Dana Bernson

Assisted Reproductive Technology and Birth Defects Among Liveborn Infants in Florida, Massachusetts, and Michigan, 2000-2010

IMPORTANCE Use of assisted reproductive technology (ART) has been associated with increased risks for birth defects. Variations in birth defect risks according to type of ART procedure have been noted, but findings are inconsistent. OBJECTIVES To examine the prevalence of birth defects among liveborn infants conceived with and without ART and to evaluate risks associated with certain ART procedures among ART-conceived infants. DESIGN, SETTING, AND PARTICIPANTS Used linked ART surveillance, birth certificates, and birth defects registry data for 3 states (Florida, Massachusetts, and Michigan). Methods for ascertaining birth defect cases varied by state. Resident live births during 2000 to 2010 were included, and the analysis was conducted between Feburary 2015 and August 2015. EXPOSURES Use of ART among all live births and use of certain ART procedures among ART births. MAIN OUTCOME AND MEASURES Prevalence of selected chromosomal and nonchromosomal birth defects that are usually diagnosed at or immediately after birth. RESULTS Of the 4 618 076 liveborn infants between 2000 and 2010, 64 861 (1.4%) were conceived using ART. Overall, the prevalence of 1 or more of the selected nonchromosomal defects was 58.59 per 10 000 for ART infants (n = 389) vs 47.50 per 10 000 for non-ART infants (n = 22 036). The association remained significant after adjusting for maternal characteristics and year of birth (adjusted risk ratio [aRR], 1.28; 95% CI, 1.15-1.42). Similar differences were observed for singleton ART births vs their non-ART counterparts (63.69 per 10 000 [n = 218] vs 47.17 per 10 000 [n = 21 251]; aRR, 1.38; 95% CI, 1.21-1.59). Among multiple births, the prevalence of rectal and large intestinal atresia/stenosis was higher for ART births compared with non-ART births (aRR, 2.39; 95% CI, 1.38-4.12). Among ART births conceived after fresh embryo transfer, infants born to mothers with ovulation disorders had a higher prevalence of nonchromosomal birth defects (aRR, 1.53; 95% CI, 1.13-2.06) than those born to mothers without the diagnosis, and use of assisted hatching was associated with birth defects among singleton births (aRR, 1.55; 95% CI, 1.10-2.19). Multiplicity-adjusted P values for these associations were greater than .05. CONCLUSIONS AND RELEVANCE Infants conceived after ART had a higher prevalence of certain birth defects. Assisted hatching and diagnosis of ovulation disorder were marginally associated with increased risks for nonchromosomal birth defects; however, these associations may be caused by other underlying factors.

Embryo transfer practices and perinatal outcomes by insurance mandate status

OBJECTIVE To use linked assisted reproductive technology (ART) surveillance and birth certificate data to compare ET practices and perinatal outcomes for a state with a comprehensive mandate requiring coverage of IVF services versus states without a mandate. DESIGN Retrospective cohort study. SETTING Not applicable. PATIENT(S) Live-birth deliveries ascertained from linked 2007-2009 National ART Surveillance System and birth certificate data for a state with an insurance mandate (Massachusetts) and two states without a mandate (Florida and Michigan). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Number of embryos transferred, multiple births, low birth weight, preterm delivery. RESULT(S) Of the 230,038 deliveries in the mandate state and 1,026,804 deliveries in the nonmandate states, 6,651 (2.9%) and 8,417 (0.8%), respectively, were conceived by ART. Transfer of three or more embryos was more common in nonmandate states, although the effect was attenuated for women 35 years or older (33.6% vs. 39.7%; adjusted relative risk [RR], 1.46; 95% confidence interval [CI], 1.17-1.81) versus women younger than 35 (7.0% vs. 26.9%; adjusted RR, 4.18; 95% CI, 2.74-6.36). Lack of an insurance mandate was positively associated with triplet/higher order deliveries (1.0% vs. 2.3%; adjusted RR, 2.44; 95% CI, 1.81-3.28), preterm delivery (22.6% vs. 30.7%; adjusted RR, 1.31; 95% CI, 1.20-1.42), and low birth weight (22.3% vs. 29.5%; adjusted RR, 1.28; 95% CI, 1.17-1.40). CONCLUSION(S) Compared with nonmandate states, the mandate state had higher overall rates of ART use. Among ART births, lack of an infertility insurance mandate was associated with increased risk for adverse perinatal outcomes.

