Time-Varying Exposures and Miscarriage: A Comparison of Statistical Models Through Simulation.

Epidemiologists face a unique challenge in measuring risk relationships involving time-varying exposures in early pregnancy. Each week in early pregnancy is distinct in its contribution to fetal development, and this period is commonly characterized by shifts in maternal behavior and, consequently, exposures. In this simulation study, we used alcohol as an example of an exposure that often changes during early pregnancy and miscarriage as an outcome affected by early exposures. Data on alcohol consumption patterns from more than 5,000 women in the Right From the Start cohort study (United States, 2000-2012) informed measures of the prevalence of alcohol exposure, the distribution of gestational age at cessation of alcohol use, and the likelihood of miscarriage by week of gestation. We then compared the bias and precision of effect estimates and statistical power from 5 different modeling approaches in distinct simulated relationships. We demonstrate how the accuracy and precision of effect estimates depended on alignment between model assumptions and the underlying simulated relationship. Approaches that incorporated data about patterns of exposure were more powerful and less biased than simpler models when risk depended on timing or duration of exposure. To uncover risk relationships in early pregnancy, it is critical to carefully define the role of exposure timing in the underlying causal hypothesis.

Maternal morbidity and mortality among patients with cancer at time of delivery.

BACKGROUND: Individuals with cancer during pregnancy are a medically complex patient population that is anticipated to grow. A better understanding of this population and patterns of risk at time of delivery would offer an opportunity for providers to mitigate maternal morbidity. OBJECTIVE: This study aimed to estimate the prevalence in the United States of concurrent cancer diagnoses at time of delivery by cancer type and associated maternal morbidity and mortality. STUDY DESIGN: Using the National Inpatient Sample, we identified delivery-associated hospitalizations between 2007 and 2018. Concurrent cancer diagnoses were classified using the Clinical Classifications Software. Main outcomes included severe maternal morbidity, as defined by the Centers for Disease Control and Prevention indicators, and mortality during delivery hospitalization. We calculated adjusted rates for cancer diagnosis at time of delivery and adjusted odds ratios of severe maternal morbidity and maternal death during hospitalization using survey-weighted multivariable logistic regression models. RESULTS: In this sample of 9,418,761 delivery-associated hospitalizations, 63 per 100,000 deliveries had a concurrent cancer diagnosis (95% confidence interval, 60-66; national weighted estimate, 46,654,042). The most common cancer types were breast cancer (8.4 per 100,000 deliveries), leukemia (8.4 per 100,000 deliveries), Hodgkin lymphoma (7.4 per 100,000 deliveries), non-Hodgkin lymphoma (5.4 per 100,000 deliveries), and thyroid cancer (4.0 per 100,000 deliveries). Patients with cancer were at significantly higher risk for any severe maternal morbidity (adjusted odds ratio, 5.25; 95% confidence interval, 4.73-5.83) and maternal death (adjusted odds ratio, 67.5; 95% confidence interval, 45.1-101.4). Risks of hysterectomy (adjusted odds ratio, 16.92; 95% confidence interval, 13.96-20.52), acute respiratory distress (adjusted odds ratio, 12.76; 95% confidence interval, 9.92-16.42), sepsis (adjusted odds ratio, 11.91; 95% confidence interval, 8.68-16.32), and embolism (adjusted odds ratio, 11.12; 95% confidence interval, 6.94-17.82) were particularly heightened among patients with cancer. Patients with leukemia, specifically, had the highest risk of adverse maternal outcomes (adjusted rate, 113 per 1000 deliveries; 95% confidence interval, 91-135 per 1000) when evaluating risk by cancer type. CONCLUSION: Patients with cancer are at markedly increased risk of maternal morbidity and all-cause mortality during delivery-associated hospitalization. Risk is distributed unevenly within this population, with certain cancer types carrying unique risks for specific morbidity events.

Week-by-week alcohol consumption in early pregnancy and spontaneous abortion risk: a prospective cohort study.

