Society for Maternal-Fetal Medicine Consult Series #59: The use of analgesia and anesthesia for maternal-fetal procedures.

Pain is a complex phenomenon that involves more than a simple physical response to external stimuli. In maternal-fetal surgical procedures, fetal analgesia is used primarily to blunt fetal autonomic responses and minimize fetal movement. The purpose of this Consult is to review the literature on what is known about the potential for fetal awareness of pain and to discuss the indications for and the risk-benefit calculus involved in the use of fetal anesthesia and analgesia. The recommendations by the Society for Maternal-Fetal Medicine are as follows: (1) we suggest that fetal paralytic agents be considered in the setting of intrauterine transfusion, if needed, for the purpose of decreasing fetal movement (GRADE 2C); (2) although the fetus is unable to experience pain at the gestational age when procedures are typically performed, we suggest that opioid analgesia should be administered to the fetus during invasive fetal surgical procedures to attenuate acute autonomic responses that may be deleterious, avoid long-term consequences of nociception and physiological stress on the fetus, and decrease fetal movement to enable the safe execution of procedures (GRADE 2C); and (3) due to maternal risk and a lack of evidence supporting benefit to the fetus, we recommend against the administration of fetal analgesia at the time of pregnancy termination (GRADE 1C).

Experiences with pain of early medical abortion: qualitative results from Nepal, South Africa, and Vietnam.

BACKGROUND: Medical abortion (MA) has become an increasingly popular choice for women even where surgical abortion services are available. Pain is often cited by women as one of the worst aspects of the MA experience, yet we know little about women's experience with pain management during the process, particularly in low resource settings. The aim of this study is to better understand women's experiences of pain with MA and strategies for improving quality of care. METHODS: This qualitative study was conducted as part of a three-arm randomized, controlled trial in Nepal, Vietnam, and South Africa to investigate the effect of prophylactic pain management on pain during MA through 63 days' gestation. We purposively sampled seven parous and seven nulliparous women with a range of reported maximum pain levels from each country, totaling 42 participants. Thematic content analysis focused on MA pain experiences and management of pain compared to menstruation, labor, and previous abortions. RESULTS: MA is relatively less painful compared to giving birth and relatively more painful than menstruation, based on four factors: pain intensity, duration, associated symptoms and side effects, and response to pain medications. We identified four types of pain trajectories: minimal overall pain, brief intense pain, intermittent pain, and constant pain. Compared to previous abortion experiences, MA pain was less extreme (but sometimes longer in duration), more private, and less frightening. There were no distinct trends in pain trajectories by treatment group, parity, or country. Methods of coping with pain in MA and menstruation are similar in each respective country context, and use of analgesics was relatively uncommon. The majority of respondents reported that counseling about pain management before the abortion and support during the abortion process helped ease their pain and emotional stress. CONCLUSIONS: Pain management during MA is increasingly essential to ensuring quality abortion care in light of the growing proportion of abortions completed with medication around the world. Incorporating a discussion about pain expectations and pain management strategies into pre-MA counseling and providing access to information and support during the MA process could improve the quality of care and experiences of MA patients. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613000017729 , registered January 8, 2013.

Two prophylactic medication approaches in addition to a pain control regimen for early medical abortion < 63 days' gestation with mifepristone and misoprostol: study protocol for a randomized, controlled trial.

