Publications by authors named "Krista F Huybrechts"

143 Publications

Association of first trimester prescription opioid use with congenital malformations in the offspring: population based cohort study.

BMJ 2021 02 10;372:n102. Epub 2021 Feb 10.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA 02120, USA.

Objective: To evaluate the risk of first trimester exposure to prescription opioids for major congenital malformations, previously reported to be associated with such exposure.

Design: Population based cohort study.

Setting: Nationwide sample of publicly and commercially insured pregnant women linked to their liveborn infants, nested in the Medicaid Analytic eXtract (MAX, 2000-14) and the MarketScan Research Database (MarketScan, 2003-15).

Participants: 1 602 580 publicly insured (MAX) and 1 177 676 commercially insured (MarketScan) pregnant women with eligibility from at least three months before pregnancy to one month after delivery; infants with eligibility for at least three months after birth.

Interventions: Use of prescription opioids was ascertained by requiring two or more dispensations of any opioid during the first trimester.

Main Outcomes Measures: Major malformations overall, cardiac malformations overall, ventricular septal defect, secundum atrial septal defect/patent foramen ovale, neural tube defect, clubfoot, and oral cleft, defined based on validated algorithms. Propensity score stratification was used to adjust for potential confounders and/or proxies for confounders. Estimates from each database were combined using meta-analysis.

Results: 70 447 (4.4%) of 1 602 580 publicly insured and 12 454 (1.1%) of 1 177 676 commercially insured pregnant women had two or more dispensations of an opioid during the first trimester. Absolute risk of malformations overall was 41.0 (95% confidence interval 39.5 to 42.5) per 1000 pregnancies exposed to opioids versus 32.0 (31.7 to 32.3) per 1000 unexposed pregnancies in the MAX cohort, and 42.6 (39.0 to 46.1) and 37.3 (37.0 to 37.7) per 1000, respectively, in the MarketScan cohort. Pooled unadjusted relative risk estimates were raised for all outcomes but shifted substantially toward the null after adjustment; for malformations overall (relative risk 1.06, 95% confidence interval 1.02 to 1.10), cardiovascular malformations (1.09, 1.00 to 1.18), ventricular septal defect (1.07, 0.95 to 1.21), atrial septal defect/patent foramen ovale (1.04, 0.88 to 1.24), neural tube defect (0.82, 0.53 to 1.27), and clubfoot (1.06, 0.88 to 1.28). The relative risk for oral clefts remained raised after adjustment (1.21, 0.98 to 1.50), with a higher risk of cleft palate (1.62, 1.23 to 2.14).

Conclusions: Prescription opioids used in early pregnancy are not associated with a substantial increase in risk for most of the malformation types considered, although a small increase in the risk of oral clefts associated with their use is possible.
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http://dx.doi.org/10.1136/bmj.n102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873721PMC
February 2021

Patient characteristics associated with SARS-CoV-2 infection in parturients admitted for labour and delivery in Massachusetts during the spring 2020 surge: A prospective cohort study.

Paediatr Perinat Epidemiol 2021 01;35(1):24-33

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Background: While studies from large cities affected by coronavirus disease 2019 (COVID-19) have reported on the prevalence of SARS-CoV-2 in the context of universal testing during admission for delivery, the patient demographic, social and clinical factors associated with SARS-CoV-2 infection in pregnant women are not fully understood.

Objective: To evaluate the epidemiological factors associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in women admitted for labour and delivery, in the context of universal screening at four Boston-area hospitals.

Methods: In this prospective cohort study, we reviewed the health records of all women admitted for labour and delivery at four hospitals from the largest health system in Massachusetts between 19 April 2020 and 27 June 2020. We calculated the risk of SARS-CoV-2 infection, including asymptomatic infection. We calculated associations between SARS-CoV-2 infection and demographic and clinical characteristics.

Results: A total of 93 patients (3.2%, 95% confidence interval 2.5, 3.8) tested positive for SARS-CoV-2 infection on admission for labour and delivery out of 2945 patients included in the analysis; 80 (86.0%) of the patients who tested positive were asymptomatic at the time of testing. Factors associated with SARS-CoV-2 infection included the following: younger age, obesity, African American or Hispanic race/ethnicity, residence in heavily affected communities (as measured in cases reported per capita), presence of a household member with known SARS-CoV-2 infection, non-health care essential worker occupation and MassHealth or Medicaid insurance compared to commercial insurance. 93.8% of patients testing positive for SARS-CoV-2 on admission had one or more identifiable factors associated with disease acquisition.

Conclusions: In this large sample of deliveries during the height of the surge in infections during the spring of 2020, SARS-CoV-2 infection was largely concentrated in patients with distinct demographic characteristics, those largely from disadvantaged communities. Racial disparities seen in pregnancy persist with respect to SARS-CoV-2 infection.
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http://dx.doi.org/10.1111/ppe.12743DOI Listing
January 2021

Hydroxychloroquine early in pregnancy and risk of birth defects: absence of evidence is not the same as evidence of absence.

Am J Obstet Gynecol 2021 Jan 9. Epub 2021 Jan 9.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.

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http://dx.doi.org/10.1016/j.ajog.2020.12.1219DOI Listing
January 2021

Chronic prescription opioid use in pregnancy in the United States.

Pharmacoepidemiol Drug Saf 2021 Apr 17;30(4):504-513. Epub 2021 Jan 17.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Purpose: To evaluate chronic opioid utilization patterns during pregnancy using nationwide data from publicly and commercially insured women.

Methods: Pregnancy cohorts were identified using data from the Medicaid Analytic eXtract 2008-2014 and the IBM Health MarketScan Research Database 2008-2015. Opioid dispensing was evaluated using claims from filled prescriptions. Two different definitions of chronic opioid use were employed: ≥90 days' supply and ≥180 days' supply of prescription opioids during pregnancy. Patient characteristics were assessed and variations in the prevalence of chronic opioid therapy were described by geographic region and over time.

Results: 1.50% of 975 169 Medicaid-insured and 0.32% of 1 037 599 commercially insured beneficiaries filled opioid prescriptions for ≥90 days' supply; 0.78% (Medicaid) and 0.17% (commercially insured) filled prescriptions for ≥180 days' supply. Prevalence approximately doubled in Medicaid beneficiaries during the study period, while it remained relatively stable for commercial insurance beneficiaries. The most commonly prescribed opioid for chronic therapy was hydrocodone, followed by oxycodone and tramadol. Indications commonly associated with chronic use were back/neck pain, abdominal/pelvic pain, musculoskeletal pain and migraine/headache. Substantial regional variation was observed, with several states reporting a frequency of ≥90 days' supply in excess of 3% in Medicaid-insured patients.