BACKGROUND: Half of women use alcohol in the first weeks of gestation, but most stop once pregnancy is detected. The relationship between timing of alcohol use cessation in early pregnancy and spontaneous abortion risk has not been determined. OBJECTIVE: This study aimed to evaluate the association between week-by-week alcohol consumption in early pregnancy and spontaneous abortion. STUDY DESIGN: Participants in Right from the Start, a community-based prospective pregnancy cohort, were recruited from 8 metropolitan areas in the United States (2000-2012). In the first trimester, participants provided information about alcohol consumed in the prior 4 months, including whether they altered alcohol use; date of change in use; and frequency, amount, and type of alcohol consumed before and after change. We assessed the association between spontaneous abortion and week of alcohol use, cumulative weeks exposed, number of drinks per week, beverage type, and binge drinking. RESULTS: Among 5353 participants, 49.7% reported using alcohol during early pregnancy and 12.0% miscarried. Median gestational age at change in alcohol use was 29 days (interquartile range, 15-35 days). Alcohol use during weeks 5 through 10 from last menstrual period was associated with increased spontaneous abortion risk, with risk peaking for use in week 9. Each successive week of alcohol use was associated with an 8% increase in spontaneous abortion relative to those who did not drink (adjusted hazard ratio, 1.08; 95% confidence interval, 1.04-1.12). This risk is cumulative. In addition, risk was not related to number of drinks per week, beverage type, or binge drinking. CONCLUSION: Each additional week of alcohol exposure during the first trimester increases risk of spontaneous abortion, even at low levels of consumption and when excluding binge drinking.

Uterine fibroids and risk of preterm birth by clinical subtypes: a prospective cohort study.

BACKGROUND: Fibroids are present in approximately one in ten pregnancies and are inconsistently linked with preterm birth. We sought to determine the association between fibroids and preterm birth in a prospective cohort with standardized research ultrasounds for characterizing fibroids in early pregnancy while accounting for the clinical paths that precede preterm birth. METHODS: Participants who were pregnant or planning a pregnancy were recruited from communities in three states between 2000 and 2012. Members of this prospective cohort had a research ultrasound in the first trimester to establish pregnancy dating and to record detailed information about the presence, size, number, and location of fibroids. Baseline information from time of enrollment and a detailed first trimester interview contributed key information about candidate confounders. Birth outcomes, including clinical classification of type of preterm birth (preterm labor, preterm premature rupture of membranes, and medically indicated preterm birth) were cross-validated from participant report, labor and delivery records, and birth certificate data. RESULTS: Among 4,622 women with singleton pregnancies, 475 had at least one fibroid (10.3%) and 352 pregnancies resulted in preterm birth (7.6%). Prevalence of fibroids was similar for women with preterm and term births (10.2% vs. 10.3%). Fibroids were not associated with increased risk of preterm birth after taking into account confounding (risk ratio adjusted for race/ethnicity and maternal age, 0.88; 95% confidence interval, 0.62-1.24) nor any clinical subtype of preterm birth. No fibroid characteristic or combination of characteristics was associated with risk. CONCLUSIONS: If fibroids increase risk of preterm birth, the effect is substantially smaller than previous estimates. Given lack of effect in a large population of women from the general population, rather than higher risk academic tertiary populations previously most studied, we encourage a reconsideration of the clinical impression that presence of fibroids is a major risk factor for preterm birth.

Gestational Age at Arrest of Development: An Alternative Approach for Assigning Time at Risk in Studies of Time-Varying Exposures and Miscarriage.

The time between arrest of pregnancy development and miscarriage represents a window in which the pregnancy is nonviable and not developing. In effect, the pregnancy loss has already occurred, and additional exposure cannot influence its outcome. However, epidemiologic studies of miscarriage traditionally use gestational age at miscarriage (GAM) to assign time in survival analyses, which overestimates duration of exposure and time at risk. In Right From the Start, a pregnancy cohort study (2000-2012), we characterized the gap between estimated gestational age at arrest of development (GAAD) and miscarriage using transvaginal ultrasound in 500 women recruited from 3 states (North Carolina, Tennessee, and Texas). We compared effect estimates from models using GAAD with GAM to assign time at risk through a simulation study of several exposure patterns with varying effect sizes. The median gap between GAAD and miscarriage was 23 days (interquartile range, 15-32). Use of GAAD decreased the bias and variance of the estimated association for time-varying exposures, whereas half the time using GAM led to estimates that differed from the true effect by more than 20%. Using GAAD to assign time at risk should result in more accurate and consistent characterization of miscarriage risk associated with time-varying exposures.