BACKGROUND: Pain is often cited as one of the worst features of medical abortion. Further, inadequate pain management may motivate some women to seek unnecessary clinical care. There is a need to identify effective methods for pain control in this setting. METHODS/DESIGN: We propose a randomized, placebo-controlled trial. 576 participants (288 nulliparous; 288 parous) from study sites in Nepal, South Africa and Vietnam will be randomly allocated to one of three treatments: (1) ibuprofen 400 mg PO and metoclopramide 10 mg PO; (2) tramadol 50 mg PO and a placebo; or (3) two placebo pills, to be taken immediately before misoprostol and repeated once four hours later. All women will be provided with supplementary analgesia for use as needed during the medical abortion. We hypothesize that women receiving prophylactic analgesia will report lower maximal pain scores in the first 8 h following misoprostol administration compared to women receiving placebos for medical abortion through 63 days' gestation. Our primary objective is to determine whether prophylactic administration of ibuprofen and metoclopramide or tramadol provides superior pain relief compared to analgesia administration after pain begins, measured during the first eight hours after misoprostol administration. Secondary objectives include identifying covariates associated with higher reported pain scores; determining any impact of the study medicines on medical abortion success; and, qualitatively exploring women's physical experiences of medical abortion, especially related to pain, and how can they be improved. Data sources include medical records, participant symptom diaries and interview data obtained on the day of enrollment, during the medical abortion, and at follow-up. Participants will be contacted via telephone on day 3 and return for follow-up will occur approximately 14 days after mifepristone, concluding study participation. A subset of 42 women will also be invited to undergo in-depth qualitative interviews following study completion. DISCUSSION: Although pain is one of the most common side effects encountered with medical abortion, little is known about optimal pain management for this process. This multi-arm trial design offers an efficient approach to evaluating two prophylactic pain management regimens compared to use of pain medication as needed. TRIAL REGISTRATION: ACTRN12613000017729 (Prospectively registered 8/1/2013).

Adjuvant misoprostol or mifepristone for cervical preparation with osmotic dilators before dilation and evacuation.

OBJECTIVES: This study aimed to compare effectiveness and safety of cervical preparation with osmotic dilators plus same-day misoprostol or overnight mifepristone prior to dilation and evacuation (D&E). STUDY DESIGN: We conducted a retrospective cohort analysis of 664 patients initiating abortion between 18 and 22 weeks at an ambulatory health center. We abstracted medical record data from two consecutive 12-month periods in 2017 to 2019. All patients received overnight dilators plus: 600 mcg buccal misoprostol 90 minutes before D&E (period 1); 200 mg oral mifepristone at time of dilators (period 2). Our primary outcome was procedure time. We report frequency of patients experiencing any acute complication, defined as unplanned procedure (i.e., reaspiration, cervical laceration repair, uterine balloon tamponade) or hospital transfer and bleeding complications. RESULTS: We observed higher mean procedure time in the mifepristone group (9.7 ± 5.3 minutes vs 7.9 ± 4.4, p = 0.004). After adjusting for race, ethnicity, insurance, body mass index, parity, prior cesarean, prior uterine surgery, gestational age, provider, trainee participation, and long-acting reversible contraception initiation, the difference remained statistically significant (relative change 1.09, 95% CI 1.01, 1.17) but failed to reach our threshold for clinical significance. The use of additional misoprostol was more common in the mifepristone group, but the use of an additional set of dilators was not different between groups. Acute complications occurred at a frequency of 4.1% in misoprostol group and 4.3% in mifepristone group (p = 0.90). CONCLUSIONS: We found procedure time to be longer with adjunctive mifepristone compared to misoprostol; however, this difference is unlikely to be clinically meaningful. Furthermore, the frequency of acute complications was similar between groups. IMPLICATIONS: Overnight mifepristone at the time of cervical dilator placement is a safe and effective alternative to adjuvant same-day misoprostol for cervical preparation prior to D&E and may offer benefits for clinic flow and patient experience.

Pharmacokinetics and ovarian suppression during use of a contraceptive vaginal ring in normal-weight and obese women.

OBJECTIVE: Many observational studies indicate higher oral contraceptive failure among obese women, but most clinical trials and physiologic studies do not support these differences. Limited data indicate higher failure rates among obese contraceptive patch users. Data regarding contraceptive vaginal ring performance in obese women are needed. STUDY DESIGN: Twenty normal weight (body mass index [BMI] 19.0-24.9; median, 21.65) and 20 obese (BMI 30.0-39.9; median, 33.7) women enrolled in a prospective study of ethinyl estradiol (EE(2)) and etonorgestrel pharmacokinetics and of ovarian follicle development, endometrial thickness, and bleeding patterns, all measured biweekly during the second cycle of contraceptive vaginal ring use. RESULTS: Thirty-seven women completed follow-up. Mean day 0-21 EE(2) concentrations were lower among obese vs normal weight women (15.0 vs 22.0 pg/mL, respectively, P = .004), whereas etonorgestrel concentrations were similar (1138 vs 1256 pg/mL, respectively, P = .39). Follicular development was minimal in both groups, with only 5 women achieving a maximum follicle diameter >13 mm at any time during 3 weeks follow-up (3 normal weight and 2 obese women); these women had serum progesterone levels <1.0. Obese women reported more bleeding or spotting than normal weight women (3.6 vs 1.4 days, respectively, P = .01). CONCLUSION: Although obese women had lower EE(2) levels during contraceptive vaginal ring use, they had excellent suppression of ovarian follicle development, similar to normal weight women. This predicts that contraceptive vaginal ring effectiveness will be similar in women with a BMI up to 39.9. The lower serum EE(2) levels in the obese women may explain the greater reported bleeding or spotting days.

