device insertion during 2001 to 2018 and information on intrauterine device type and patient and medical characteristics. Of note, 4 research sites with access to electronic health records contributed data for the study: 3 Kaiser Permanente-integrated healthcare systems (Northern California, Southern California, and Washington) and 1 healthcare system using data from a healthcare information exchange in Indiana (Regenstrief Institute). Perforation was classified as any extension of the device into or through the myometrium. Expulsion was classified as complete (not visible in the uterus or abdomen or patient reported) or partial (any portion in the cervix or malpositioned). We estimated the crude incidence rates and crude cumulative incidence by intrauterine device type. The risks of perforation and expulsion associated with levonorgestrel-releasing intrauterine devices vs copper intrauterine devices were estimated using Cox proportional-hazards regression with propensity score overlap weighting to adjust for confounders.Among 322,898 women included in this analysis, the incidence rates of perforation per 1000 person-years were 1.64 (95% confidence interval, 1.53-1.76) for levonorgestrel-releasing intrauterine devices and 1.27 (95% confidence interval, 1.08-1.48) for copper intrauterine devices; 1-year and 5-year crude cumulative incidence was 0.22% (95% confidence interval, 0.20-0.24) and 0.63% (95% confidence interval, 0.57-0.68) for levonorgestrel-releasing intrauterine devices and 0.16% (95% confidence interval, 0.13-0.20) and 0.55% (95% confidence interval, 0.44-0.68) for copper intrauterine devices, respectively. The incidence rates of expulsion per 1000 person-years were 13.95 (95% confidence interval, 13.63-14.28) for levonorgestrel-releasing intrauterine devices and 14.08 (95% confidence interval, 13.44-14.75) for copper intrauterine devices; 1-year and 5-year crude cumulative incidence was 2.30% (95% confidence interval, 2.24-2.36) and 4.52% (95% confidence interval, 4.40-4.65) for levonorgestrel-releasing intrauterine devices and 2.30% (95% confidence interval, 2.18-2.44) and 4.82 (95% confidence interval, 4.56-5.10) for copper intrauterine devices, respectively. Comparing levonorgestrel-releasing intrauterine devices with copper intrauterine devices, the adjusted hazard ratios were 1.49 (95% confidence intervals, 1.25-1.78) for perforation and 0.69 (95% confidence intervals, 0.65-0.73) for expulsion.After adjusting for potential confounders, levonorgestrel-releasing intrauterine devices were associated with an increased risk of uterine perforation and a decreased risk of expulsion relative to copper intrauterine devices. Given that the absolute numbers of these events are low in both groups, these differences may not be clinically meaningful.

Bariatric surgery is a widely used treatment option for obesity that often provides long-term weight control and health benefits. Although a growing number of women are becoming pregnant after bariatric surgery, only a few population-based studies have assessed the impact thereof on perinatal outcomes.This study aimed to examine the association between bariatric surgery and adverse perinatal outcomes in pregnant women and to examine whether the risk for adverse perinatal outcomes is modified by the postsurgery weight, gestational weight gain, type of bariatric surgery, timing of pregnancy after bariatric surgery, and maternal comorbidities.A retrospective cohort study was performed with the use of the Bariatric Surgery Registry and hospital inpatient and outpatient physician encounter records. The International Classification of Diseases, Ninth and Tenth Revision codes from hospitalizations during pregnancy and infant birth records were used to ascertain the outcomes of interest. Women eligible for BS who delivered at ≥20 weeks of gestation (n=20,213) at Kaiser Permanente Southern California hospitals (January 1, 2007 to December 31, 2018) were included in the study. Adjusted odds ratios were derived from logistic regression models with inverse probability of treatment weighting to adjust for confounding using propensity scores.Bariatric surgery was associated with a reduction in the risks for gestational diabetes (adjusted odds ratio, 0.60; 95% confidence interval, 0.53-0.69; P.001), preeclampsia (adjusted odds ratio, 0.53; 95% confidence interval, 0.46-0.61; P.001), chorioamnionitis (adjusted odds ratio, 0.45; 95% confidence interval, 0.32-0.63; P.001), cesarean delivery (adjusted odds ratio, 0.65; 95% confidence interval, 0.59-0.72; P.001), large for gestational age neonate (adjusted odds ratio, 0.23; 95% confidence interval, 0.19-0.29; P.001), macrosomia (adjusted odds ratio, 0.24; 95% confidence interval, 0.19-0.30; P.001), and neonatal intensive care unit admission (adjusted odds ratio, 0.70; 95% confidence interval, 0.61-0.81; P.001). However, bariatric surgery was also associated with a significantly increased risk for small for gestational age neonates (adjusted odds ratio, 2.46; 95% confidence interval, 2.16-2.79; P.001). The risk for the adverse outcomes is independent of the time interval between the surgery and subsequent pregnancy.These data suggest that there are many pregnancy outcome benefits for women with severe obesity who undergo bariatric surgery; however, women who have undergone bariatric surgery before pregnancy should be monitored closely to reduce the risk for small for gestational age neonates and postpartum hemorrhage.