Accuracy of Assisted Reproductive Technology Information on Birth Certificates: Florida and Massachusetts, 2004–06

BACKGROUND Assisted Reproductive Technology (ART) includes fertility procedures where both egg and sperm are handled in the lab. ART use has increased considerably in recent years, accounting for 47,090 livebirths in the U.S. in 2010. ART increases the probability of multiple gestation births, which are at higher risks than singletons for adverse outcomes. Additionally, ART is associated with a greater risk of complications during pregnancy, labour, and delivery, and increased risk of adverse perinatal outcomes in singleton births. METHODS We merged Florida and Massachusetts birth records from 2004-06 with the National ART Surveillance System (NASS) and using NASS as the gold standard, calculated sensitivity, specificity, and positive predictive value (PPV) of ART reporting on the birth certificates by maternal, infant, and hospital characteristics. We fit random-effects logistic regression models to evaluate simultaneously the association of ART reporting with these predictors while accounting for correlation among births occurring in the same hospital. RESULTS Sensitivity of ART reporting on the birth certificate was 28.9% in Florida and 41.4% in Massachusetts. Specificity was >99% in both states. PPV was 45.5% in Florida and 54.6% in Massachusetts. The odds of ART reporting varied by state and by several maternal and delivery characteristics including age, parity, history of fetal loss, plurality, race/Hispanic ethnicity, delivery payment source, pre-existing conditions, and complications during pregnancy or labour and delivery. CONCLUSIONS There was significant under-reporting of ART procedures on the birth certificates. Using data on ART births identified only from birth certificates yields a biased sample of the population of ART births.

Estimates of Lifetime Infertility from Three States: The Behavioral Risk Factor Surveillance System

BACKGROUND Knowledge of state-specific infertility is limited. The objectives of this study were to explore state-specific estimates of lifetime prevalence of having ever experienced infertility, sought treatment for infertility, types of treatments sought, and treatment outcomes. METHODS Male and female adult residents aged 18-50 years from three states involved in the States Monitoring Assisted Reproductive Technology Collaborative (Florida, Massachusetts, and Michigan) were asked state-added infertility questions as part of the 2012 Behavioral Risk Factor Surveillance System, a state-based, health-related telephone survey. Analysis involved estimation of lifetime prevalence of infertility. RESULTS The estimated lifetime prevalence of infertility among 1,285 adults in Florida, 1,302 in Massachusetts, and 3,360 in Michigan was 9.7%, 6.0%, and 4.2%, respectively. Among 736 adults in Florida, 1,246 in Massachusetts, and 2,742 in Michigan that have ever tried to get pregnant, the lifetime infertility prevalence was 25.3% in Florida, 9.9% in Massachusetts, and 5.8% in Michigan. Among those with a history of infertility, over half sought treatment (60.7% in Florida, 70.6% in Massachusetts, and 51.6% in Michigan), the most common being non-assisted reproductive technology fertility treatments (61.3% in Florida, 66.0% in Massachusetts, and 75.9% in Michigan). CONCLUSION State-specific estimates of lifetime infertility prevalence in Florida, Massachusetts, and Michigan varied. Variations across states are difficult to interpret, as they likely reflect both true differences in prevalence and differences in data collection questionnaires. State-specific estimates are needed for the prevention, detection, and management of infertility, but estimates should be based on a common set of questions appropriate for these goals.