Conclusions: Despite growing awareness of the risks associated with chronic opioid use and emphasis on improving opioid prescription patterns, prevalence of chronic use in pregnancy among publicly insured women nearly doubled from 2008-2014 and was 5-fold more common when compared to commercially insured women. Findings call for the development of guidelines on chronic pain management during pregnancy.
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http://dx.doi.org/10.1002/pds.5194DOI Listing
April 2021

Antiemetic Drugs During Pregnancy: What Can We Learn From Spontaneous Reporting System Database Analyses?-Reply.

JAMA Pediatr 2021 Mar;175(3):327-328

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jamapediatrics.2020.5177DOI Listing
March 2021

Active Surveillance of the Safety of Medications Used in Pregnancy.

Am J Epidemiol 2021 Jan 11. Epub 2021 Jan 11.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States.

We rely on post-marketing approaches to define the risk of medications in pregnancy because information at the time of drug approval is limited. Most studies in pregnancy focus on a single or selected outcomes. However, women must balance the benefit of treatment against all possible adverse effects. Our objective was to apply and evaluate a tree-based scan statistic data mining method (TreeScan) as a safety surveillance approach that allows for simultaneous evaluation of a comprehensive range of adverse pregnancy outcomes, while preserving the overall false positive rate. We evaluated TreeScan with a cohort design and adjustment via propensity score techniques using two test cases: (1) opioids and neonatal opioid withdrawal syndrome, and (2) valproate and congenital malformations, implemented in pregnancy cohorts nested in the Medicaid Analytic eXtract (1/1/2000 - 12/31/2014) and IBM MarketScan Research Database (1/1/2003 - 9/30/2015). In both cases, we identified known safety concerns, with only one previously unreported alert at the preset statistical alerting threshold. This evaluation shows the promise of TreeScan-based approaches for systematic drug safety monitoring in pregnancy. A targeted screening approach followed by deeper investigation to refine understanding of potential signals will ensure pregnant women and their physicians have access to the best available evidence to inform treatment decisions.
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http://dx.doi.org/10.1093/aje/kwaa288DOI Listing
January 2021

Prescription opioid use after vaginal delivery and subsequent persistent opioid use and misuse.

Am J Obstet Gynecol MFM 2020 Dec 28;3(2):100304. Epub 2020 Dec 28.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Background: Vaginal delivery is the most common reason for hospitalization in the United States, and approximately 30% of women fill an opioid prescription after vaginal delivery, making this a common source of opioid exposure in women of reproductive age.

Objective: This study aimed to evaluate the effect of receiving an opioid prescription after vaginal delivery on the risk of subsequent persistent opioid use, opioid use disorders, and overdose.

Study Design: We assembled a nationwide cohort of Medicaid beneficiaries in the United States using the Medicaid Analytic eXtract 2009-2014. The study population included pregnant women who delivered vaginally between 2009 and 2013 and were continuously enrolled in Medicaid from 90 days before to 365 days after delivery. We identified patients with prescription opioids dispensed within 7 days of the date of vaginal delivery. Persistent opioid use was defined as ≥10 opioid fills or >120 days' supply dispensed from 30 to 365 days after delivery. Incident diagnoses of opioid use disorder and overdose were ascertained during the same interval. Propensity score matching was used to control for potential confounding factors.

Results: Among 459,829 pregnancies ending in vaginal deliveries, 140,807 (30.62%) had an opioid dispensed within 7 days of delivery. Overall, 5770 of 140,807 (4.10%) women who filled an opioid prescription vs 2668 of 319,022 (0.84%) unexposed women had subsequent persistent opioid use, with an unadjusted relative risk of 4.90 (95% confidence interval, 4.68-5.13) and a risk difference of 3.26% (95% confidence interval, 3.15-3.37). After propensity score matching, the risk remained higher among pregnancies with an opioid prescription dispensed, with a relative risk of 2.57 (95% confidence interval, 2.43-2.72) and a risk difference of 2.21% (95% confidence interval, 2.08-2.33), which was confirmed by the instrumental variable analysis with a risk difference of 1.31% (95% confidence interval, 1.06-1.56) by using the rate of opioid prescribing at the delivery facility in a given geographic region as the instrument. The adjusted relative risk of newly diagnosed opioid use disorder and overdose was 1.48 (95% confidence interval, 1.40-1.57) and 1.92 (95% confidence interval, 1.20-3.09), respectively.

Conclusion: Opioid dispensing following vaginal delivery is associated with future persistent opioid use and misuse, independent of confounding factors. Opioid prescriptions to women after vaginal delivery should be avoided, except in rare circumstances.
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http://dx.doi.org/10.1016/j.ajogmf.2020.100304DOI Listing
December 2020

Drug-drug interactions in pregnancy: An important frontier for pharmacoepidemiology.

Paediatr Perinat Epidemiol 2021 Mar 22;35(2):194-195. Epub 2020 Dec 22.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1111/ppe.12733DOI Listing
March 2021

Pregravid contraceptive use and fecundability: prospective cohort study.

BMJ 2020 11 11;371:m3966. Epub 2020 Nov 11.

Department of Epidemiology, Boston University School of Public Health, 715 Albany Street, Boston, MA 02118 USA.

Objective: To evaluate the association between pregravid use of a variety of contraceptive methods and subsequent fecundability.

Design: Prospective cohort study.

Setting: Denmark and North America, 2007-19.

Participants: 17 954 women who had tried to conceive for up to six menstrual cycles at study entry. At baseline, participants reported their contraceptive histories, and personal, medical, and lifestyle characteristics.

Main Outcome Measures: Pregnancy, determined by bimonthly follow-up questionnaires for up to 12 months.

Results: Approximately 38% (n=6735) of participants had recently used oral contraceptives, 13% (n=2398) had used long acting reversible contraceptive methods, and 31% (n=5497) had used barrier methods. Women who had recently stopped using oral contraceptives, the contraceptive ring, and some long acting reversible contraceptive methods experienced short term delays in return of fertility compared with users of barrier methods. Use of injectable contraceptives was associated with decreased fecundability compared with use of barrier methods (fecundability ratio 0.65; 95% confidence interval 0.47 to 0.89). Users of injectable contraceptives had the longest delay in return of normal fertility (five to eight menstrual cycles), followed by users of patch contraceptives (four cycles), users of oral and ring contraceptives (three cycles), and users of hormonal and copper intrauterine devices and implant contraceptives (two cycles). Lifetime length of use of hormonal contraceptive methods was not associated with fecundability.