Objectives Nearly 100% of North American women have detectable levels of flame retardants such as polybrominated diphenyl ethers (PBDEs) in their plasma. These molecules have structural homology to thyroid hormones and may function as endocrine disruptors. Thyroid dysfunction has previously been associated with increased risk for preterm birth. Therefore, we conducted a multi-center, case-cohort study to evaluate if high plasma concentrations of a common PBDE congener in the first trimester increases the risk of preterm birth and its subtypes. Methods Pregnant women were recruited at the onset of initiation of prenatal care at Kaiser-Permanente Southern California (KPSC)-West Los Angeles and KPSC-San Diego medical centers. Plasma samples from women whose pregnancies ended preterm and random subset of those delivering at term were assayed for PBDE-47 and thyroid-stimulating hormone (TSH) by immunoassay. Quartile cutoffs were calculated for the patients at term and used to determine if women with exposures in the 4th quartile are at increased risk for preterm birth using logistic regression. Results We found that high concentrations of PBDE-47 in the first trimester significantly increased the odds of both indicated (adjusted odds ratio, adjOR=2.35, 95% confidence interval [CI]: 1.31, 4.21) and spontaneous (adjOR=1.76, 95% CI: 1.02, 3.03) preterm birth. Regardless of pregnancy outcome, TSH concentrations did not differ between women with high and low concentrations of PBDE-47. Conclusions These results suggest that high plasma concentrations of PBDE-47 in the first trimester, increases the risk of indicated and spontaneous preterm birth.

Importance There are few population-based studies addressing trends in neonatal intensive care unit (NICU) admission and NICU patient-days, especially in the subpopulation that, by gestational age (GA) and birth weight (BW), might otherwise be able to stay in the room with their mothers. Objective To describe population-based trends in NICU admissions, NICU patient-days, readmissions, and mortality in the birth population of a large integrated health care system. Design, Setting, and Participants This cohort study was conducted using data extracted from electronic medical records at Kaiser Permanente Southern California (KPSC) health care system. Participants included all women who gave birth at KPSC hospitals and their newborns from January 1, 2010, through December 31, 2018. Data extraction was limited to data entry fields whose contents were either numbers or fixed categorical choices. Rates of NICU admission, NICU patient-days, readmission rates, and mortality rates were measured in the total population, in newborns with GA 35 weeks or greater and BW 2000 g or more (high GA and BW group), and in the remaining newborns (low GA and BW group). Admissions to the NICU and NICU patient-days were risk adjusted with a machine learning model based on demographic and clinical characteristics before NICU admission. Changes in the trends were assessed with 2-sided correlated seasonal Mann-Kendall test. Data analysis was performed in August 2019. Exposures Admission to the NICU and NICU patient-days among the birth cohort. Main Outcomes and Measures The primary outcomes were NICU admission and NICU patient-days in the total neonatal population and GA and BW subgroups. The secondary outcomes were readmission and mortality rates. Results Over the study period there were 320 340 births (mean [SD] age of mothers, 30.1 [5.7] years; mean [SD] gestational age, 38.6 [1.97] weeks; mean [SD] birth weight, 3302 [573] g). The risk-adjusted NICU admission rate decreased from a mean of 14.5% (95% CI, 14.2%-14.7%) to 10.9% (95% CI, 10.7%-11.7%) (P for trend = .002); 92% of the change was associated with changes in the care of newborns in the high GA and BW group. The number of risk-adjusted NICU patient-days per birth decreased from a mean of 1.50 patient-days (95% CI, 1.43-1.54 patient-days) to 1.40 patient-days (95% CI, 1.36-1.48 patient-days) (P for trend = .03); 70% of the change was associated with newborns in the high GA and BW group. The unadjusted 30-day readmission rates and mortality rates did not change. Conclusions and Relevance Admission rates to the NICU and numbers of NICU patient-days decreased over the study period without an increase in readmissions or mortality. The observed decrease was associated with the high GA and BW newborn population. How much of this decrease is attributable to intercurrent health care systemwide quality improvement initiatives would require further investigation. The remaining unexplained variation suggests that further changes are also possible.

Purpose To examine the frequency of ophthalmic immune-related adverse events (OirAEs) in melanoma, other cancers, and after immune checkpoint inhibitor (ICI) treatment. Design Retrospective clinical cohort study. Methods This study identified patients diagnosed with OirAEs between January 1, 2011, and December 31, 2018, in the Kaiser Permanente Southern California electronic health records. The primary exposures of interest were prior initiation of ICIs and underlying cancer diagnosis. Risk-adjusted prevalence of OirAEs was evaluated in patients with melanoma, with nonmelanoma cancer, and without cancer. The 1-year incidence of OirAEs and recurrence of prior ophthalmic disease were identified in ICI-receiving patients with melanoma and nonmelanoma. Results Among 4,695,669 unique patients identified, 9.9% had a cancer diagnosis, of whom 2.8% had a diagnosis of melanoma. Overall prevalence for uveitis and selected neuro-ophthalmic diagnoses was 341.8/100,000 patient-years in patients with melanoma and 369.6/100,000 patient-years in patients with nonmelanoma cancer regardless of ICI treatment, compared with 142.2/100,000 patient-years in patients without cancer. A total of 2,911 unique patients received ICI therapy. Compared with patients with nonmelanoma cancer, patients with melanoma on any ICI had elevated 1-year incidence rates of uveitis (1.2% vs 0.2%; risk-adjusted odds ratio, 6.45). High 1-year recurrence rates for uveitis in ICI patients with a prior uveitis history were also observed. Conclusions The prevalence of all OirAEs was substantially higher in patients with cancer, with ICI-related uveitis risk specifically increased in patients with melanoma compared with patients with nonmelanoma cancer. Evidence-based guidelines for ophthalmic monitoring of patients undergoing ICI treatment may require different risk stratifications based on underlying cancer diagnosis, specific ICI used, and prior history of uveitis.