Medication for Opioid Use Disorder After Nonfatal Opioid Overdose and Association With Mortality: A Cohort Study

The United States is in the midst of a crisis of opioid-related harms (1). Some efforts to address this crisis focus on expanding access to effective treatment of opioid use disorders (OUDs) (2). Prior nonfatal opioid overdose is a known risk factor for subsequent nonfatal and fatal overdoses (37), and engaging persons in treatment who survive an overdose may be effective in limiting subsequent fatalities. However, data on the association between treatment of OUD and mortality after a nonfatal overdose are limited to a single retrospective cohort study that analyzed enrollment in methadone maintenance treatment (MMT) at a single time point and found no association (3). The 3 medications for OUD (MOUD) approved by the U.S. Food and Drug Administration are methadone, buprenorphine, and naltrexone. Randomized controlled trials of these medications have shown consistent benefits across many outcomes, including increased treatment retention and suppression of illicit opioid use (810). A recent systematic review and meta-analysis of 19 observational cohort studies identified substantial reductions in all-cause and overdose mortality for methadone and buprenorphine (11). However, the mortality benefit in this analysis was limited to time actively retained in treatment, and the 4-week period after discontinuation was associated with an especially high risk for death. The few studies that examined mortality among patients receiving naltrexone show an unclear effect (1215). Massachusetts has been particularly affected by the opioid crisis: Opioid overdose deaths more than tripled between 2010 and 2016 (16). Through Chapter 55 of the Acts of 2015, the state legislature permitted individual-level linkage of data from 16 Massachusetts government agencies to gain a deeper understanding of the circumstances that influence fatal and nonfatal opioid overdoses (17). For this analysis, we identified a cohort of persons in the Chapter 55 data set who survived an opioid overdose and described any episodes of treatment with MOUD before and after that overdose. Specifically, we sought to determine whether treatment with MOUD, including receipt of MMT, buprenorphine, or naltrexone, was associated with reduced risk for all-cause and opioid-related mortality. Methods Study Design and Data Source We did a retrospective cohort study using the Massachusetts Chapter 55 data set, which includes data between 2011 and 2015 on residents aged 11 years or older with health insurance (as reported in the Massachusetts All-Payer Claims Database [APCD]) and represents more than 98% of Massachusetts residents. Data from APCD were linked at the individual level with records from other data sets using a multistage deterministic linkage technique described elsewhere (18). For this study, we used 7 linked Massachusetts databases: APCD, the Registry of Vital Records and Statistics, the prescription monitoring program, the Acute Hospital Case Mix, the Ambulance Trip Record Information System, the Bureau of Substance Addiction Services licensed treatment encounters, and the cancer registry. This work was mandated by Massachusetts law and conducted by a public health authority that required no institutional board review. The Boston University Medical Campus Institutional Review Board also determined that this study was not human subjects research. Cohort Selection We identified persons who had had a nonfatal opioid overdose between January 2012 and December 2014 to allow 12 months of observation before and after the overdose. We restricted the cohort to persons aged 18 years or older because access to OUD treatment substantially differs in adolescents versus adults (19). We identified opioid overdose in 2 ways. First, we identified emergency department, observation, or inpatient encounters with a medical claim containing a diagnosis code for opioid poisoning from the International Classification of Diseases, Ninth Revision, Clinical Modification (codes 965.00, 965.01, 965.02, 965.09, E850.0, E850.1, and E850.2). A study validated these codes by showing positive predictive values of 81% for identifying fatal or nonfatal opioid overdose and 94% for an opioid overdose or opioid-related adverse event (20). Second, we identified persons with an ambulance encounter for opioid overdose (available in 2013 and 2014 only). In collaboration with the Centers for Disease Control and Prevention, the Massachusetts Department of Public Health created and refined an algorithm to use with emergency medical services data to identify opioid-related overdoses; this algorithm was previously validated against internal emergency medical services data on opioid overdose events (Supplement). Supplement. Supplementary Material We examined the first qualifying event (nonfatal opioid overdose) for each person, hereafter called the index overdose. Of 20155 persons with an event, we excluded 1203 who died within 30 days after the