Alcohol Use in Pregnancy and Miscarriage: A Systematic Review and Meta-Analysis.

To systematically review and critically evaluate studies reporting alcohol exposure during pregnancy and miscarriage. We searched PubMed, EMBASE, PsycINFO, and ProQuest Theses for publications from January 1970 to January 2019. We identified studies about alcohol exposure during pregnancy and miscarriage. Information about study population, alcohol exposure assessment, outcome definition, covariates, and measures of association was collected. We assessed study quality using an adapted Newcastle-Ottawa Scale. Data were abstracted by 2 investigators independently. We conducted a random-effects meta-analysis to calculate the association between alcohol exposure and miscarriage risk and performed subgroup analyses to determine robustness of results to study differences. For studies reporting dose-specific effects, a pooled dose-response association was estimated using generalized least squares regression with and without restricted cubic spline terms for number of drinks consumed per week. Of 2,164 articles identified, 24 were eligible for inclusion. Meta-analysis of data from 231,808 pregnant women finds those exposed to alcohol during pregnancy have a greater risk of miscarriage compared to those who abstained (odds ratio [OR] 1.19, 95% confidence intervals [CI] 1.12, 1.28). Estimates did not vary by study design, study country, or method of alcohol ascertainment. For alcohol use of 5 or fewer drinks per week, each additional drink per week was associated with a 6% increase in miscarriage risk (OR 1.06, 95% CI 1.01, 1.10). Common study limitations reflect challenges inherent to this research, including difficulty recruiting participants early enough in pregnancy to observe miscarriage and collecting and quantifying information about alcohol consumption during pregnancy that accurately reflects use. This review provides evidence that alcohol consumption during pregnancy is associated with a dose-mediated increase in miscarriage risk. Future studies evaluating change in alcohol use in pregnancy are needed to provide insight into how alcohol consumption prior to pregnancy recognition impacts risk.

Relationship between very low low-density lipoprotein cholesterol concentrations not due to statin therapy and risk of type 2 diabetes: A US-based cross-sectional observational study using electronic health records.