Background Surveillance of ectopic pregnancy (EP) using electronic databases is important. To our knowledge, no published study has assessed the validity of EP case ascertainment using electronic health records. Objective We aimed to assess the validity of an enhanced version of a previously validated algorithm, which used a combination of encounters with EP-related diagnostic/procedure codes and methotrexate injections. Methods Medical records of 500 women aged 15-44 years with membership at Kaiser Permanente Southern and Northern California between 2009 and 2018 and a potential EP were randomly selected for chart review, and true cases were identified. The enhanced algorithm included diagnostic/procedure codes from the International Classification of Diseases, Tenth Revision, used telephone appointment visits, and excluded cases with only abdominal EP diagnosis codes. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall performance (Youden index and F-score) of the algorithm were evaluated and compared to the validated algorithm. Results There were 334 true positive and 166 true negative EP cases with available records. True positive and true negative EP cases did not differ significantly according to maternal age, race/ethnicity, and smoking status. EP cases with only one encounter and non-tubal EPs were more likely to be misclassified. The sensitivity, specificity, PPV, and NPV of the enhanced algorithm for EP were 97.6%, 84.9%, 92.9%, and 94.6%, respectively. The Youden index and F-score were 82.5% and 95.2%, respectively. The sensitivity and NPV were lower for the previously published algorithm at 94.3% and 88.1%, respectively. The sensitivity of surgical procedure codes from electronic chart abstraction to correctly identify surgical management was 91.9%. The overall accuracy, defined as the percentage of EP cases with correct management (surgical, medical, and unclassified) identified by electronic chart abstraction, was 92.3%. Conclusions The performance of the enhanced algorithm for EP case ascertainment in integrated health care databases is adequate to allow for use in future epidemiological studies. Use of this algorithm will likely result in better capture of true EP cases than the previously validated algorithm.

BACKGROUND Surveillance of ectopic pregnancy (EP) using electronic databases is important. To our knowledge, no published study has assessed the validity of EP case ascertainment using electronic health records. OBJECTIVE We aimed to assess the validity of an enhanced version of a previously validated algorithm, which used a combination of encounters with EP-related diagnostic/procedure codes and methotrexate injections. METHODS Medical records of 500 women aged 15-44 years with membership at Kaiser Permanente Southern and Northern California between 2009 and 2018 and a potential EP were randomly selected for chart review, and true cases were identified. The enhanced algorithm included diagnostic/procedure codes from the International Classification of Diseases, Tenth Revision, used telephone appointment visits, and excluded cases with only abdominal EP diagnosis codes. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall performance (Youden index and F-score) of the algorithm were evaluated and compared to the validated algorithm. RESULTS There were 334 true positive and 166 true negative EP cases with available records. True positive and true negative EP cases did not differ significantly according to maternal age, race/ethnicity, and smoking status. EP cases with only one encounter and non-tubal EPs were more likely to be misclassified. The sensitivity, specificity, PPV, and NPV of the enhanced algorithm for EP were 97.6%, 84.9%, 92.9%, and 94.6%, respectively. The Youden index and F-score were 82.5% and 95.2%, respectively. The sensitivity and NPV were lower for the previously published algorithm at 94.3% and 88.1%, respectively. The sensitivity of surgical procedure codes from electronic chart abstraction to correctly identify surgical management was 91.9%. The overall accuracy, defined as the percentage of EP cases with correct management (surgical, medical, and unclassified) identified by electronic chart abstraction, was 92.3%. CONCLUSIONS The performance of the enhanced algorithm for EP case ascertainment in integrated health care databases is adequate to allow for use in future epidemiological studies. Use of this algorithm will likely result in better capture of true EP cases than the previously validated algorithm.

CONTEXT: Current guidelines recommend a nonfluoroquinolone agent as first-line treatment of acute uncomplicated cystitis (AUC) because of concerns of antimicrobial resistance and adverse effects. OBJECTIVE: To test whether a multifaceted intervention involving education and feedback reduced primary care practitioners’ ciprofloxacin prescriptions for AUC therapy. DESIGN: Primary care practitioners at 3 medical offices participated: 65 in the intervention group and 51 in the control group. Intervention group participants received an educational lecture and emailed summary of antimicrobial guidelines, their AUC prescriptions were audited, and feedback was provided on inappropriate antibiotic choices. Prescriptions at AUC encounters were tracked during baseline, intervention, and postintervention periods. MAIN OUTCOME MEASURES: Proportion of AUC encounters at which ciprofloxacin was prescribed vs recommended first-line antibiotics. RESULTS: Intervention group participants had 5262 eligible AUC encounters, and control group participants had 5473. At baseline, ciprofloxacin was prescribed at 29.7% and 33.7% of eligible AUC encounters in the intervention and control groups, respectively (p = 0.003). After intervention, ciprofloxacin was prescribed at 10.8% of eligible AUC encounters in the intervention group and 34.3% in the control (p < 0.001). Adjusted odds ratios of ciprofloxacin prescription for AUC therapy were significantly lower in the intervention group during postintervention and intervention periods vs baseline (0.29, 95% confidence interval = 0.20–0.44, p < 0.001 and 0.80, 95% confidence interval = 0.66–0.97, p = 0.03). Adjusted odds ratios did not change over time in the controls. CONCLUSION: Educating primary care practitioners and conducting audit and feedback reduced their prescriptions of ciprofloxacin for AUC therapy.

