Folic Acid Supplementation to Prevent Neural Tube Defects: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Neural tube defects are among the most common birth defects in the US. Objective: To review new evidence on the benefits and harms of folic acid supplementation for the prevention of neural tube defects to inform the US Preventive Services Task Force. Evidence Review: Sources included PubMed, Cochrane Library, Embase, and trial registries from July 1, 2015, through July 2, 2021; references; and experts, with surveillance through February 10, 2023. Two investigators independently reviewed English-language randomized studies and nonrandomized cohort studies in very highly developed countries that focused on the use of folic acid supplementation for the prevention of neural tube defect-affected pregnancies; methodological quality was dually and independently assessed. Findings: Twelve observational studies (reported in 13 publications) were eligible for this limited update (N = 1 244 072). Of these, 3 studies (n = 990 372) reported on the effect of folic acid supplementation on neural tube defects. For harms, 9 studies were eligible: 1 randomized clinical trial (n = 431) reported on variations in twin delivery, 7 observational studies (n = 761 125) reported on the incidence of autism spectrum disorder, and 1 observational study (n = 429 004) reported on maternal cancer. Two cohort studies and 1 case-control study newly identified in this update reported on the association between folic acid supplementation and neural tube defects (n = 990 372). One cohort study reported a statistically significant reduced risk of neural tube defects associated with folic acid supplementation taken before pregnancy (adjusted relative risk [aRR], 0.54 [95% CI, 0.31-0.91]), during pregnancy (aRR, 0.62 [95% CI, 0.39-0.97]), and before and during pregnancy (aRR, 0.49 [95% CI, 0.29-0.83]), but this association occurred for only the later of 2 periods studied (2006-2013 and not 1999-2005). No other statistically significant benefits were reported overall. No study reported statistically significant harms (multiple gestation, autism, and maternal cancer) associated with pregnancy-related folic acid exposure. Conclusions and Relevance: New evidence from observational studies provided additional evidence of the benefit of folic acid supplementation for preventing neural tube defects and no evidence of harms related to multiple gestation, autism, or maternal cancer. The new evidence was consistent with previously reviewed evidence on benefits and harms.

Understanding the perspective of women who use the Billings Ovulation Method®: a focus group study.

BACKGROUND: The Billings Ovulation Method®(the Billings Method) is a fertility awareness-based method (FABM) of family planning that relies on the observation of patterns of fertility and infertility based on vulvar sensations and appearance of discharges. This allows people to choose when to have intercourse, depending on whether they want to avoid or achieve pregnancy. Few studies have documented user experiences with FABMs. METHODS: We conducted four virtual focus groups (FGs) in May and June 2021 with current adult women users of the Billings Method. We asked questions about users' reasons for selecting a FABM and the Billings Method, positive experiences and challenges learning and using the Billings Method, and suggestions for improving the user experience. We performed a content analysis of the transcribed FGs to explore key themes from the discussions. COREQ guidelines were followed. RESULTS: Twenty women between the ages of 23 and 43 participated in the FGs. Reasons women described choosing a FABM included to follow religious beliefs, to avoid side effects of hormonal contraception, and/or to learn more about their bodies. Reasons for selecting the Billings Method included perceiving it as more precise and easier to understand than other FABMs, having a scientific basis, and being recommended by family and friends. Experiences related to learning and using the Billings Method were mainly positive. They included finding the method easy to use and learn, successfully using it to either postpone or achieve a pregnancy and increasing their awareness of their bodies. Challenges for participants included the inherent learning curve for identifying sensations at the vulva and the required periods of abstinence. Participants provided suggestions and recommendations for improving users' experience, including raising awareness of the Billings Method among healthcare providers. CONCLUSIONS: Users of the Billings Method expressed an overall positive experience when learning and using it for family planning and body awareness. Some challenges were identified that offer opportunities to improve how the Billings Method is taught and delivered. These findings can also enhance healthcare providers' interactions with FABM users, including those of the Billings Method.

Listening to patients: Opportunities to improve reproductive wellness for women with chronic conditions.