Conclusions: Use of some hormonal contraceptive methods was associated with delays in return of fertility, with injectable contraceptives showing the longest delay. The findings indicated little or no lasting effect of long term use of these methods on fecundability.
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http://dx.doi.org/10.1136/bmj.m3966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656314PMC
November 2020

Development and Validation of a Pediatric Comorbidity Index.

Am J Epidemiol 2020 Oct 30. Epub 2020 Oct 30.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Comorbidity scores are widely used to help address confounding bias in nonrandomized studies conducted within healthcare databases, but existing scores were developed to predict all-cause mortality in adults and may not be appropriate for use in pediatric studies. We developed and validated a pediatric comorbidity index, using healthcare utilization data from the tenth revision of the International Classification of Diseases. Within the MarketScan database, pediatric patients (<18 years) continuously enrolled between October 1, 2015-September 30, 2017 were identified. Logistic regression was used to predict the 1-year risk of hospitalization based on 27 predefined conditions and empirically-identified conditions derived from the most prevalent diagnoses among patients with the outcome. A single numerical index was created by assigning weights to each condition based on its beta coefficient. We conducted internal validation of the index and compared its performance to existing adult scores. The pediatric comorbidity index consisted of 24 conditions and achieved a c-statistic of 0.718 (95% confidence interval [CI] 0.714, 0.723). The index oasutperformed existing adult scores in a pediatric population (c-statistics ranging from 0.522 to 0.640). The pediatric comorbidity index provides a summary measure of disease burden and can be used for risk adjustment in epidemiologic studies of pediatric patients.
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http://dx.doi.org/10.1093/aje/kwaa244DOI Listing
October 2020

Antidiabetic medication use in commercially insured children and adolescents in the United States from 2004 to 2019.

Diabetes Obes Metab 2021 Feb 18;23(2):444-454. Epub 2020 Nov 18.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.

Aim: To describe the patterns of non-insulin antidiabetic medication use, initiation and adherence in the paediatric population.

Methods: We conducted a descriptive study of non-insulin antidiabetic medication use in children and adolescents (aged 10-18 years) using real-world data from a nationwide US commercial claims database (January 2004-September 2019). Trends in the prevalence of non-insulin antidiabetic medication use overall and by class were evaluated. Among new users of non-insulin antidiabetic agents, medication adherence was examined using group-based trajectory models.

Results: In a cohort of more than 1 million paediatric patients, the prevalence of any non-insulin antidiabetic medication use was 75.7 per 100 000 patients in 2004 and more than doubled to 162.0 per 100 000 in 2019. Biguanides (metformin) was by far the most widely used medication class. The use of newer classes was low (<10 per 100 000), but there was an uptake in the use of glucagon-like peptide-1 receptor agonists after liraglutide received paediatric approval in 2019. Medication adherence was poor during the 18 months after treatment initiation: 79.6% of initiators experienced an early treatment interruption (median time to interruption: 90 days among metformin monotherapy initiators) and 21% of initiators did not return for a prescription refill after the first month.

Conclusions: There was a substantial increase in non-insulin antidiabetic medication use among commercially insured paediatric patients from 2004 to 2019. Nearly all patients were treated with metformin, while the use of newer agents remained low. Despite the increase in medication use, short treatment episodes were observed, even among patients with a diagnosis of type 2 diabetes, raising concern over poor adherence.
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http://dx.doi.org/10.1111/dom.14237DOI Listing
February 2021

Predicting overdose among individuals prescribed opioids using routinely collected healthcare utilization data.

PLoS One 2020 20;15(10):e0241083. Epub 2020 Oct 20.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.

Introduction: With increasing rates of opioid overdoses in the US, a surveillance tool to identify high-risk patients may help facilitate early intervention.

Objective: To develop an algorithm to predict overdose using routinely-collected healthcare databases.

Methods: Within a US commercial claims database (2011-2015), patients with ≥1 opioid prescription were identified. Patients were randomly allocated into the training (50%), validation (25%), or test set (25%). For each month of follow-up, pooled logistic regression was used to predict the odds of incident overdose in the next month based on patient history from the preceding 3-6 months (time-updated), using elastic net for variable selection. As secondary analyses, we explored whether using simpler models (few predictors, baseline only) or different analytic methods (random forest, traditional regression) influenced performance.

Results: We identified 5,293,880 individuals prescribed opioids; 2,682 patients (0.05%) had an overdose during follow-up (mean: 17.1 months). On average, patients who overdosed were younger and had more diagnoses and prescriptions. The elastic net model achieved good performance (c-statistic 0.887, 95% CI 0.872-0.902; sensitivity 80.2, specificity 80.1, PPV 0.21, NPV 99.9 at optimal cutpoint). It outperformed simpler models based on few predictors (c-statistic 0.825, 95% CI 0.808-0.843) and baseline predictors only (c-statistic 0.806, 95% CI 0.787-0.26). Different analytic techniques did not substantially influence performance. In the final algorithm based on elastic net, the strongest predictors were age 18-25 years (OR: 2.21), prior suicide attempt (OR: 3.68), opioid dependence (OR: 3.14).

Conclusions: We demonstrate that sophisticated algorithms using healthcare databases can be predictive of overdose, creating opportunities for active monitoring and early intervention.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241083PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575098PMC
December 2020

Hydroxychloroquine early in pregnancy and risk of birth defects.

Am J Obstet Gynecol 2021 03 19;224(3):290.e1-290.e22. Epub 2020 Sep 19.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.

Background: Hydroxychloroquine is generally considered safe in pregnancy for the treatment of rheumatic conditions, but studies have been too small to evaluate teratogenicity. Quantifying the risk of congenital malformations associated with early pregnancy exposure to hydroxychloroquine is important in both the context of its ongoing use for rheumatological disorders and its potential future use for coronavirus disease 2019 prophylaxis, for which a number of clinical trials are ongoing despite initial trials for coronavirus disease 2019 treatment having been negative.