Intrauterine device (IUD) expulsion increases the risk of unintended pregnancy; how timing of postpartum IUD insertion and breastfeeding are associated with risk of expulsion is relevant to the benefit-risk profile.To evaluate the association of postpartum timing of IUD insertion and breastfeeding status with incidence and risk of IUD expulsion.The Association of Perforation and Expulsion of Intrauterine Devices (APEX-IUD) cohort study included women aged 50 years or younger with an IUD insertion between 2001 and 2018. The breastfeeding analysis focused on a subcohort of women at 52 or fewer weeks post partum with known breastfeeding status. The study was conducted using data from electronic health records (EHRs) at 4 research sites with access to EHR: 3 Kaiser Permanente sites (Northern California, Southern California, Washington) and the Regenstrief Institute (Indiana). Data analysis was conducted from June to November 2019.Timing of IUD insertion post partum was categorized into discrete time periods: 0 to 3 days, 4 days to 6 or fewer weeks, more than 6 weeks to 14 or fewer weeks, more than 14 weeks to 52 or fewer weeks, and non-post partum (52 weeks or no evidence of delivery). Breastfeeding status at the time of insertion was determined from clinical records, diagnostic codes, or questionnaires from well-baby visits.Incidence rates and adjusted hazard ratios (aHRs) were estimated using propensity scores to adjust for confounding.The full cohort included 326 658 women (mean [SD] age, 32.0 [8.3] years; 38 911 [11.9%] Asian or Pacific Islander; 696 [0.2%] Hispanic Black; 56 180 [17.2%] Hispanic other; 42 501 [13.0%] Hispanic White; 28 323 [8.7%] non-Hispanic Black; 137 102 [42.0%] non-Hispanic White), and the subcohort included 94 817 women. Most IUDs were levonorgestrel-releasing (259 234 [79.4%]). There were 8943 expulsions. The 5-year cumulative incidence of IUD expulsion was highest for insertions 0 to 3 days post partum (10.73%; 95% CI, 9.12%-12.61%) and lowest for insertions more than 6 weeks to 14 or fewer weeks post partum (3.18%; 95% CI, 2.95%-3.42%). Adjusted HRs using women with non-post partum IUD insertion as the referent were 5.34 (95% CI, 4.47-6.39) for those with postpartum insertion at 0 to 3 days; 1.22 (95% CI, 1.05-1.41) for those with postpartum insertion at 4 days to 6 or fewer weeks; 1.06 (95% CI, 0.95-1.18) for those with postpartum insertion at more than 6 to 14 or fewer weeks; and 1.43 (95% CI, 1.29-1.60) for those with postpartum insertion at more than 14 to 52 or fewer weeks. In the subcohort, 5-year cumulative incidence was 3.49% (95% CI, 3.25%-3.73%) for breastfeeding women and 4.57% (95% CI, 4.22%-4.95%) for nonbreastfeeding women; the adjusted HR for breastfeeding vs not breastfeeding was 0.71 (95% CI, 0.64-0.78).In this study of real-world data, IUD expulsion was rare but more common with immediate postpartum insertion. Breastfeeding was associated with lower expulsion risk.

BackgroundEpidemiological findings are inconsistent regarding the associations between air pollution exposure during pregnancy and gestational diabetes mellitus (GDM). Several limitations exist in previous studies, including potential outcome and exposure misclassification, unassessed confounding, and lack of simultaneous consideration of air pollution mixtures and particulate matter (PM) constituents.ObjectivesTo assess the association between GDM and maternal residential exposure to air pollution, and the joint effect of the mixture of air pollutants and PM constituents.MethodsDetailed clinical data were obtained for 395,927 pregnancies in southern California (2008-2018) from Kaiser Permanente Southern California (KPSC) electronic health records. GDM diagnosis was based on KPSC laboratory tests. Monthly average concentrations of fine particulate matter&nbsp