BACKGROUND: Observations from statin clinical trials and from Mendelian randomization studies suggest that low low-density lipoprotein cholesterol (LDL-C) concentrations may be associated with increased risk of type 2 diabetes mellitus (T2DM). Despite the findings from statin clinical trials and genetic studies, there is little direct evidence implicating low LDL-C concentrations in increased risk of T2DM. METHODS AND FINDINGS: We used de-identified electronic health records (EHRs) at Vanderbilt University Medical Center to compare the risk of T2DM in a cross-sectional study among individuals with very low (≤60 mg/dl, N = 8,943) and normal (90-130 mg/dl, N = 71,343) LDL-C levels calculated using the Friedewald formula. LDL-C levels associated with statin use, hospitalization, or a serum albumin level < 3 g/dl were excluded. We used a 2-phase approach: in 1/3 of the sample (discovery) we used T2DM phenome-wide association study codes (phecodes) to identify cases and controls, and in the remaining 2/3 (validation) we identified T2DM cases and controls using a validated algorithm. The analysis plan for the validation phase was constructed at the time of the design of that component of the study. The prevalence of T2DM in the very low and normal LDL-C groups was compared using logistic regression with adjustment for age, race, sex, body mass index (BMI), high-density lipoprotein cholesterol, triglycerides, and duration of care. Secondary analyses included prespecified stratification by sex, race, BMI, and LDL-C level. In the discovery cohort, phecodes related to T2DM were significantly more frequent in the very low LDL-C group. In the validation cohort (N = 33,039 after applying the T2DM algorithm to identify cases and controls), the risk of T2DM was increased in the very low compared to normal LDL-C group (odds ratio [OR] 2.06, 95% CI 1.80-2.37; P < 2 × 10-16). The findings remained significant in sensitivity analyses. The association between low LDL-C levels and T2DM was significant in males (OR 2.43, 95% CI 2.00-2.95; P < 2 × 10-16) and females (OR 1.74, 95% CI 1.42-2.12; P = 6.88 × 10-8); in normal weight (OR 2.18, 95% CI 1.59-2.98; P = 1.1× 10-6), overweight (OR 2.17, 95% CI 1.65-2.83; P = 1.73× 10-8), and obese (OR 2.00, 95% CI 1.65-2.41; P = 8 × 10-13) categories; and in individuals with LDL-C < 40 mg/dl (OR 2.31, 95% CI 1.71-3.10; P = 3.01× 10-8) and LDL-C 40-60 mg/dl (OR 1.99, 95% CI 1.71-2.32; P < 2.0× 10-16). The association was significant in individuals of European ancestry (OR 2.67, 95% CI 2.25-3.17; P < 2 × 10-16) but not in those of African ancestry (OR 1.09, 95% CI 0.81-1.46; P = 0.56). A limitation was that we only compared groups with very low and normal LDL-C levels; also, since this was not an inception cohort, we cannot exclude the possibility of reverse causation. CONCLUSIONS: Very low LDL-C concentrations occurring in the absence of statin treatment were significantly associated with T2DM risk in a large EHR population; this increased risk was present in both sexes and all BMI categories, and in individuals of European ancestry but not of African ancestry. Longitudinal cohort studies to assess the relationship between very low LDL-C levels not associated with lipid-lowering therapy and risk of developing T2DM will be important.

Prospective Cohort Study of Uterine Fibroids and Miscarriage Risk.

We sought to determine the relationship of fibroids to pregnancy loss in a prospective cohort in which fibroid status was uniformly documented in early pregnancy. Participants had an intake interview, transvaginal ultrasonography, computer-assisted telephone interview, and follow-up assessment of outcomes. We recruited diverse participants for the Right From the Start study from 8 metropolitan areas in 3 states in the United States during 2000-2012. Participants were at least 18 years of age, trying to become pregnant or at less than 12 weeks' gestation, not using fertility treatments, fluent in English or Spanish, and available for telephone interviews. Miscarriage was defined as loss before 20 weeks' gestation. Fibroid presence, number, type, and volume were assessed using standardized ultrasonography methods. We used proportional hazards models to estimate associations. Among 5,512 participants, 10.4% had at least 1 fibroid, and 10.8% experienced a miscarriage. Twenty-three percent had experienced a prior miscarriage and 52% prior births. Presence of fibroids was associated with miscarriage in models without adjustments. Adjusting for key confounders indicated no increase in risk (adjusted hazard ratio = 0.83, 95% confidence interval: 0.63, 1.08). No characteristic of fibroids was associated with risk. Prior evidence attributing miscarriage to fibroids is potentially biased. These findings imply that surgical removal of fibroids to reduce risk of miscarriage deserves careful scrutiny.

High rates of venous thromboembolism among deliveries complicated by cancer.

BACKGROUND: Venous thromboembolism (VTE) risk is increased independently by both cancer and pregnancy. OBJECTIVES: To estimate VTE risk in the postpartum period among patients delivering with a cancer diagnosis, stratified by cancer type and delivery route. METHODS: We performed a retrospective cohort study utilizing the large, all-payer Nationwide Readmissions Database from October 2015 through December 2020. We identified delivery hospitalizations, cancer diagnoses, and VTE using patient demographics and diagnosis codes. The primary outcome was VTE incidence at 42 and 330 days from delivery admission date, comparing patients with and without cancer diagnoses. A secondary analysis included VTE risk stratified by cancer diagnosis and delivery route. Outcomes were compared using inverse probability-weighted survival curves. RESULTS: The study population included 9 793 503 delivery hospitalizations (weighted estimate, 18 207 346), with a weighted estimate of 10 428 (0.06%) pregnant patients with cancer. Individuals with cancer were older, with higher rates of comorbid conditions, than those without cancer. VTE incidence in individuals with cancer at 42 and 330 days was 1.11% and 2.19%, respectively, vs 0.11% and 0.14%, respectively, in those without cancer. At 330 days, this finding was significant in both unadjusted (relative risk, 15.52; 95% CI, 11.54-19.51) and adjusted (relative risk, 9.68; 95% CI, 7.18-12.18) models. Stratification by cancer type and delivery route demonstrated elevated VTE risk across cancer types, with cesarean delivery conferring a greater risk. CONCLUSION: Cancer in pregnancy confers excess thromboembolic risk extending beyond the immediate postpartum period. Further study is needed to identify optimal VTE prophylactic strategies for this population.