overdose using dates of death from the Registry of Vital Records and Statistics. We excluded 1338 persons with evidence of cancer at any time in the 5 years of Chapter 55 data because of high competing risk for death. Cancer was identified using International Classification of Diseases, Ninth Revision, diagnosis codes in APCD (Supplement) or entry in the state-based cancer registry. We also excluded 46 persons whose age or sex was unknown, yielding a final cohort of 17568 persons. Key Variables We identified exposure to MOUD in monthly intervals. Exposure to MMT was identified in 2 ways: a medical claim from APCD for methadone administration via Healthcare Common Procedure Coding System code H0020 or a record of treatment with methadone in data from the Bureau of Substance Addiction Services. We used the prescription monitoring program to identify dispensing of buprenorphine or buprenorphine and naloxone combined. Naltrexone was identified via a pharmacy claim for injectable or oral naltrexone in APCD. We examined all-cause and opioid-related mortality as identified in death files. Classification of opioid-related death was based on medical examiner determination or standardized assessment by the Massachusetts Department of Public Health (Supplement). We examined potential confounding variables. We obtained patient sex and age from APCD and categorized age as 18 to 29 years, 30 to 44 years, or 45 years or older. We identified monthly dispensings of opioid analgesics and benzodiazepines from the prescription monitoring program. We identified diagnosis of anxiety or depression using International Classification of Diseases, Ninth and Tenth Revisions, diagnosis codes from APCD (Supplement). We identified OUD treatment services, including inpatient detoxification episodes and postdetoxification treatment in short- and long-term residential facilities, through the Bureau of Substance Addiction Services. Statistical Analysis To compare baseline characteristics by receipt of MOUD, we developed the following 5 categories of MOUD receipt in the 12 months after the index overdose: no MOUD during follow-up, 1 or more months of buprenorphine, 1 or more months of methadone, 1 or more months of naltrexone, and 1 or more months of 2 or 3 MOUDs combined. We compared baseline characteristics among these mutually exclusive treatment groups using 2 tests. We did time-to-event analyses for all-cause and opioid-related mortality using MOUD as a monthly time-varying exposure variable. We used 2 dichotomous classifications for MOUD exposure, with discontinuation and on treatment. Several studies have shown an increased risk for all-cause and opioid-related mortality in the 4 weeks immediately after MOUD discontinuation (11, 21). Thus, we defined a with discontinuation exposure variable, which we considered the primary classification, to attribute any effect of MOUD discontinuation on mortality to the MOUD. For this classification, persons were considered exposed to MOUD in any month in which they received it and in the month after last receipt. We defined an on treatment exposure variable as the secondary classification, in which persons were considered exposed to MOUD only in months in which they received it (Figure 1). Figure 1. MOUD exposure classification. For the primary classification (with discontinuation), MOUD exposure extends through the month after discontinuation (light and dark-green months). For the secondary classification (on treatment), exposure is limited to months in which treatment is received (light-green months only). In the illustrative examples, participant 1 is not exposed to MOUD through follow-up; participant 2 is exposed in months 12 and 712 for the primary classification and months 1 and 712 for the secondary classification. In the month of death, participant 3 would be considered exposed in the primary classification only, participant 4 would be considered exposed in both primary and secondary exposure classifications, and participant 5 would be considered not exposed to MOUD. MOUD= medication for opioid use disorder. We used an extended KaplanMeier estimator allowing for time-varying exposure to MOUD to generate cumulative incidence curves (Supplement) (22). We developed a multivariable Cox regression model of time to all-cause and opioid-related mortality. The predictors of interest were monthly receipt of MMT, buprenorphine, and naltrexone as time-varying exposure variables. Covariates were age; sex; monthly time-varying receipt of prescription opioids, benzodiazepines, and OUD treatment services; baseline characteristics, including mental health diagnoses; and prior receipt of medication or OUD treatment services. We calculated the E-value to identify the minimum strength of association that an unmeasured confounder would need to have with both treatment and outcome, conditional on the measured covariates, to explain away the observed associations between MOUD and mortality (23). We used SAS Studio, version 3.5 (SAS Institute), for analyses (Supplemen