Purpose Dupuytren disease is a common benign fibroproliferative disorder causing thickening and shortening of the palmar fascia of the hand. The exact etiology of the disease is unclear but known risk factors such as increased age, male sex, and northern European ethnicity have been established. A link between body mass index (BMI) and Dupuytren disease has not been established previously. The purpose of this study was to test the hypothesis that lower BMI is associated with increased risk for Dupuytren disease diagnosis. Methods After we obtained institutional review board approval, we performed a retrospective review using an electronic medical record and an administrative database from Kaiser Permanente Southern California to identify all enrolled patients there between 2007 and 2014 who were diagnosed with Dupuytren disease. Basic demographic data including age, sex, ethnicity, and BMI were collected. Bivariate and multivariable logistical regression analyses were performed to evaluate for associations between Dupuytren disease and BMI. Results A total of 2,049,803 patients aged 18 years and older were enrolled in Kaiser Permanente Southern California from 2007 to 2014. During that period, 14,844 patients were identified as having Dupuytren disease. The data were consistent with well-defined demographic trends in Dupuytren disease, with increased rates seen in males, Caucasians, and patients aged 50 years and older. In the multivariable analysis, when controlling for age, race, and sex, the risk of Dupuytren disease was inversely proportional to BMI. Conclusions The current study showed that higher BMI is associated with decreased odds of having Dupuytren disease. Further work will be required to determine the cause for the apparent relationship between Dupuytren disease and BMI and whether physiologic factors related to obesity may be protective against the development of Dupuytren disease. Type of study/level of evidence Prognostic II.

Background Intrauterine devices are effective and safe, long-acting reversible contraceptives, but the risk of uterine perforation occurs with an estimated incidence of 1 to 2 per 1000 insertions. The European Active Surveillance Study for Intrauterine Devices, a European prospective observational study that enrolled 61,448 participants (2006–2012), found that women breastfeeding at the time of device insertion or with the device inserted at ≤36 weeks after delivery had a higher risk of uterine perforation. The Association of Uterine Perforation and Expulsion of Intrauterine Device (APEX-IUD) study was a Food and Drug Administration–mandated study designed to reflect current United States clinical practice. The aims of the APEX-IUD study were to evaluate the risk of intrauterine device–related uterine perforation and device expulsion among women who were breastfeeding or within 12 months after delivery at insertion. Objective We aimed to describe the APEX-IUD study design, methodology, and analytical plan and present population characteristics, size of risk factor groups, and duration of follow-up. Study Design APEX-IUD study was a retrospective cohort study conducted in 4 organizations with access to electronic health records: Kaiser Permanente Northern California, Kaiser Permanente Southern California, Kaiser Permanente Washington, and Regenstrief Institute in Indiana. Variables were identified through structured data (eg, diagnostic, procedural, medication codes) and unstructured data (eg, clinical notes) via natural language processing. Outcomes include uterine perforation and device expulsion; potential risk factors were breastfeeding at insertion, postpartum timing of insertion, device type, and menorrhagia diagnosis in the year before insertion. Covariates include demographic characteristics, clinical characteristics, and procedure-related variables, such as difficult insertion. The first potential date of inclusion for eligible women varies by research site (from January 1, 2001 to January 1, 2010). Follow-up begins at insertion and ends at first occurrence of an outcome of interest, a censoring event (device removal or reinsertion, pregnancy, hysterectomy, sterilization, device expiration, death, disenrollment, last clinical encounter), or end of the study period (June 30, 2018). Comparisons of levels of exposure variables were made using Cox regression models with confounding adjusted by propensity score weighting using overlap weights. Results The study population includes 326,658 women with at least 1 device insertion during the study period (Kaiser Permanente Northern California, 161,442; Kaiser Permanente Southern California, 123,214; Kaiser Permanente Washington, 20,526; Regenstrief Institute, 21,476). The median duration of continuous enrollment was 90 (site medians 74–177) months. The mean age was 32 years, and the population was racially and ethnically diverse across the 4 sites. The mean body mass index was 28.5 kg/m2, and of the women included in the study, 10.0% had menorrhagia ≤12 months before insertion, 5.3% had uterine fibroids, and 10% were recent smokers; furthermore, among these women, 79.4% had levonorgestrel-releasing devices, and 19.5% had copper devices. Across sites, 97,824 women had an intrauterine device insertion at ≤52 weeks after delivery, of which 94,817 women (97%) had breastfeeding status at insertion determined; in addition, 228,834 women had intrauterine device insertion at >52 weeks after delivery or no evidence of a delivery in their health record. Conclusion Combining retrospective data from multiple sites allowed for a large and diverse study population. Collaboration with clinicians in the study design and validation of outcomes ensured that the APEX-IUD study results reflect current United States clinical practice. Results from this study will provide valuable information based on real-world evidence about risk factors for intrauterine devices perforation and expulsion for clinicians.

Objective To examine the association between exposures to perinatal factors and autism spectrum disorders (ASD). Study Design A retrospective cohort study of ASD among children born in Kaiser Permanente Southern California hospitals between 1991 and 2009 (n = 594,638). Medical records were used to determine exposure to perinatal (antepartum and intrapartum) complications. ASD was diagnosed using DSM-IV criteria. Multivariable Cox regression was used to estimate hazard ratios (HRs). Result Children with ASD were more likely to be exposed to perinatal complications (HR = 1.15, 95% confidence interval [CI]: 1.09–1.21) than neurotypical children. Children exposed to antepartum (HR = 1.22, 95% CI: 1.10–1.36) and intrapartum (HR = 1.10, 95% CI: 1.04–1.17) complications were at increased risk of ASD. The risk was even greater when both antepartum and intrapartum conditions were present (HR = 1.44, 95% CI: 1.26–1.63). Conclusion Exposure to antepartum or intrapartum complications increases the risk of ASD in the offspring. Therefore, pregnancy complications may help identify children who could benefit from early screening and intervention for this common neurodevelopmental condition.