Association between First Trimester Antidepressant Use and Risk of Spontaneous Abortion.

STUDY OBJECTIVE: The potential for maternal antidepressant use to influence the risk of spontaneous abortion, one of the most important adverse pregnancy outcomes, is not clear. We aimed to assess whether first trimester antidepressant exposure was associated with an increased risk of spontaneous abortion. DESIGN: Community-based prospective cohort study (Right from the Start). SETTING: Eight metropolitan areas in North Carolina, Tennessee, and Texas. PARTICIPANTS: A total of 5451 women (18 years of age or older) who were planning to conceive or were pregnant (before 12 weeks of completed gestation) and were enrolled in the study between 2000 and 2012; of those women, 223 used antidepressants (selective serotonin reuptake inhibitors [SSRIs] only [170], SSRIs and non-SSRIs [9], and non-SSRIs only [44]) during their first trimester, and 5228 did not (never users). Measurements and Main Results First trimester antidepressant use was determined during a first trimester telephone interview. Spontaneous abortion was self-reported and verified by medical records. The association of first trimester antidepressant use and spontaneous abortion was assessed by using Cox proportional hazard regression. Among the 5451 women enrolled, 223 (4%) reported first trimester antidepressant use, and 659 (12%) experienced a spontaneous abortion. SSRIs were the most common class of antidepressants used (179 [80%]). Compared with women who never used antidepressants during the first trimester of pregnancy, women who reported antidepressant use were 34% (adjusted hazard ratio [aHR] 1.34, 95% confidence interval [CI] 0.97-1.85) more likely to experience a spontaneous abortion after adjusting for covariates. Women who reported ever using SSRIs were 45% (aHR 1.45, 95% CI 1.02-2.06) more likely to experience a spontaneous abortion compared with never users. When time of loss relative to the time of interview was taken into consideration, the association between first trimester SSRI use and spontaneous abortion was significant only among those with losses before the interview (aHR 1.49, 95% CI 1.04-2.13) but was not significant among those with losses after the interview (aHR 0.43, 95% CI 0.06-3.15). CONCLUSION: The association between use of first trimester antidepressants, particularly SSRI use, and spontaneous abortion was significant only among women whose exposure status was assessed after loss. In this instance, reporting bias may create a spurious association. Future studies should take the timing of data collection relative to the timing of loss into consideration.

The Scope of Extraprofessional Caregiving Challenges Among Early Career Faculty: Findings From a University Medical Center.

PURPOSE: Academic scientists work in competitive environments, and many institutions invest in career development supports. These investments may be imperiled when extraprofessional demands challenge a faculty member's reserve capacity. This research assessed prevalence of caregiving challenges and estimated incidence of stressful life events. METHOD: In 2015-2016, the authors surveyed recipients of career development awards supporting ≥ 75% effort and individuals within the funding period of their first National Institutes of Health R01 or equivalent at Vanderbilt University Medical Center. Domains included family structure, hospitalizations of family members, responsibility for coordination of caregiving, and an inventory of stressful life events. RESULTS: Seventy-two percent (152 of 210) of early career researchers responded. Over half endorsed experiencing one or more substantial caregiving challenges in the prior year. This included 35 (23%) having a child or adult in the household hospitalized in the prior year and 36 (24%) being responsible for health care needs for a child or adult in the household, or for coordinating elder care, assisted living, or hospice care. The majority experienced one or more caregiving challenges. Stressful life events increased relative risk of "thinking about leaving academics" by 70% (risk ratio: 1.7; 95% confidence interval: 1.2, 2.4). Prevalence and incidence of caregiving demands did not differ by gender. CONCLUSIONS: Leaders, administrators, mentors, and faculty should anticipate that most women and men early career researchers will experience substantial caregiving challenges and life events in any given year. Sufficient need exists to warrant investigation of institutional programs to address caregiving challenges.