OBJECTIVE: To understand how Black and Native American women with chronic conditions experience reproductive health care and identify patient-centered strategies to improve care. STUDY SETTING AND PARTICIPANTS: We held a series of virtual focus groups between February 2021 and December 2021 with 34 women who self-identified as Black or Native American, were of childbearing age, had one or more chronic conditions, and lived in North Carolina. STUDY DESIGN AND ANALYSIS: This qualitative, community-engaged study reviewed notes, video recordings, and graphic illustrations from the focus group sessions. Content analysis was used to iteratively identify themes. Emerging themes were reviewed by community and patient partners. PRINCIPAL FINDINGS: There were six thematic areas that emerged on the current state of reproductive health care for people with chronic conditions: (1) lack of trust in health care providers and institutions, (2) lack of health care provider knowledge, (3) uncoordinated care, (4) need for self-advocacy, (5) provider bias, and (6) mental health strain from coping. Six approaches for care improvement emerged: (1) build on models of coordinated health care services from other conditions to design more comprehensive care clinics, (2) involve care coordinators or navigators, (3) improve educational materials for patients, (4) train clinicians to increase their capacity to be trustworthy and provide quality, equitable, person-focused care, (5) design scripts to improve clinicians' ability to talk with women about infertility, miscarriage, infant loss, and (6) all interventions and research should be co-designed to address patient priorities. CONCLUSIONS: Engaging Black and Native American patient partners with chronic conditions in research planning is feasible, necessary, and beneficial using methods that support connection, respect, and bi-directional learning. Patient partners defined actionable strategies to improve reproductive care and wellness including comprehensive care clinics with patient navigators, trust-enhancing interventions, and better provision of reproductive health related education.

Effectiveness of fertility awareness-based methods for pregnancy prevention during the postpartum period.

OBJECTIVES: To summarize the evidence on typical and perfect-use effectiveness of fertility awareness-based methods for avoiding pregnancy during the postpartum period, whether breastfeeding or not. STUDY DESIGN: We conducted a systematic review of studies published in English, Spanish, French, or German by November 2021 in MEDLINE, EMBASE, CINAHL, Web of Science, and ClinicalTrials.gov. Abstract and full text reviews were completed by 2 independent reviewers. Study inclusion: at least 50 subjects who enrolled prior to experiencing 3 cycles after childbirth and were using a specific fertility awareness-based method to avoid pregnancy; unintended pregnancy rate or probability calculated; postpartum amenorrheic and postpartum cycling individuals analyzed separately; and prospectively measured pregnancy intentions and outcomes. Outcomes were abstracted and study quality was systematically assessed by 2 independent investigators. RESULTS: Four studies provided effectiveness data for 1 specific fertility awareness-based method among postpartum individuals. Of these, there were zero high quality, 1 moderate quality, and 3 low quality for our question of interest. Typical-use pregnancy probability for the first 6 cycles postpartum for Marquette Method users was 12.0 per 100 women years (standard error [SE] not reported) and for Billings Ovulation Method users ranged from 9.1 (SE 3.9) for non-lactating women <30 years old to 26.8 (SE 4.6) for lactating women <30 years old. Typical-use pregnancy probabilities for the first 6 months post-first menses for the Postpartum Bridge to Standard Days Method users was 11.8 (95% confidence interval 6.01-17.16) and for Billings Ovulation Method users was 8.5 per 100 women (SE 1.7). CONCLUSION: The current evidence on the effectiveness of each fertility awareness-based method for postpartum persons is very limited and of mostly low quality. More high quality studies on the effectiveness of fertility awareness-based method in postpartum persons are needed to inform clinical counseling and patient-centered decision-making. IMPLICATIONS: Although postpartum individuals may desire to use fertility awareness-based methods to avoid pregnancy, the evidence of the effectiveness of fertility awareness-based methods in this population is limited. More high-quality studies are needed to inform shared decision-making.

Assessing Preconception Wellness in the Clinical Setting Using Electronic Health Data.