Objective Influenza vaccination during pregnancy is known to prevent severe influenza illness but its effects on other outcomes and the extent to which its safety is affected by timing of vaccination, maternal race/ethnicity and the type of vaccine is less clear. Therefore, we examined this in a large retrospective cohort. Methods We analyzed medical and vaccination records from the Kaiser Permanente Southern California (KPSC) records and from the Kaiser Immunization Tracking System (2008–2016). The study included women who were pregnant with singletons during the influenza season. Odds ratios (OR) and their 95% confidence intervals (CI) were used to quantify the associations between immunization status during pregnancy and prenatal and postnatal outcomes after adjusting for confounders. Results Of the 247,036 women in these analyses, 53% were vaccinated during their pregnancy. No association between influenza vaccination during pregnancy and adverse prenatal and neonatal outcomes were observed. Influenza vaccination is associated with reduced risk of influenza (OR: 0.49, 95% CI: 0.39–0.62), maternal fever (OR: 0.40, 95% CI: 0.35–0.45), preeclampsia (OR: 0.93, 95% CI: 0.90–0.96), placental abruption (OR: 0.89, 95% CI: 0.82–0.96), stillbirth (OR: 0.88, 95% CI: 0.78–0.99), and NICU admission (OR: 0.89, 95% CI: 0.87–0.92). Both active and inactive vaccines were found to be safe in vaccinated pregnant women regardless of timing of vaccination. Conclusions This study found no evidence of adverse maternal and infant outcomes associated with seasonal influenza vaccine during pregnancy. On the contrary, vaccinated women were less likely to have adverse outcomes than unvaccinated women. The lack of increased adverse outcomes associated with influenza vaccination suggests that the benefits of vaccination during pregnancy to the woman and her child far outweigh any risk, if there is one, from the vaccination.

BACKGROUND The widespread use of antepartum and intrapartum antibiotics has raised concerns about the possible disruption of the child's gut microbiota, and effects on the ‘maturation’ from the infant to the adult microbiome. The Fetal Antibiotic EXposure (FAX) Study provides a cohort to examine the association between in-utero exposure to antibiotics and adverse childhood outcomes including body weight, atopic diseases, and autism spectrum disorders and to investigate the role of other potential factors mitigating or moderating the risk for adverse outcomes. OBJECTIVE To describe the methods, cohort characteristics, and retention of infants included in the study cohort. METHODS For this retrospective cohort study, we included children born in KPSC hospitals between January 1, 2007 and December 31, 2015 within 22-44 weeks of gestation with KPSC insurance coverage during the first year of life. Follow-up data collection is through electronic medical record (EMR) data from Kaiser Permanente Southern California (KPSC). RESULTS The study cohort was comprised of 223,431 children of which 65.7% were exposed to antibiotics in-utero; 19.0% were exposed during the antepartum period, 30.0% during the intrapartum period, and 16.7% exposed during both the antepartum and intrapartum periods. During their first year of life, children had a median of 5 BMI measurements; the frequency of BMI measurements declined to a median of 3 in their second year of life and 2 for 3-5 years of age. The 5-year retention of children in the health plan was over 80% with the highest retention for Hispanic children. CONCLUSIONS This cohort of children will provide a unique opportunity to address key questions regarding the long-term sequelae of in-utero exposure to antibiotics using real-world data. The high retention and multiple medical visits over time allow us to model the trajectories of BMI over time.

BACKGROUND: Increasing vaccination of pregnant women makes it important to assess safety events potentially linked to prenatal vaccination. This study investigates the association between prenatal tetanus, diphtheria, acellular pertussis (Tdap) vaccination and autism spectrum disorder (ASD) risk in offspring. METHODS: This is a retrospective cohort study of mother-child pairs with deliveries January 1, 2011 to December 31, 2014 at Kaiser Permanente Southern California hospitals. Maternal Tdap vaccination from pregnancy start to delivery date was obtained from electronic medical records. A diagnosis of ASD was obtained by using International Classification of Diseases, Ninth and Tenth Revision codes. Children were managed from birth to first ASD diagnosis, end of membership, or end of follow-up (June 30, 2017). Cox proportional hazards models estimated the unadjusted and adjusted hazard ratios (HRs) for the association between maternal Tdap vaccination and ASD, with inverse probability of treatment weighting to adjust for confounding. RESULTS: Women vaccinated were more likely to be Asian American or Pacific Islander, be nulliparous, have a higher education, receive influenza vaccination prenatally, and give birth at term. ASD was diagnosed in 1341 (1.6%) children, and the incidence rate was 3.78 per 1000 person years in the Tdap exposed and 4.05 per 1000 person years in the unexposed group (HR: 0.98, 95% confidence interval: 0.88–1.09). The inverse probability of treatment weighting–adjusted analyses revealed that prenatal Tdap vaccination was not associated with an increased ASD risk (HR: 0.85, 95% confidence interval: 0.77–0.95). CONCLUSIONS: Prenatal Tdap vaccination was not associated with an increased ASD risk. We support recommendations to vaccinate pregnant women to protect infants, who are at highest risk of death after pertussis infection.