Gestational diabetes mellitus is associated with increased CD163 expression and iron storage in the placenta.

PROBLEM: GDM has been associated with disturbances in iron homeostasis and exaggerated immune activation. We sought to investigate the extent to which placental iron storage and macrophage accumulations were altered in GDM. METHOD OF STUDY: We conducted a retrospective, case-control study of archived placental tissues obtained from 22 pregnancies complicated by GDM and 22 unaffected controls. Controls were matched to cases based on maternal age, gestational age at birth, and method of delivery. Placental tissues were assessed for altered histology and CD68 and CD163 staining. Tissue iron was assessed using Prussian blue staining. RESULTS: Maternal hematocrit levels were higher in GDM participants compared to controls (P = 0.02). The presence of meconium-laden macrophages was significantly greater within the amnion of GDM cases (adjusted odds ratio (OR) 12.51). Although the total abundance of CD68-expressing macrophages was not significantly different between groups, we detected a significantly greater abundance of CD163 expression within the chorion and decidua of cases. The total area staining positive for iron was 24% (95% confidence intervals of 2%-46%) greater in GDM placentae versus controls. CONCLUSION: GDM is associated with altered placental histology and increases in meconium-laden macrophages. Greater iron stores within the placentae of women with GDM is consistent with reports that iron excess is associated with an increased risk for GDM. The higher level of expression of CD163 on macrophage-like cells of the chorion and decidua in GDM suggests an increase in M2-like macrophages. Overall, our results add to growing evidence that GDM has direct effects on placental structure.

Prognostic value of D-dimer and markers of coagulation for stratification of abdominal aortic aneurysm growth.

Abdominal aortic aneurysm (AAA) is associated with high morbidity and mortality and is an established cause of unbalanced hemostasis. A number of hemostatic biomarkers have been associated with AAA; however, the utility of hemostatic biomarkers in AAA diagnosis and prognosis is unclear. The aim of the present study was to characterize the potential prognostic value of D-dimer and markers of altered hemostasis in a large cohort of patients with AAAs characterized by either fast or slow aneurysm growth (frequency matched for baseline diameter) and subaneurysmal dilations. We measured plasma concentrations of thrombin-antithrombin (TAT) complex, platelet factor 4 (PF4), and D-dimer in 352 patients with either fast-growing AAAs (>2 mm/y), slow-growing AAAs (<2 mm/y), subaneurysmal aortic dilations, or nonaneurysmal aortas. Plasma D-dimer and TAT were significantly elevated in both AAA and subaneurysmal dilation patients compared with controls. Individuals with D-dimer levels ≥500 ng/mL had 3.09 times the odds of subaneurysms, 6.23 times the odds of slow-growing AAAs, and 7.19 times the odds of fast-growing AAAs than individuals with D-dimer level <500 ng/mL. However, no differences in D-dimer concentration were noted between fast- and slow-growing aneurysms. Plasma D-dimer and TAT were strong independent predictors of AAA growth rate with multivariate analysis revealing a 500-ng/mL increase in D-dimer or 1-µg/mL increase in TAT led to additional 0.21-mm and 0.24-mm changes in aortic diameter per year, respectively. Rising levels of plasma TAT, in addition to D-dimer, may predict disease progression and aneurysm growth in patients with AAA or subaneurysmal dilation.

Pregnancy Intention and Maternal Alcohol Consumption.