Background: One key strategy to reduce maternal morbidity and mortality involves optimizing prepregnancy health. Although nine core indicators of preconception wellness (PCW) have been proposed by clinical experts, few studies have attempted to assess the preconception health status of a population using these indicators. Methods: We conducted a retrospective chart review study of patients who received prenatal or primary care, identified by pregnancy-related ICD-10 codes, at either of two health systems in geographically and socioeconomically different areas of North Carolina between October 1, 2015, and September 30, 2018. Our primary study aim was to determine the feasibility of measuring the proposed PCW indicators through retrospective review of prenatal electronic health records at these two institutions. Results: Data were collected from 15,384 patients at Site 1 and 6,983 patients at Site 2. The indicators most likely to be documented and to meet the preconception health goal at each site were avoidance of teratogenic medications (98.8% and 98.3% at Sites 1 and 2, respectively) and entry to care in the first trimester (64.5% and 73.5% at Sites 1 and 2, respectively), whereas our measures of folic acid use, depression screening, and discussion of family planning were documented less than 20% of the time at both sites. Conclusions: Differences in measuring and documenting PCW indicators across the two health systems in our study presented barriers to monitoring and optimizing PCW. Efforts to address health and wellness before pregnancy will likely require health systems and payors to standardize, incorporate, and promote preconception health indicators that can be consistently measured and analyzed across health systems.

The Impact of Pregnancy on Antihypertensive Drug Metabolism and Pharmacokinetics: Current Status and Future Directions.

INTRODUCTION: Hypertensive disorders of pregnancy (HDP) are rising in prevalence, and increase risk of adverse maternal and fetal outcomes. Physiologic changes occur during pregnancy that alter drug pharmacokinetics. However, antihypertensive drugs lack pregnancy-specific dosing recommendations due to critical knowledge gaps surrounding the extent of gestational changes in antihypertensive drug pharmacokinetics and underlying mechanisms. AREAS COVERED: This review (1) summarizes currently recommended medications and dosing strategies for non-emergent HDP treatment, (2) reviews and synthesizes existing literature identified via a comprehensive PubMed search evaluating gestational changes in the maternal pharmacokinetics of commonly prescribed HDP drugs (notably labetalol and nifedipine), and (3) offers insight into the metabolism and clearance mechanisms underlying altered HDP drug pharmacokinetics during pregnancy. Remaining knowledge gaps and future research directions are summarized. EXPERT OPINION: A series of small pharmacokinetic studies illustrate higher oral clearance of labetalol and nifedipine during pregnancy. Pharmacokinetic modeling and preclinical studies suggest these effects are likely due to pregnancy-associated increases in hepatic UGT1A1- and CYP3A4-mediated first-pass metabolism and lower bioavailability. Accordingly, higher and/or more frequent doses may be needed to lower blood pressure during pregnancy. Future research is needed to address various evidence gaps and inform the development of more precise antihypertensive drug dosing strategies.

Risk of Diabetes After Hysterectomy With or Without Oophorectomy in Postmenopausal Women.

The aim of this study was to determine the associations between hysterectomy, bilateral salpingo-oophorectomy (BSO), and incidence of diabetes in postmenopausal women participating in the Women's Health Initiative (WHI), a series of trials conducted in the United States, during the period 1993-1998. A total of 67,130 postmenopausal women aged 50-79 years were followed for a mean of 13.4 years. Among them, 7,430 cases of diabetes were diagnosed. Multivariable Cox proportional hazards models were used to assess the association between hysterectomy/oophorectomy status and diabetes incidence. Compared with women without hysterectomy, women with hysterectomy had a significantly higher risk of diabetes (hazard ratio = 1.13, 95% confidence interval: 1.06, 1.21). The increased risk of diabetes was similar for women with hysterectomy only and for women with hysterectomy with concomitant BSO. Compared with hysterectomy alone, hysterectomy with BSO was not associated with additional risk of diabetes after stratification by age at hysterectomy and hormone therapy status. In our large, prospective study, we observed that hysterectomy, regardless of oophorectomy status, was associated with increased risk of diabetes among postmenopausal women. However, our data did not support the hypothesis that early loss of ovarian estrogens is a risk factor for type 2 diabetes. The modest increased risk of diabetes associated with hysterectomy may be due to residual confounding, such as the reasons for hysterectomy.