Objective: The study objective was to evaluate the risk of major congenital malformations associated with exposure to hydroxychloroquine during the first trimester of pregnancy, the period of organogenesis.

Study Design: We performed a population-based cohort study nested in the Medicaid Analytic eXtract (MAX, 2000-2014) and IBM MarketScan Research Database (MarketScan, 2003-2015). The source cohort included 2045 hydroxychloroquine-exposed pregnancies and 3,198,589 pregnancies not exposed to hydroxychloroquine continuously enrolled in their respective insurance program for 3 months before the last menstrual period through at least 1 month after delivery; infants were enrolled for at least 3 months after birth. We compared the risk of congenital malformations in women using hydroxychloroquine during the first trimester of pregnancy with that of those not using hydroxychloroquine, restricting the cohort to women with rheumatic disorders and using propensity score matching to control for indication, demographics, medical comorbidities, and concomitant medications (1867 hydroxychloroquine-exposed pregnancies and 19,080 pregnancies not exposed to hydroxychloroquine). The outcomes considered included major congenital malformations diagnosed during the first 90 days after delivery and specific malformation types for which there were at least 5 exposed events: oral cleft, cardiac, respiratory, gastrointestinal, genital, urinary, musculoskeletal, and limb defects.

Results: Overall, 54.8 per 1000 infants exposed to hydroxychloroquine were born with a major congenital malformation versus 35.3 per 1000 unexposed infants, corresponding to an unadjusted relative risk of 1.51 (95% confidence interval, 1.27-1.81). Patient characteristics were balanced in the restricted, propensity score-matched cohort. The adjusted relative risk was 1.26 (95% confidence interval, 1.04-1.54); it was 1.33 (95% confidence interval, 1.08-1.65) for a daily dose of ≥400 mg and 0.95 (95% confidence interval, 0.60-1.50) for a daily dose of <400 mg. Among the different malformation groups considered, more substantial increases in the risk of oral clefts, respiratory anomalies, and urinary defects were observed, although estimates were imprecise. No pattern of malformation was identified.

Conclusion: Our findings suggest a small increase in the risk of malformations associated with first-trimester hydroxychloroquine use. For most patients with autoimmune rheumatic disorders, the benefits of treatment during pregnancy will likely outweigh this risk. If hydroxychloroquine were shown to be effective for coronavirus disease 2019 prophylaxis in ongoing trials, the risk of malformations would need to be balanced against such benefits.
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http://dx.doi.org/10.1016/j.ajog.2020.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501839PMC
March 2021

Brief discussion on sampling variability in 1:1 propensity score matching without replacement.

Pharmacoepidemiol Drug Saf 2020 09 10;29(9):1194-1197. Epub 2020 Aug 10.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1002/pds.5094DOI Listing
September 2020

Trends in Human Papillomavirus Vaccination in Commercially Insured Children in the United States.

Pediatrics 2020 10 14;146(4). Epub 2020 Sep 14.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts; and.

Objectives: The human papillomavirus (HPV) vaccine was recommended in 2006 for girls and in 2011 for boys. The Healthy People 2020 goal for 2-dose HPV vaccination coverage is 80% by age 15 for girls and boys. We used nationwide population-based data to describe trends in HPV vaccination in children.

Methods: We conducted a cohort study nested within the MarketScan health care database between January 2003 and December 2017. Children were followed from the year they turned 9 until HPV vaccination, insurance disenrollment, or the end of the year when they turned 17, whichever came first. We estimated the cumulative incidence of at least 1- and 2-dose HPV vaccination, stratified by birth year, sex, and state. In secondary analyses, we evaluated the association between state-level vaccination policies and HPV vaccination coverage.

Results: This study included 7 837 480 children and 19.8 million person-years. The proportion of 15-year-old girls and boys with at least a 1-dose HPV vaccination increased from 38% and 5% in 2011 to 57% and 51% in 2017, respectively; the proportion with at least a 2-dose vaccination went from 30% and 2% in 2011 to 46% and 39% in 2017, respectively. By 2017, 2-dose HPV vaccination coverage varied from 80% in Washington, District of Columbia, among girls to 15% in Mississippi among boys and was positively correlated with legislation for HPV vaccine education and pediatrician availability.

Conclusions: Despite the increasing trends in uptake, HPV vaccine coverage among commercially insured children in the United States remains behind target levels, with substantial disparities by state.
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http://dx.doi.org/10.1542/peds.2019-3557DOI Listing
October 2020

Association Between Congenital Cytomegalovirus and the Prevalence at Birth of Microcephaly in the United States.

JAMA Pediatr 2020 Sep 14. Epub 2020 Sep 14.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.

Importance: Congenital cytomegalovirus (cCMV) has received far less clinical and public health attention as a teratogenic infection than the Zika virus epidemic. However, cCMV may be responsible for a large fraction of microcephaly cases in the United States.

Objective: To evaluate the association between cCMV and the prevalence at birth of microcephaly in the United States.

Design, Setting, And Participants: This population-based cohort study included pregnant women and their newborns identified in 2 insurance claims databases from the United States: Medicaid Analytic eXtract (January 1, 2000, to December 31, 2013) and IBM Research MarketScan, a database for employer-sponsored private health insurance (January 1, 2011, to September 30, 2015). All pregnancies that resulted in live births in women with full health benefits were included. Analysis began June 2016 and ended May 2020.

Exposures: Congenital cytomegalovirus infection documented in inpatient or outpatient newborn claims records.

Main Outcomes And Measures: The primary outcome was microcephaly at birth documented in inpatient or outpatient newborn and/or maternal claims records. Cases with chromosomal abnormalities or neural tube defects were excluded. The association between cCMV and microcephaly was estimated in the pooled cohort using prevalence ratios (PRs) and 95% CIs.

Results: In the pooled cohort of 2 338 580 pregnancies (2 075 410 pregnancies [88.7%] were among women younger than 35 years), 336 infants (0.014%) had a cCMV diagnosis. The prevalence of microcephaly among newborns with and without a cCMV diagnosis was 655 and 2.8 per 10 000 live births, respectively (PR, 232; 95% CI, 154-350). After restricting to CMV-tested newborns (572 [0.024%]) to correct for preferential testing of infants with microcephaly, the PR was 15 (95% CI, 5.2-41). However, this PR is biased if other cCMV-related outcomes (eg, hearing loss) trigger testing because cCMV prevalence in tested infants, with ([46%]) or without microcephaly (22 of 559 [3.9%]), would overestimate that in the source population. Therefore, the prevalence of cCMV in overall infants with microcephaly (22 of 669 [3.2%]) was compared with that from an external unbiased sample of US infants screened at birth (449 of 100 332 [0.45%]) to estimate a PR of 7.4 (95% CI, 4.8-11.5) as a conservative lower bound.