Lymphoid malignancies are among the most common cancers diagnosed in adolescents and young adults (AYAs). However, little is known about the factors affecting survival in AYAs with non-Hodgkin lymphoma (NHL). We evaluated if survival differs by race/ethnicity and neighborhood socioeconomic status in AYAs with NHL.AYAs aged 15-39 diagnosed with incident NHL during 1990-2010 at Kaiser Permanente Southern California (KPSC), a large managed care organization, were identified. Demographic information and cancer characteristics were obtained from KPSC's cancer registry. Mortality data were obtained from California and national death files. Patients were followed from NHL diagnosis to 5 years postdiagnosis or 12/31/2012, whichever came first. Multivariable Cox model was used to evaluate the association between race/ethnicity, neighborhood income/education level, and mortality, adjusting for age, gender, stage, year of diagnosis, and histology subtype.A total of 718 AYAs with NHL were included (mean age at diagnosis: 31 years); 45% were non-Hispanic white, 10% were African American, 36% were Hispanic, and 8% were Asian/Pacific Islander. Overall 5-year mortality was 30%. Compared to non-Hispanic whites, Asians/Pacific Islanders had increased 5-year mortality (hazard ratio=1.95, 95% confidence interval: 0.93-4.07). No significant increase in mortality was found for Hispanics or African Americans. Lower neighborhood income but not education level was associated with worse overall survival.A survival disparity for Asians/Pacific Islanders and low-income neighborhoods was observed in AYAs with NHL despite relatively equal access to care. These results call for studies to further understand mechanisms underlying the inferior outcomes among disadvantaged subgroups.

Author(s): Gabayan, Gelareh Z.; Gould, Michael K.; Weiss, Robert E.; Chiu, Vicki Y.; Sarkisian, Catherine A. | Abstract: Introduction: The emergency department (ED) is an inherently high-risk setting. Risk scores can help practitioners understand the risk of ED patients for developing poor outcomes after discharge. Our objective was to develop two risk scores that predict either general inpatient admission or death/intensive care unit (ICU) admission within seven days of ED discharge.Methods: We conducted a retrospective cohort study of patients age g 65 years using clinical data from a regional, integrated health system for years 2009-2010 to create risk scores to predict two outcomes, a general inpatient admission or death/ICU admission. We used logistic regression to predict the two outcomes based on age, body mass index, vital signs, Charlson comorbidity index (CCI), ED length of stay (LOS), and prior inpatient admission.Results: Of 104,025 ED visit discharges, 4,638 (4.5%) experienced a general inpatient admission and 531 (0.5%) death or ICU admission within seven days of discharge. Risk factors with the greatest point value for either outcome were high CCI score and a prolonged ED LOS. The C-statistic was 0.68 and 0.76 for the two models.Conclusion: Risk scores were successfully created for both outcomes from an integrated health system, inpatient admission or death/ICU admission. Patients who accrued the highest number of points and greatest risk present to the ED with a high number of comorbidities and require prolonged ED evaluations.

BackgroundTo determine whether hypothyroidism is associated with autism spectrum disorders (ASD) and how this association is influenced by race-ethnicity, sex, and timing of exposure.MethodsA retrospective cohort study was conducted using records from 397,201 children who were delivered from 1991 to 2011 and remained health plan members from 1993 to 2014.ResultsChildren of hypothyroid women had higher ASD rates than children of women without the diagnosis (2.14 vs. 1.62/1,000 person-years; adjusted hazard ratios (adj.HR), 1.31; 95% confidence interval (CI), 1.13-1.53). This occurred in women diagnosed before as well as during pregnancy. Maternal hypothyroidism was associated with ASD for both boys (3.93 vs. 2.62/1,000 person-years; adj.HR, 1.27; 95% CI, 1.07-1.50) and girls (1.10 vs. 0.61/1,000 person-years; adj.HR, 1.51; 95% CI, 1.10-2.08). Of women with a diagnosis of hypothyroidism during pregnancy, normal thyroid-stimulating hormone (TSH) and free thyroxine (fT4) levels were not associated with an increased risk of ASD in children. Compared with white children, prenatal hypothyroidism was associated with an increased risk of ASD in children of Hispanics (adj.HR, 1.09; 95% CI, 1.01-1.17) and women of other/mixed race-ethnicity (adj.HR, 1.08; 95% CI, 1.00-1.16).ConclusionMaternal hypothyroidism is associated with ASD in children in a manner dependent on race-ethnicity. Management of maternal hypothyroidism may ameliorate the risk of ASD.