Overweight, Obesity, and Postmenopausal Invasive Breast Cancer Risk: A Secondary Analysis of the Women's Health Initiative Randomized Clinical Trials.

IMPORTANCE: More than two-thirds of US women are overweight or obese, placing them at increased risk for postmenopausal breast cancer. OBJECTIVE: To investigate in this secondary analysis the associations of overweight and obesity with risk of postmenopausal invasive breast cancer after extended follow-up in the Women's Health Initiative (WHI) clinical trials. DESIGN, SETTING, AND PARTICIPANTS: The WHI clinical trial protocol incorporated measured height and weight, baseline and annual or biennial mammography, and adjudicated breast cancer end points in 67 142 postmenopausal women ages 50 to 79 years at 40 US clinical centers. The women were enrolled from 1993 to 1998 with a median of 13 years of follow-up through 2010; 3388 invasive breast cancers were observed. MAIN OUTCOMES AND MEASURES: Height and weight were measured at baseline, and weight was measured annually thereafter. Data were collected on demographic characteristics, personal and family medical history, and personal habits (smoking, physical activity). Women underwent annual or biennial mammograms. Breast cancers were verified by medical records reviewed by physician adjudicators. RESULTS: Women who were overweight and obese had an increased invasive breast cancer risk vs women of normal weight. Risk was greatest for obesity grade 2 plus 3 (body mass index [BMI], calculated as weight in kilograms divided by height in meters squared, >35.0) (hazard ratio [HR] for invasive breast cancer, 1.58; 95% CI, 1.40-1.79). A BMI of 35.0 or higher was strongly associated with risk for estrogen receptor-positive and progesterone receptor-positive breast cancers (HR, 1.86; 95% CI, 1.60-2.17) but was not associated with estrogen receptor-negative cancers. Obesity grade 2 plus 3 was also associated with advanced disease, including larger tumor size (HR, 2.12; 95% CI, 1.67-2.69; P = .02), positive lymph nodes (HR, 1.89; 95% CI, 1.46-2.45; P = .06), regional and/or distant stage (HR, 1.94; 95% CI, 1.52-2.47; P = .05), and deaths after breast cancer (HR, 2.11; 95% CI, 1.57-2.84; P < .001). Women with a baseline BMI of less than 25.0 who gained more than 5% of body weight over the follow-up period had an increased breast cancer risk (HR, 1.36; 95% CI, 1.1-1.65), but among women already overweight or obese we found no association of weight change (gain or loss) with breast cancer during follow-up. There was no effect modification of the BMI-breast cancer relationship by postmenopausal hormone therapy, and the direction of association across BMI categories was similar for never, past, and current hormone therapy use. CONCLUSIONS AND RELEVANCE: Obesity is associated with increased invasive breast cancer risk in postmenopausal women. These clinically meaningful findings should motivate programs for obesity prevention. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.

"We Know but We Don't Really Know": Diet, Physical Activity and Cardiovascular Disease Prevention Knowledge and Beliefs Among Underserved Pregnant Women.

To describe the knowledge of underserved pregnant women related to diet, physical activity, and cardiovascular disease (CVD). Underserved pregnant women from the University of North Carolina and Pitt County, North Carolina participated in 9 focus group interviews. Focus group questions focused on knowledge of CVD risk factors, lifestyle prevention strategies such as diet and physical activity, and the sources of such knowledge. Data were analyzed with the constant comparative method. Prior to the focus group, each woman was invited to complete a telephone survey to collect demographic information and responses to a 13-item CVD knowledge questionnaire. Means and frequency procedures were used to analyze demographic information. Fifty women participated in nine focus group interviews. Participants possessed basic knowledge of CVD risk factors and preventive strategies, such as basic guidelines and recommendations for healthy diet and physical activity in pregnancy. However, women often receive incomplete guidance from obstetric providers, and women, therefore, desired more information on these topics. Some gaps were filled by nurses and nutritionists. Women also sought information from female friends and relatives. Incorrect knowledge was demonstrated in all groups and led to less healthful behaviors in some cases. Underserved pregnant women have basic knowledge about healthy lifestyle and CVD prevention behaviors; however important gaps and misinformation exist.

Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review.

Oral contraceptives may influence the risk of certain cancers. As part of the AHRQ Evidence Report, Oral Contraceptive Use for the Primary Prevention of Ovarian Cancer, we conducted a systematic review to estimate associations between oral contraceptive use and breast, cervical, colorectal, and endometrial cancer incidence. We searched PubMed, Embase, and Cochrane Database of Systematic Reviews. Study inclusion criteria were women taking oral contraceptives for contraception or ovarian cancer prevention; includes comparison group with no oral contraceptive use; study reports quantitative associations between oral contraceptive exposure and relevant cancers; controlled study or pooled patient-level meta-analyses; sample size for nonrandomized studies ≥100; peer-reviewed, English-language; published from January 1, 2000 forward. Random-effects meta-analyses were conducted by estimating pooled ORs with 95% confidence intervals (CIs). We included 44 breast, 12 cervical, 11 colorectal, and 9 endometrial cancers studies. Breast cancer incidence was slightly but significantly increased in users (OR, 1.08; CI, 1.00-1.17); results show a higher risk associated with more recent use of oral contraceptives. Risk of cervical cancer was increased with duration of oral contraceptive use in women with human papillomavirus infection; heterogeneity prevented meta-analysis. Colorectal cancer (OR, 0.86; CI, 0.79-0.95) and endometrial cancer incidences (OR, 0.57; CI, 0.43-0.77) were significantly reduced by oral contraceptive use. Compared with never use, ever use of oral contraceptives is significantly associated with decreases in colorectal and endometrial cancers and increases in breast cancers. Although elevated breast cancer risk was small, relatively high incidence of breast cancers means that oral contraceptives may contribute to a substantial number of cases.

Oral contraceptive pills as primary prevention for ovarian cancer: a systematic review and meta-analysis.

OBJECTIVE: To estimate the overall reduction in ovarian cancer risk associated with the use of oral contraceptive pills (OCPs) and whether reduction in risk is affected by specifics of OCP use, such as formulation or duration of use. DATA SOURCES: We searched PubMed, Embase, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for studies published from January 1990 to June 2012, with primary analysis of studies published since January 2000. METHODS OF STUDY SELECTION: We reviewed 6,476 citations. We included English-language controlled studies with human participants reporting a quantitative association between exposure to OCPs (in which the explicit or implicit indication for OCP use was prevention of pregnancy or ovarian cancer) compared with no use of OCPs. Two investigators independently reviewed the title and abstract and full-text of articles for inclusion or exclusion decision; discordant decisions were resolved by team review and consensus. TABULATION, INTEGRATION, AND RESULTS: Fifty-five studies met inclusion criteria. A random-effects meta-analysis of 24 case-control and cohort studies showed significant reduction in ovarian cancer incidence in ever-users compared with never-users (odds ratio 0.73, 95% confidence interval 0.66-0.81). There was a significant duration-response relationship, with reduction in incidence of more than 50% among women using OCPs for 10 or more years. The lifetime reduction in ovarian cancer attributable to the use of OCPs is approximately 0.54% for a number-needed-to-treat of approximately 185 for a use period of 5 years. CONCLUSION: Significant duration-dependent reductions in ovarian cancer incidence in the general population are associated with OCP use.

Screening low-income women of reproductive age for cardiovascular disease risk factors.