Conclusions And Relevance: Congenital cytomegalovirus infection increases the prevalence of microcephaly at birth by at least 7-fold. Prevention of CMV infection during pregnancy might substantially reduce the number of newborns with microcephaly and other cCMV-related outcomes in the United States.
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http://dx.doi.org/10.1001/jamapediatrics.2020.3009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490747PMC
September 2020

Association of Selective Serotonin Reuptake Inhibitors With the Risk of Type 2 Diabetes in Children and Adolescents.

JAMA Psychiatry 2021 Jan;78(1):91-100

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.

Importance: Concerns exist that use of selective serotonin reuptake inhibitors (SSRIs) increases the risk of developing type 2 diabetes (T2D) in adults, but evidence in children and adolescents is limited. In the absence of a randomized clinical trial, evidence must be generated using real-world data.

Objective: To evaluate the safety of SSRI use in children and adolescents with respect to the associated risk of T2D.

Design, Setting, And Participants: This cohort study of patients aged 10 to 19 years with a diagnosis for an SSRI treatment indication was conducted within the nationwide Medicaid Analytic eXtract (MAX; January 1, 2000, to December 31, 2014) and the IBM MarketScan (January 1, 2003, to September 30, 2015) databases. Data were analyzed from November 1, 2018, to December 6, 2019.

Exposures: New users of an SSRI medication and comparator groups with no known metabolic adverse effects (no antidepressant exposure, bupropion hydrochloride exposure, or psychotherapy exposure). Within-class individual SSRI medications were compared with fluoxetine hydrochloride.

Main Outcomes And Measures: Incident T2D during follow-up. Intention-to-treat effects were estimated using Cox proportional hazards regression models, adjusting for confounding through propensity score stratification. As-treated effects to account for continuous treatment were estimated using inverse probability weighting and marginal structural models.

Results: A total of 1 582 914 patients were included in the analysis (58.3% female; mean [SD] age, 15.1 [2.3] years). The SSRI-treated group included 316 178 patients in the MAX database (publicly insured; mean [SD] age, 14.7 [2.1] years; 62.2% female) and 211 460 in the MarketScan database (privately insured; mean [SD] age, 15.8 [2.3] years; 63.9% female) with at least 2 SSRI prescriptions filled, followed up for a mean (SD) of 2.3 (2.0) and 2.2 (1.9) years, respectively. In publicly insured patients, initiation of SSRI treatment was associated with a 13% increased hazard of T2DM (intention-to-treat adjusted hazard ratio [aHR], 1.13; 95% CI, 1.04-1.22) compared with untreated patients. The association strengthened for continuous SSRI treatment (as-treated aHR, 1.33; 95% CI, 1.21-1.47), corresponding to 6.6 (95% CI, 4.2-10.4) additional cases of T2D per 10 000 patients treated for at least 2 years. Adjusted HRs were lower in privately insured patients (intention-to-treat aHR, 1.01 [95% CI, 0.84-1.23]; as-treated aHR, 1.10 [95% CI, 0.88-1.36]). Findings were similar when comparing SSRI treatment with psychotherapy (publicly insured as-treated aHR, 1.44 [95% CI, 1.25-1.65]; privately insured as-treated aHR, 1.21 [95% CI, 0.93-1.57]), whereas no increased risk was observed compared with bupropion treatment publicly insured as-treated aHR, 1.01 [95% CI, 0.79-1.29]; privately insured as-treated aHR, 0.87 [95% CI, 0.44-1.70]). For the within-class analysis, no medication had an increased hazard of T2D compared with fluoxetine.

Conclusions And Relevance: These findings suggest that children and adolescents initiating SSRI treatment may be at a small increased risk of developing T2D, particularly publicly insured patients. The magnitude of association was more modest than previously reported, and the absolute risk was small. The potential small risk should be viewed in relation to the efficacy of SSRIs for its major indications in young patients.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.2762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489393PMC
January 2021

Gabapentin in pregnancy and the risk of adverse neonatal and maternal outcomes: A population-based cohort study nested in the US Medicaid Analytic eXtract dataset.

PLoS Med 2020 09 1;17(9):e1003322. Epub 2020 Sep 1.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.

Background: Despite the widespread use, only sparse information is available on the safety of gabapentin during pregnancy. We sought to evaluate the association between gabapentin exposure during pregnancy and risk of adverse neonatal and maternal outcomes.

Methods And Findings: Using the United States Medicaid Analytic eXtract (MAX) dataset, we conducted a population-based study of 1,753,865 Medicaid-eligible pregnancies between January 2000 and December 2013. We examined the risk of major congenital malformations and cardiac defects associated with gabapentin exposure during the first trimester (T1), and the risk of preeclampsia (PE), preterm birth (PTB), small for gestational age (SGA), and neonatal intensive care unit admission (NICUa) associated with gabapentin exposure early, late, or both early and late in pregnancy. Gabapentin-unexposed pregnancies served as the reference. We estimated relative risks (RRs) and 95% confidence intervals (CIs) using fine stratification on the propensity score (PS) to control for over 70 confounders (e.g., maternal age, race/ethnicity, indications for gabapentin, other pain conditions, hypertension, diabetes, use of opioids, and specific morphine equivalents). We identified 4,642 pregnancies exposed in T1 (mean age = 28 years; 69% white), 3,745 exposed in early pregnancy only (28 years; 67% white), 556 exposed in late pregnancy only (27 years; 60% white), and 1,275 exposed in both early and late pregnancy (29 years; 75% white). The reference group consisted of 1,744,447 unexposed pregnancies (24 years; 40% white). The adjusted RR for major malformations was 1.07 (95% CI 0.94-1.21, p = 0.33) and for cardiac defects 1.12 (0.89-1.40, p = 0.35). Requiring ≥2 gabapentin dispensings moved the RR to 1.40 (1.03-1.90, p = 0.03) for cardiac defects. There was a higher risk of preterm birth among women exposed to gabapentin either late (RR, 1.28 [1.08-1.52], p < 0.01) or both early and late in pregnancy (RR, 1.22 [1.09-1.36], p < 0.001), SGA among women exposed to gabapentin early (1.17 [1.02-1.33], p = 0.02), late (1.39 [1.01-1.91], p = 0.05), or both early and late in pregnancy (RR, 1.32 [1.08-1.60], p < 0.01), and NICU admission among women exposed to gabapentin both early and late in pregnancy (RR, 1.35 [1.20-1.52], p < 0.001). There was no higher risk of preeclampsia among women exposed to gabapentin after adjustment. Study limitations include the potential for residual confounding and exposure misclassification.