Assisted reproductive technology and newborn size in singletons resulting from fresh and cryopreserved embryos transfer

Objectives and Study Design The aim of this study was two-fold: to investigate the association of Assisted Reproductive Technology (ART) and small newborn size, using standardized measures; and to examine within strata of fresh and cryopreserved embryos transfer, whether this association is influenced by parental infertility diagnoses. We used a population-based retrospective cohort from Michigan (2000–2009), Florida and Massachusetts (2000–2010). Our sample included 28,946 ART singletons conceived with non-donor oocytes and 4,263,846 non-ART singletons. Methods Regression models were used to examine the association of ART and newborn size, measured as small for gestational age (SGA) and birth-weight-z-score, among four mutually exclusive infertility groups: female infertility only, male infertility only, combined female and male infertility, and unexplained infertility, stratified by fresh and cryopreserved embryos transfer. Results We found increased SGA odds among ART singletons from fresh embryos transfer compared with non-ART singletons, with little difference by infertility source [adjusted odds-ratio for SGA among female infertility only: 1.18 (95% CI 1.10, 1.26), male infertility only: 1.20 (95% CI 1.10, 1.32), male and female infertility: 1.18 (95% CI 1.06, 1.31) and unexplained infertility: 1.24 (95% CI 1.10, 1.38)]. Conversely, ART singletons, born following cryopreserved embryos transfer, had lower SGA odds compared with non-ART singletons, with mild variation by infertility source [adjusted odds-ratio for SGA among female infertility only: 0.56 (95% CI 0.45, 0.71), male infertility only: 0.64 (95% CI 0.47, 0.86), male and female infertility: 0.52 (95% CI 0.36, 0.77) and unexplained infertility: 0.71 (95% CI 0.47, 1.06)]. Birth-weight-z-score was significantly lower for ART singletons born following fresh embryos transfer than non-ART singletons, regardless of infertility diagnoses.

Embryo cryopreservation and preeclampsia risk

OBJECTIVE To determine whether assisted reproductive technology (ART) cycles involving cryopreserved-warmed embryos are associated with the development of preeclampsia. DESIGN Retrospective cohort study. SETTING IVF clinics and hospitals. PATIENT(S) A total of 15,937 births from ART: 9,417 singleton and 6,520 twin. INTERVENTION(S) We used linked ART surveillance, birth certificate, and maternal hospitalization discharge data, considering resident singleton and twin births from autologous or donor eggs from 2005-2010. MAIN OUTCOME MEASURE(S) We compared the frequency of preeclampsia diagnosis for cryopreserved-warmed versus fresh ET and used multivariable logistic regression to adjust for confounders. RESULT(S) Among pregnancies conceived with autologous eggs resulting in singletons, preeclampsia was greater after cryopreserved-warmed versus fresh ET (7.51% vs. 4.29%, adjusted odds ratio = 2.17 [95% CI 1.67-2.82]). Preeclampsia without and with severe features, preeclampsia with preterm delivery, and chronic hypertension with superimposed preeclampsia were more frequent after cryopreserved-warmed versus fresh ET (3.99% vs. 2.55%; 2.95% vs. 1.41%; 2.76 vs. 1.48%; and 0.95% vs. 0.43%, respectively). Among pregnancies from autologous eggs resulting in twins, the frequency of preeclampsia with severe features (9.26% vs. 5.70%) and preeclampsia with preterm delivery (14.81% vs. 11.74%) was higher after cryopreserved versus fresh transfers. Among donor egg pregnancies, rates of preeclampsia did not differ significantly between cryopreserved-warmed and fresh ET (10.78% vs. 12.13% for singletons and 28.0% vs. 25.15% for twins). CONCLUSION(S) Among ART pregnancies conceived using autologous eggs resulting in live births, those involving transfer of cryopreserved-warmed embryos, as compared with fresh ETs, had increased risk for preeclampsia with severe features and preeclampsia with preterm delivery.