Background Emergency department (ED) crowding has been identified as a major threat to public health. Objectives We assessed patient transit times and ED system crowding measures based on their associations with outcomes. Research design Retrospective cohort study. Subjects We accessed electronic health record data on 136,740 adults with a visit to any of 13 health system EDs from January 2008 to December 2010. Measures Patient transit times (waiting, evaluation and treatment, boarding) and ED system crowding [nonindex patient length-of-stay (LOS) and boarding, bed occupancy] were determined. Outcomes included individual inpatient mortality and admission LOS. Covariates included demographic characteristics, past comorbidities, severity of illness, arrival time, and admission diagnoses. Results No patient transit time or ED system crowding measure predicted increased mortality after control for patient characteristics. Index patient boarding time and lower bed occupancy were associated with admission LOS (based on nonoverlapping 95% CI vs. the median value). As boarding time increased from none to 14 hours, admission LOS increased an additional 6 hours. As mean occupancy decreased below the median (80% occupancy), admission LOS decreased as much as 9 hours. Conclusions Measures indicating crowded ED conditions were not predictive of mortality after case-mix adjustment. The first half-day of boarding added to admission LOS rather than substituted for it. Our findings support the use of boarding time as a measure of ED crowding based on robust prediction of admission LOS. Interpretation of measures based on other patient ED transit times may be limited to the timeliness of care.

Background The widespread use of antepartum and intrapartum antibiotics has raised concerns about the possible disruption of the child’s gut microbiota and effects on the maturation from the infant to the adult microbiome. The Fetal Antibiotic EXposure (FAX) study provides a cohort to examine the association between in-utero exposure to antibiotics and adverse childhood outcomes including body weight, atopic diseases, and autism spectrum disorders and to investigate the role of other potential factors mitigating or moderating the risk for adverse outcomes. Objective The aim of this paper was to describe the methods, cohort characteristics, and retention of infants included in the study cohort. Methods For this retrospective cohort study, we included children born in Kaiser Permanente Southern California (KPSC) hospitals between January 1, 2007, and December 31, 2015, within 22 to 44 completed weeks of gestation with KPSC insurance coverage during the first year of life. Follow-up data collection was performed through electronic medical records. Results The study cohort was comprised 223,431 children of which 65.7% (146,720/223,431) were exposed to antibiotics in-utero: 19.0% (42,511/223,431) were exposed during the antepartum period, 30.0% (66,896/223,431) during the intrapartum period, and 16.7% (37,313/223,431) exposed during both the antepartum and intrapartum periods. Conclusions This cohort of children will provide a unique opportunity to address key questions regarding the long-term sequelae of in-utero exposure to antibiotics using real-world data. The high retention and multiple medical visits over time allow us to model the trajectories of body mass index over time. International Registered Report Identifier (IRRID) DERR1-10.2196/12065

The risk of hypothyroidism after hemithyroidectomy is variable, and most estimates come from single institutional studies. The purpose of the present study was to determine the incidence of hypothyroidism at the population level, and to evaluate predictive factors for hypothyroidism after hemithyroidectomy. This retrospective study identified euthyroid patients who underwent hemithyroidectomy between 2000 and 2010 for benign disease in Kaiser Permanente Southern California regional hospitals. The incidence of hypothyroidism [thyroid stimulating hormone (TSH) levels >4 μIU/ml] was analyzed. The independent effect of age-quartile, gender, race, thyroiditis, and preoperative TSH level on the development of hypothyroidism was evaluated. Of 1,240 euthyroid patients identified, 417 (34 %) developed hypothyroidism, and 314 (25 % of total group) needed levothyroxine. Hypothyroidism was more common in age-quartile 2 (32 %), age-quartile 3 (37 %), and age-quartile 4 (42 %) than in age-quartile 1 (25 %) [adjusted odds ratio (OR) = 1.87; 95 % confidence interval (CI) 1.27–2.76, p = 0.002; age-quartile 4 compared to age-quartile 1]. Hypothyroidism was more frequent with increasing preoperative TSH levels 36, 72, and 92 % in patients with TSH levels of 1.0–2, 2.01–3, and 3.01–4 μIU/ml, respectively, compared to 17 % in those with TSH levels

To determine the feasibility of conducting survivorship research for long-term health outcomes with survivors of cancer diagnosed as an adolescent or young adult (AYA) and enrolled in Kaiser Permanente Southern California (KPSC), an integrated managed care organization.Survivors diagnosed at ages 15-39 during 1990 and 2000 at KPSC were included. A 1:5 age-, gender-, and calendar-year-matched non-cancer KPSC comparison group was also identified. Date of cancer diagnosis was defined as the study baseline. KPSC insurance retention rate was calculated at 5 and 10 years post-baseline among survivors. Multivariable logistic regression was used to examine demographic and cancer characteristics associated with KPSC insurance retention at ≥5 years after baseline.A total of 6170 AYA cancer patients were identified: 4745 (77%) and 4471 (72%) survived at 5 and 10 years after diagnosis respectively. Of these survivors, 3654 (77%) and 2817 (63%) remained insured at KPSC at 5 and 10 years post-cancer diagnosis respectively. Those aged 20-29 years when diagnosed and those with stage 4 cancer were less likely to retain KPSC insurance than other survivors. For non-cancer comparison subjects, the KPSC insurance retention rate was lower: 66% at 5 years and 51% at 10 years post-baseline. Younger age, female gender, white race, and later calendar years of study baseline were associated with a lower likelihood of KPSC insurance retention.These results demonstrate the feasibility and potential limitations of conducting survivorship research to characterize long-term health outcomes for survivors of AYA cancer in a large, integrated managed care organization.