OBJECTIVE: To evaluate whether women planning a pregnancy are less likely to use alcohol in early pregnancy than those with unintended pregnancies. METHODS: Right From the Start (2000-2012) is a prospective, community-based pregnancy cohort. Maternal demographic, reproductive, and behavioral data were collected in telephone interviews at enrollment (mean±standard deviation 48±13 days of gestation) and later in the first trimester (mean±standard deviation 85±21 days of gestation). Alcohol consumption characteristics were included in the interviews. We used logistic regression to investigate the association of pregnancy intention with alcohol use. RESULTS: Among 5,036 women, 55% reported using alcohol in the first trimester with 6% continuing use at the first-trimester interview. Pregnancy was planned by 70% of participants. Alcohol use occurred in 55% and 56% of intended and unintended pregnancies, respectively (P=.32). Adjusting for confounders, women with intended pregnancies were 31% less likely to consume any alcohol in early pregnancy (adjusted odds ratio [OR] 0.69, 95% confidence interval [CI] 0.60-0.81) or binge drink (adjusted OR 0.68, 95% CI 0.54-0.86). Most women, regardless of intention, stopped or decreased alcohol consumption in early pregnancy. CONCLUSION: The majority of women, irrespective of intention, stopped or decreased drinking after pregnancy recognition. This suggests promoting early pregnancy awareness could prove more effective than promoting abstinence from alcohol among all who could conceive.

Interpregnancy Interval After Pregnancy Loss and Risk of Repeat Miscarriage.

OBJECTIVE: To assess whether interpregnancy interval length after a pregnancy loss is associated with risk of repeat miscarriage. METHODS: This analysis includes pregnant women participating in the Right From the Start (2000-2012) community-based prospective cohort study whose most recent pregnancy before enrollment ended in miscarriage. Interpregnancy interval was defined as the time between a prior miscarriage and the last menstrual period of the study pregnancy. Miscarriage was defined as pregnancy loss before 20 weeks of gestation. Cox proportional hazard models were used to estimate crude and adjusted hazard ratios and 95% CIs for the association between different interpregnancy interval lengths and miscarriage in the study pregnancy. Adjusted models included maternal age, race, parity, body mass index, and education. RESULTS: Among the 514 study participants who reported miscarriage as their most recent pregnancy outcome, 15.7% had a repeat miscarriage in the study pregnancy (n=81). Median maternal age was 30 years (interquartile range 27-34) and 55.6% of participants had at least one previous livebirth (n=286). When compared with women with interpregnancy intervals of 6-18 months (n=136), women with intervals of less than 3 months (n=124) had the lowest risk of repeat miscarriage (7.3% compared with 22.1%; adjusted hazard ratio 0.33, 95% CI 0.16-0.71). Neither maternal race nor parity modified the association. Attempting to conceive immediately was not associated with increased risk of miscarriage in the next pregnancy. CONCLUSION: An interpregnancy interval after pregnancy loss of less than 3 months is associated with the lowest risk of subsequent miscarriage. This implies counseling women to delay conception to reduce risk of miscarriage may not be warranted.

Validation of maternal recall of early pregnancy medication exposure using prospective diary data.

PURPOSE: Data about maternal recall accuracy for classifying early pregnancy medication exposure are meager. Nonetheless, studies often rely on recall to evaluate potential impact of pharmaceuticals on the developing fetus. METHODS: Right from the Start is a community-based pregnancy cohort that enrolled women from North Carolina, Tennessee, and Texas. A subset of 318 women participated in daily medication diaries initiated before conception (2006-2012). We examined nonsteroidal anti-inflammatory drugs (NSAIDs) as an example of a drug type that is difficult to study due to its intermittent and primarily over-the-counter use as well as its incomplete documentation in medical and pharmaceutical records. Selective serotonin reuptake inhibitors (SSRI) were assessed as a prescription medication comparator. Maternal recall of NSAID and SSRI use in early pregnancy was examined by comparing diary data (gold standard) to first-trimester interview. RESULTS: Sensitivity and specificity for recall of NSAID exposure were 78.6% and 62.3%, respectively (kappa statistic: 0.41), with 72.3% agreement for exposure classification. Sensitivity and specificity for recall of SSRI exposure were 77.8% and 99.0%, respectively (kappa statistic: 0.79), with 97.8% agreement. CONCLUSIONS: Our findings suggest the validity of maternal recall varies with medication type and prospective data collection should be prioritized when studying early pregnancy drug exposures.