Conclusions: In this large population-based study, we did not find evidence for an association between gabapentin exposure during early pregnancy and major malformations overall, although there was some evidence of a higher risk of cardiac malformations. Maternal use of gabapentin, particularly late in pregnancy, was associated with a higher risk of PTB, SGA, and NICUa.
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http://dx.doi.org/10.1371/journal.pmed.1003322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462308PMC
September 2020

Association Between Number of In-Person Health Care Visits and SARS-CoV-2 Infection in Obstetrical Patients.

JAMA 2020 Sep;324(12):1210-1212

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jama.2020.15242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428807PMC
September 2020

The Association Between Antidepressant Exposure and Birth Defects-Are We There Yet?

JAMA Psychiatry 2020 Aug 5. Epub 2020 Aug 5.

Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jamapsychiatry.2020.1512DOI Listing
August 2020

Prevalence trends and individual patterns of antiepileptic drug use in pregnancy 2006-2016: A study in the five Nordic countries, United States, and Australia.

Pharmacoepidemiol Drug Saf 2020 08 3;29(8):913-922. Epub 2020 Jun 3.

Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway.

Purpose: To describe recent international trends in antiepileptic drug (AED) use during pregnancy and individual patterns of use including discontinuation and switching.

Methods: We studied pregnancies from 2006 to 2016 within linked population-based registers for births and dispensed prescription drugs from Denmark, Finland, Iceland, Norway, Sweden, and New South Wales, Australia and claims data for public and private insurance enrollees in the United States. We examined the prevalence of AED use: the proportion of pregnancies with ≥1 prescription filled from 3 months before pregnancy until birth, and individual patterns of use by trimester.

Results: Prevalence of AED use in almost five million pregnancies was 15.3 per 1000 (n = 75 249) and varied from 6.4 in Sweden to 34.5 per 1000 in the publicly-insured US population. AED use increased in all countries in 2006-2012 ranging from an increase of 22% in Australia to 104% in Sweden, and continued to rise or stabilized in the countries in which more recent data were available. Lamotrigine, clonazepam, and valproate were the most commonly used AEDs in the Nordic countries, United States, and Australia, respectively. Among AED users, 31% only filled a prescription in the 3 months before pregnancy. Most filled a prescription in the first trimester (59%) but few filled prescriptions in every trimester (22%).

Conclusions: Use of AEDs in pregnancy rose from 2006 to 2016. Trends and patterns of use of valproate and lamotrigine reflected the safety data available during this period. Many women discontinued AEDs during pregnancy while some switched to another AED.
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http://dx.doi.org/10.1002/pds.5035DOI Listing
August 2020

Association Between Male Use of Pain Medication and Fecundability.

Am J Epidemiol 2020 11;189(11):1348-1359

Administration of pain relievers has been associated with both lower and higher risks of adverse reproductive outcomes in animals. In the sole investigation of male pain-reliever use and human fertility carried out to date, Smarr et al. (Hum Reprod. 2016;31(9):2119-2127) found a 35% reduction in fecundability among males with urinary acetaminophen concentrations in the highest quartile (>73.5 ng/mL) versus the lowest (<5.4 ng/mL). We analyzed data from 1,956 males participating in Pregnancy Study Online, a preconception cohort study of North American couples enrolled between 2013 and 2019. Males and females completed baseline questionnaires on sociodemographic characteristics, lifestyle, medication use, and medical history; females completed bimonthly follow-up questionnaires for up to 12 months. We categorized pain medications by active ingredient (ibuprofen, acetaminophen, naproxen, aspirin) and cumulative monthly dose. We used proportional probabilities models to calculate fecundability ratios and 95% confidence intervals, adjusting for potential confounders. In the 4 weeks before baseline, 51.7% of males used pain medications. Adjusted fecundability ratios were 1.02 for ibuprofen (95% confidence interval (CI): 0.91, 1.13), 0.89 for acetaminophen (95% CI: 0.77, 1.03), 1.07 for naproxen (95% CI: 0.85, 1.35), and 1.05 for aspirin (95% CI: 0.81, 1.35), as compared with nonuse of each medication. In this study, male use of pain medications at low doses was not notably associated with fecundability.
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http://dx.doi.org/10.1093/aje/kwaa096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731989PMC
November 2020

Contextualizing Potential Risks of Medications in Pregnancy for the Newborn-the Case of Ondansetron.

JAMA Pediatr 2020 Aug;174(8):747-748

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jamapediatrics.2020.1325DOI Listing
August 2020

Ondansetron Use in Pregnancy and Congenital Malformations-Reply.

JAMA 2020 05;323(20):2097-2098

Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jama.2020.5067DOI Listing
May 2020

Oral fluconazole use in the first trimester and risk of congenital malformations: population based cohort study.

BMJ 2020 May 20;369:m1494. Epub 2020 May 20.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA 02120, USA.

Objective: To examine the risk of congenital malformations associated with exposure to oral fluconazole at commonly used doses in the first trimester of pregnancy for the treatment of vulvovaginal candidiasis.

Design: Population based cohort study.

Setting: A cohort of pregnancies publicly insured in the United States, with data from the nationwide Medicaid Analytic eXtract 2000-14.

Participants: Pregnancies of women enrolled in Medicaid from three or more months before the last menstrual period to one month after delivery, and infants enrolled for three or more months after birth.

Interventions: Use of fluconazole and topical azoles was established by requiring one or more prescriptions during the first trimester of pregnancy.

Main Outcome Measures: Risk of musculoskeletal malformations, conotruncal malformations, and oral clefts (primary outcomes), associated with exposure to oral fluconazole, diagnosed during the first 90 days after delivery, were examined.