The Impact of ART on Live Birth Outcomes: Differing Experiences across Three States

BACKGROUND Research has shown an association between assisted reproductive technology (ART) and adverse birth outcomes. We identified whether birth outcomes of ART-conceived pregnancies vary across states with different maternal characteristics, insurance coverage for ART services, and type of ART services provided. METHODS CDCs National ART Surveillance System data were linked to Massachusetts, Florida, and Michigan vital records from 2000 through 2006. Maternal characteristics in ART- and non-ART-conceived live births were compared between states using chi-square tests. We performed multivariable logistic regression analyses and calculated adjusted odds ratios (aOR) to assess associations between ART use and singleton preterm delivery (<32 weeks, <37 weeks), singleton small for gestational age (SGA) (<5th and <10th percentiles) and multiple birth. RESULTS ART use in Massachusetts was associated with significantly lower odds of twins as well as triplets and higher order births compared to Florida and Michigan (aOR 22.6 vs. 30.0 and 26.3, and aOR 37.6 vs. 92.8 and 99.2, respectively; Pinteraction < 0.001). ART use was associated with increased odds of SGA in Michigan only, and with preterm delivery (<32 and <37 weeks) in all states (aOR range: 1.60, 1.87). CONCLUSIONS ART use was associated with an increased risk of preterm delivery among singletons that showed little variability between states. The number of twins, triplets and higher order gestations per cycle was lower in Massachusetts, which may be due to the availability of insurance coverage for ART in Massachusetts.

Non-fatal opioid-related overdoses among adolescents in Massachusetts 2012–2014

BACKGROUND Opioid-related overdoses and deaths among adolescents in the United States continue to increase, but little is known about adolescents who experience opioid-related non-fatal overdose (NFOD). Our objective was to describe (1) the characteristics of adolescents aged 11-17 who experienced NFOD and (2) their receipt of medications for opioid use disorder (MOUD) in the 12 months following NFOD, compared with adults. METHODS We created a retrospective cohort using six Massachusetts state agency datasets linked at the individual level, with information on 98% of state residents. Individuals entered the cohort if they experienced NFOD between January 1, 2012 and December 31, 2014. We compared adolescents to adults experiencing NFOD, examining individual characteristics and receipt of medications for opioid use disorder (MOUD)-methadone, buprenorphine, or naltrexone. RESULTS Among 22,506 individuals who experienced NFOD during the study period, 195 (0.9%) were aged 11-17. Fifty-two percent (102/195) of adolescents were female, whereas only 38% of adults were female (P < 0.001). In the year prior to NFOD, 11% (21/195) of adolescents received a prescription opioid, compared to 43% of adults (P < 0.001), and <5% (<10/195) received any MOUD compared to 23% of adults (P < 0.001). In the 12 months after NFOD, only 8% (15/195) of adolescents received MOUD, compared to 29% of adults. CONCLUSION Among individuals experiencing NFOD, adolescents were more likely to be female and less likely to have been prescribed opioids in the year prior. Few adolescents received MOUD before or after NFOD. Non-fatal overdose is a missed opportunity for starting evidence-based treatment in adolescents.

Assisted reproduction and risk of preterm birth in singletons by infertility diagnoses and treatment modalities: a population-based study

PurposeThe purpose of this study is to examine the spectrum of infertility diagnoses and assisted reproductive technology (ART) treatments in relation to risk of preterm birth (PTB) in singletons.MethodsPopulation-based assisted reproductive technology surveillance data for 2000–2010 were linked with birth certificates from three states: Florida, Massachusetts, and Michigan, resulting in a sample of 4,370,361 non-ART and 28,430 ART-related singletons. Logistic regression models with robust variance estimators were used to compare PTB risk among singletons conceived with and without ART, the former grouped by parental infertility diagnoses and treatment modalities. Demographic and pregnancy factors were included in adjusted analyses.ResultsART was associated with increased PTB risk across all infertility diagnosis groups and treatment types: for conventional ART, adjusted relative risks ranged from 1.4 (95% CI 1.0, 1.9) for male infertility to 2.4 (95% CI 1.8, 3.3) for tubal ligation. Adding intra-cytoplasmic sperm injection and/or assisted hatching to conventional ART treatment did not alter associated PTB risks. Singletons conceived by mothers without infertility diagnosis and with donor semen had an increased PTB risk relative to non-ART singletons.ConclusionsPTB risk among ART singletons is increased within each treatment type and all underlying infertility diagnosis, including male infertility. Preterm birth in ART singletons may be attributed to parental infertility, ART treatments, or their combination.