UNLABELLED: Abstract Background: Identifying and treating chronic diseases, their precursors, and other cardiovascular disease (CVD) risk factors during family planning visits may improve long-term health and reproductive outcomes among low-income women. A cross-sectional study design was used to describe the prevalence of chronic diseases (hypertension, high cholesterol, and diabetes), their precursors (pre-hypertension, borderline high cholesterol, and pre-diabetes), and related CVD risk factors (such as obesity, smoking, and physical inactivity) among low-income women of reproductive age. METHODS: Prevalence of chronic diseases, their precursors, and related CVD risk factors were assessed for 462 out of 859 (53.8%) female family planning patients, ages 18-44 years, who attended a Title X clinic in eastern North Carolina during 2011 and 2012 and consented to participate. Data were obtained from clinical measurements, blood test results, and questionnaire. Differences in distribution of demographic and health care characteristics and CVD risk factors by presence of prehypertension and pre-diabetes were assessed by Pearson chi-square tests. RESULTS: The prevalence of hypertension was 12%, high cholesterol 16%, and diabetes 3%. Nearly two-thirds of women with hypertension were newly diagnosed (62%) as were 75% of women with diabetes. The prevalence of pre-hypertension was 35%, pre-diabetes 31%, obesity 41%, smoking 32%, and physical inactivity 42%. The majority of participants (87%) had one or more chronic disease or related cardiovascular disease risk factor. CONCLUSIONS: CVD screening during family planning visits can identify significant numbers of women at risk for poor pregnancy outcomes and future chronic disease and can provide prevention opportunities if effective interventions are available and acceptable to this population.

Oral contraceptive use for the primary prevention of ovarian cancer.

OBJECTIVE: To estimate the overall balance of harms and benefits from the potential use of oral contraceptives (OCs) for the primary prevention of ovarian cancer DATA SOURCES: We searched PubMed®, Embase®, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for English-language studies published from January 1990 to June 2012 that evaluated the potential benefits (reduction in ovarian, colorectal, and endometrial cancers) and harms (increase in breast and cervical cancer, and vascular complications) of OC use. REVIEW METHODS: Two investigators screened each abstract and full-text article for inclusion; the investigators abstracted data, and they performed quality ratings, applicability ratings, and evidence grading. Random-effects models were used to compute summary estimates of effects. A simulation model was used to estimate the effects of OC use on the overall balance of benefits and harms. RESULTS: We reviewed 55 studies relevant to ovarian cancer outcomes, 66 relevant to other cancers, and 50 relevant to vascular events. Ovarian cancer incidence was significantly reduced in OC users (OR [odds ratio], 0.73; 95% CI [confidence interval], 0.66 to 0.81), with greater reductions seen with longer duration of use. Breast cancer incidence was slightly but significantly increased in OC users (OR, 1.08; 95% CI, 1.00 to 1.17), with a significant reduction in risk as time since last use increased. The risk of cervical cancer was significantly increased in women with persistent human papillomavirus infection who used OCs, but heterogeneity prevented a formal meta-analysis. Incidences of both colorectal cancer (OR, 0.86; 95% CI, 0.79 to 0.95) and endometrial cancer (OR, 0.57; 95% CI, 0.43 to 0.76) were significantly reduced by OC use. The risk of vascular events was increased in current OC users compared with nonusers, although the increase in myocardial infarction was not statistically significant. The overall strength of evidence for ovarian cancer prevention was moderate to low, primarily because of the lack of randomized trials and inconsistent reporting of important characteristics of use, such as duration. The simulation model predicted that the combined increase in risk of breast and cervical cancers and vascular events was likely to be equivalent to or greater than the decreased risk in ovarian cancer, although the harm/benefit ratio was much more favorable when protection against endometrial and colorectal cancers was added, resulting in net gains in life expectancy of approximately 1 month. CONCLUSIONS: There is insufficient evidence to recommend for or against the use of OCs solely for the primary prevention of ovarian cancer. Although the net effects of the current patterns of OC use likely result in increased life expectancy when other noncontraceptive benefits are included, the harm/benefit ratio for ovarian cancer prevention alone is uncertain, particularly when the potential quality-of-life impact of breast cancer and vascular events are considered.