Leiomyomas in Pregnancy and Spontaneous Abortion: A Systematic Review and Meta-analysis.

OBJECTIVE: To systematically review studies reporting the risk of spontaneous abortion among pregnant women of typical reproductive potential with and without uterine leiomyomas. DATA SOURCES: We searched PubMed, EMBASE, Web of Science, and ClinicalTrials.gov for publications from January 1970 to December 2016. METHODS OF STUDY SELECTION: We excluded studies that did not use imaging to uniformly document leiomyoma status of all participants, did not have a comparison group without leiomyomas, or primarily included women seeking care for recurrent miscarriage, infertility care, or assisted reproductive technologies. TABULATION, INTEGRATION, AND RESULTS: Two authors independently reviewed eligibility, extracted data, and assigned overall quality ratings based on predetermined criteria. Of 1,469 articles identified, nine were eligible. Five enrolled general obstetric populations and four included women undergoing amniocentesis. In five studies in general obstetric populations that included 21,829 pregnancies (1,394 women with leiomyomas and 20,435 without), only one adjusted for potential confounders. This meta-analysis revealed no increase in risk of spontaneous abortion among those with leiomyomas compared with those without (11.5% compared with 8.0%; risk ratio 1.16, 95% CI 0.80-1.52). When bias from confounding was estimated for nonadjusted studies, the aggregate calculated risk ratio was 0.83 (95% CI 0.68-0.98). CONCLUSION: Leiomyoma presence was not associated with increased risk of spontaneous abortion in an analysis of more than 20,000 pregnant women. Failure of prior studies to adjust for confounders may have led to the common clinical belief that leiomyomas are a risk factor for spontaneous abortion.

The impact of maternal adiposity specialization on infant birthweight: upper versus lower body fat.

BACKGROUND: The specialization of human fat deposits is an inquiry of special importance in the study of fetal growth. It has been theorized that maternal lower-body fat is designated specifically for lactation and not for the growth of the fetus. OBJECTIVE: Our goal was to compare the contributions of maternal upper-body versus lower-body adiposity to infant birth weight. We hypothesized that upper-body adiposity would be strongly associated with infant birth weight and that lower-body adiposity would be weakly or negligibly associated with infant birth weight-after adjusting for known determinants. STUDY DESIGN: In this prospective cohort study, 355 women initiated medical pre-natal care during the first trimester of pregnancy at The University of Oklahoma Health Sciences Center during 1990-1993. Maternal anthropometric measurements were assessed at the first clinic visit: (a) height; (b) weight; (c) circumferences of the upper arm, forearm, and thigh; and, (d) skin-fold measurements of the bicep, subscapular region, and thigh. RESULTS: Infant birth weight was regressed on known major determinants to create the foundational model. Maternal anthropometric variables subsequently were added one at a time into this multiple regression model. The highest contribution by a single anthropometric variable to infant birthweight was, in order: subscapular skin-fold, forearm circumference, and thigh circumference. With one upper-body (subscapular skin-fold) and one lower-body (circumference of the thigh) adiposity measure in the model, the z-score regression coefficient (s.e.) was 85.7g (30.8) [p=0.0057] for maternal subscapular skin-fold and 19.0g (31.6) [p=0.5477] for circumference of the thigh. When the second-best upper-body contributor to infant birthweight (circumference of the forearm) was entered with one lower-body measure into the model, the z-score regression coefficient (s.e.) was 77.5g (38.5) [p=0.0451] for maternal forearm circumference and 14.1g (38.5) [p=0.7146] for circumference of the thigh. When both subscapular skinfold and forearm circumference were added to the model in place of BMI, the explained variance (r2=0.5478) was similar to the model using BMI (r2=0.5487). CONCLUSION: Upper-body adiposity - whether operationalized by subscapular skin-fold or circumference of the forearm - was a markedly larger determinant of infant birth weight than lower-body adiposity.