Results: The study cohort of 1 969 954 pregnancies included 37 650 (1.9%) pregnancies exposed to oral fluconazole and 82 090 (4.2%) pregnancies exposed to topical azoles during the first trimester. The risk of musculoskeletal malformations was 52.1 (95% confidence interval 44.8 to 59.3) per 10 000 pregnancies exposed to fluconazole versus 37.3 (33.1 to 41.4) per 10 000 pregnancies exposed to topical azoles. The risks of conotruncal malformations were 9.6 (6.4 to 12.7) versus 8.3 (6.3 to 10.3) per 10 000 pregnancies exposed to fluconazole and topical azoles, respectively; risks of oral clefts were 9.3 (6.2 to 12.4) versus 10.6 (8.4 to 12.8) per 10 000 pregnancies, respectively. The adjusted relative risk after fine stratification of the propensity score was 1.30 (1.09 to 1.56) for musculoskeletal malformations, 1.04 (0.70 to 1.55) for conotruncal malformations, and 0.91 (0.61 to 1.35) for oral clefts overall. Based on cumulative doses of fluconazole, the adjusted relative risks for musculoskeletal malformations, conotruncal malformations, and oral clefts overall were 1.29 (1.05 to 1.58), 1.12 (0.71 to 1.77), and 0.88 (0.55 to 1.40) for 150 mg of fluconazole; 1.24 (0.93 to 1.66), 0.61 (0.26 to 1.39), and 1.08 (0.58 to 2.04) for more than 150 mg up to 450 mg of fluconazole; and 1.98 (1.23 to 3.17), 2.30 (0.93 to 5.65), and 0.94 (0.23 to 3.82) for more than 450 mg of fluconazole, respectively.

Conclusions: Oral fluconazole use in the first trimester was not associated with oral clefts or conotruncal malformations, but an association with musculoskeletal malformations was found, corresponding to a small adjusted risk difference of about 12 incidents per 10 000 exposed pregnancies overall.
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http://dx.doi.org/10.1136/bmj.m1494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237981PMC
May 2020

Antipsychotic drug use in pregnancy: A multinational study from ten countries.

Schizophr Res 2020 06 12;220:106-115. Epub 2020 Apr 12.

Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Internal Medicine, Danderyd Hospital, Stockholm, Sweden.

Aim: To compare the prevalence and trends of antipsychotic drug use during pregnancy between countries across four continents.

Methods: Individually linked health data in Denmark (2000-2012), Finland (2005-2014), Iceland (2004-2017), Norway (2005-2015), Sweden (2006-2015), Germany (2006-2015), Australia (New South Wales, 2004-2012), Hong Kong (2001-2015), UK (2006-2016), and the US (Medicaid, 2000-2013, and IBM MarketScan, 2012-2015) were used. Using a uniformed approach, we estimated the prevalence of antipsychotic use as the proportion of pregnancies where a woman filled at least one antipsychotic prescription within three months before pregnancy until birth. For the Nordic countries, data were meta-analyzed to investigate maternal characteristics associated with the use of antipsychotics.

Results: We included 8,394,343 pregnancies. Typical antipsychotic use was highest in the UK (4.4%) whereas atypical antipsychotic use was highest in the US Medicaid (1.5%). Atypical antipsychotic use increased over time in most populations, reaching 2% in Australia (2012) and US Medicaid (2013). In most countries, prochlorperazine was the most commonly used typical antipsychotic and quetiapine the most commonly used atypical antipsychotic. Use of antipsychotics decreased across the trimesters of pregnancy in all populations except Finland. Antipsychotic use was elevated among smokers and those with parity ≥4 in the Nordic countries.

Conclusion: Antipsychotic use during pregnancy varied considerably between populations, partly explained by varying use of the typical antipsychotic prochlorperazine, which is often used for nausea and vomiting in early pregnancy. Increasing usage of atypical antipsychotics among pregnant women reflects the pattern that was previously reported for the general population.
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http://dx.doi.org/10.1016/j.schres.2020.03.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306443PMC
June 2020

Effectiveness and Safety of Apixaban Compared With Rivaroxaban for Patients With Atrial Fibrillation in Routine Practice: A Cohort Study.

Ann Intern Med 2020 04 10;172(7):463-473. Epub 2020 Mar 10.

Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (S.S., K.F.H., K.J.L., J.J.G.).

Background: Apixaban and rivaroxaban are the most commonly prescribed direct oral anticoagulants for adults with atrial fibrillation, but head-to-head data comparing their safety and effectiveness are lacking.

Objective: To compare the safety and effectiveness of apixaban versus rivaroxaban for patients with nonvalvular atrial fibrillation.

Design: New-user, active-comparator, retrospective cohort study.

Setting: A U.S. nationwide commercial health care claims database from 28 December 2012 to 1 January 2019.

Patients: Adults newly prescribed apixaban (n = 59 172) or rivaroxaban (n = 40 706).

Measurements: The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial hemorrhage or gastrointestinal bleeding.

Results: 39 351 patients newly prescribed apixaban were propensity score matched to 39 351 patients newly prescribed rivaroxaban. Mean age was 69 years, 40% of patients were women, and mean follow-up was 288 days for new apixaban users and 291 days for new rivaroxaban users. The incidence rate of ischemic stroke or systemic embolism was 6.6 per 1000 person-years for adults prescribed apixaban compared with 8.0 per 1000 person-years for those prescribed rivaroxaban (hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.98]; rate difference, 1.4 fewer events per 1000 person-years [CI, 0.0 to 2.7]). Adults prescribed apixaban also had a lower rate of gastrointestinal bleeding or intracranial hemorrhage (12.9 per 1000 person-years) compared with those prescribed rivaroxaban (21.9 per 1000 person-years), corresponding to an HR of 0.58 (CI, 0.52 to 0.66) and a rate difference of 9.0 fewer events per 1000 person-years (CI, 6.9 to 11.1).

Limitation: Unmeasured confounding, incomplete laboratory data.

Conclusion: In routine care, adults with atrial fibrillation prescribed apixaban had a lower rate of both ischemic stroke or systemic embolism and bleeding compared with those prescribed rivaroxaban.

Primary Funding Source: Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital.
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http://dx.doi.org/10.7326/M19-2522DOI Listing
April 2020

Validation of algorithms to identify adverse perinatal outcomes in the Medicaid Analytic Extract database.

Pharmacoepidemiol Drug Saf 2020 04 2;29(4):419-426. Epub 2020 Mar 2.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Background: The Medicaid Analytic eXtract (MAX) is a health care utilization database from publicly insured individuals that has been used for studies of drug safety in pregnancy. Claims-based algorithms for defining many important maternal and neonatal outcomes have not been validated.

Objective: To validate claims-based algorithms for identifying selected pregnancy outcomes in MAX using hospital medical records.

Methods: The medical records of mothers who delivered between 2000 and 2010 within a single large healthcare system were linked to their claims in MAX. Claims-based algorithms for placental abruption, preeclampsia, postpartum hemorrhage, small for gestational age, and noncardiac congenital malformation were defined. Fifty randomly sampled cases for each outcome identified using these algorithms were selected, and their medical records were independently reviewed by two physicians to confirm the presence of the diagnosis of interest; disagreements were resolved by a third physician reviewer. Positive predictive values (PPVs) and 95% confidence intervals (CIs) of the claims-based algorithms were calculated using medical records as the gold standard.

Results: The linked cohort included 10,899 live-birth pregnancies. The PPV was 92% (95% CI, 82%-97%) for placental abruption, 82% (95% CI, 70%-91%) for preeclampsia, 74% (95% CI, 61%-85%) for postpartum hemorrhage, 92% (95% CI, 82%-97%) for small for gestational age, and 86% (95% CI, 74%-94%) for noncardiac congenital malformation.

Conclusions: Across the perinatal outcomes considered, PPVs ranged between 74% and 92%. These PPVs can inform bias analyses that correct for outcome misclassification.
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http://dx.doi.org/10.1002/pds.4967DOI Listing
April 2020

Maternal and fetal outcomes following exposure to duloxetine in pregnancy: cohort study.

BMJ 2020 02 19;368:m237. Epub 2020 Feb 19.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Objective: To evaluate the risk of adverse maternal and infant outcomes following in utero exposure to duloxetine.

Design: Cohort study nested in the Medicaid Analytic eXtract for 2004-13.

Setting: Publicly insured pregnancies in the United States.

Participants: Pregnant women 18 to 55 years of age and their liveborn infants.

Interventions: Duloxetine exposure during the etiologically relevant time window, compared with no exposure to duloxetine, exposure to selective serotonin reuptake inhibitors, exposure to venlafaxine, and exposure to duloxetine before but not during pregnancy.

Main Outcome Measures: Congenital malformations overall, cardiac malformations, preterm birth, small for gestational age infant, pre-eclampsia, and postpartum hemorrhage.

Results: Cohort sizes ranged from 1.3 to 4.1 million, depending on the outcome. The number of women exposed to duloxetine varied by cohort and exposure contrast and was around 2500-3000 for early pregnancy exposure and 900-950 for late pregnancy exposure. The base risk per 1000 unexposed women was 36.6 (95% confidence interval 36.3 to 36.9) for congenital malformations overall, 13.7 (13.5 to 13.9) for cardiovascular malformations, 107.8 (107.3 to 108.3) for preterm birth, 20.4 (20.1 to 20.6) for small for gestational age infant, 33.6 (33.3 to 33.9) for pre-eclampsia, and 23.3 (23.1 to 23.4) for postpartum hemorrhage. After adjustment for measured potential confounding variables, all baseline characteristics were well balanced for all exposure contrasts. In propensity score adjusted analyses versus unexposed pregnancies, the relative risk was 1.11 (95% confidence interval 0.93 to 1.33) for congenital malformations overall and 1.29 (0.99 to 1.68) for cardiovascular malformations. For preterm birth, the relative risk was 1.01 (0.92 to 1.10) for early exposure and 1.19 (1.04 to 1.37) for late exposure. For small for gestational age infants the relative risks were 1.14 (0.92 to 1.41) and 1.20 (0.83 to 1.72) for early and late pregnancy exposure, respectively, and for pre-eclampsia they were 1.12 (0.96 to 1.31) and 1.04 (0.80 to 1.35). The relative risk for postpartum hemorrhage was 1.53 (1.08 to 2.18). Results from sensitivity analyses were generally consistent with the findings from the main analyses.

Conclusions: On the basis of the evidence available to date, duloxetine is unlikely to be a major teratogen but may be associated with an increased risk of postpartum hemorrhage and a small increased risk of cardiac malformations. While continuing to monitor the safety of duloxetine as data accumulate over time, these potential small increases in risk of relatively uncommon outcomes must be weighed against the benefits of treating depression and pain during pregnancy in a given patient.

Trial Registration: EUPAS 15946.
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http://dx.doi.org/10.1136/bmj.m237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190016PMC
February 2020

Perinatal Outcomes Associated with Maternal Asthma and Its Severity and Control During Pregnancy.

J Allergy Clin Immunol Pract 2020 06 22;8(6):1928-1937.e3. Epub 2020 Jan 22.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Mass.

Background: Estimates of the effects of maternal asthma on pregnancy outcomes are inconsistent across studies, possibly because of differences in exposure definition.

Objective: To evaluate the risk of adverse perinatal outcomes associated with maternal asthma diagnosis, severity, and control in a large, nationally representative cohort.

Methods: This study was conducted within the IBM Health MarketScan Commercial Claims and Encounters Database (2011-2015) and the Medicaid Analytic eXtract database (2000-2014). Asthma was identified by diagnosis and treatment codes, severity was based on medications dispensed, and control was based on short-acting β-agonist dispensations and exacerbations. We estimated the relative risks (RRs) of stillbirth, spontaneous abortion, preterm birth, small for gestational age (SGA), neonatal intensive care unit (NICU) admission, and congenital malformations, comparing pregnancies with differing asthma disease status.

Results: We identified 29,882 pregnancies complicated by asthma in the MarketScan database and 160,638 in the Medicaid Analytic eXtract database. We observed no consistent associations between asthma diagnosis, severity, or control, and stillbirth, abortions, or malformations. However, we observed increased risks of prematurity, SGA, and NICU admission among women with asthma compared with those without asthma. Compared with women with well-controlled asthma, women with poor control late in pregnancy had an increased risk of preterm birth (relative risk, 1.39; 95% CI, 1.32-1.46) and NICU admission (relative risk, 1.26; 95% CI, 1.17-1.35). More severe asthma was associated with SGA (relative risk, 1.18; 95% CI, 1.07-1.30).

Conclusions: We did not observe an increased risk of pregnancy losses or malformations among women with asthma. However, we found an association between asthma severity and SGA, and between exacerbations late in pregnancy and preterm delivery and NICU admission.
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http://dx.doi.org/10.1016/j.jaip.2020.01.016DOI Listing
June 2020