Integrating self-managed medication abortion with medical care.

In this commentary, we distill key messages from a new framework for self-managed medication abortion developed by Global Doctors for Choice. Since Global Doctors for Choice supports doctors working in different contexts around the world, the document also highlights clinical concerns and advocacy opportunities for clinicians in both low- and high-resource settings, and in places with varying legal and administrative restrictions on abortion.

Same-Day Compared With Overnight Cervical Preparation Before Dilation and Evacuation Between 16 and 19 6/7 Weeks of Gestation: A Randomized Controlled Trial.

We performed a double-blind, placebo-controlled, randomized noninferiority trial to compare same-day osmotic dilators plus misoprostol with overnight osmotic dilators alone for cervical preparation before dilation and evacuation (D&E) between 16 0/7 and 19 6/7 weeks of gestation. The primary outcome was procedure time. The study was halted early owing to poor accrual. However, the median procedure time was 5.7 minutes in the same-day group compared with 4.2 minutes in the overnight group. The median absolute difference in procedure time was 1.5 minutes, which corresponded to a 35% increase in procedure time (relative difference 35%, one-sided 95% CI -Inf to 52%). Same-day cervical preparation with osmotic dilators plus buccal misoprostol before D&E may be a timely option. Clinical Trial Registration: ClinicalTrials.gov, NCT03002441.

Society for Maternal-Fetal Medicine Consult Series #59: The use of analgesia and anesthesia for maternal-fetal procedures.

Pain is a complex phenomenon that involves more than a simple physical response to external stimuli. In maternal-fetal surgical procedures, fetal analgesia is used primarily to blunt fetal autonomic responses and minimize fetal movement. The purpose of this Consult is to review the literature on what is known about the potential for fetal awareness of pain and to discuss the indications for and the risk-benefit calculus involved in the use of fetal anesthesia and analgesia. The recommendations by the Society for Maternal-Fetal Medicine are as follows: (1) we suggest that fetal paralytic agents be considered in the setting of intrauterine transfusion, if needed, for the purpose of decreasing fetal movement (GRADE 2C); (2) although the fetus is unable to experience pain at the gestational age when procedures are typically performed, we suggest that opioid analgesia should be administered to the fetus during invasive fetal surgical procedures to attenuate acute autonomic responses that may be deleterious, avoid long-term consequences of nociception and physiological stress on the fetus, and decrease fetal movement to enable the safe execution of procedures (GRADE 2C); and (3) due to maternal risk and a lack of evidence supporting benefit to the fetus, we recommend against the administration of fetal analgesia at the time of pregnancy termination (GRADE 1C).

Transcutaneous Electrical Nerve Stimulation to Reduce Pain With Medication Abortion: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether high-frequency transcutaneous electrical nerve stimulation (hfTENS) reduces pain during medication abortion. METHODS: We conducted a randomized, placebo-controlled trial. Participants who were undergoing medication abortion with mifepristone and misoprostol through 70 days of gestation either received active 80 Hz hfTENS or sham to use for a minimum of 60 minutes within 8 hours of misoprostol. Maximum pain on an 11-point numerical rating scale at 8 hours after misoprostol was the primary outcome. We estimated 20 per group for 80% power to detect a 2-point difference and up to 10% attrition. Secondary outcomes included a maximum pain score at 24 hours, additional analgesia use, the difference in score before and after treatment, the experience of side effects, abortion outcomes, and acceptability. We collected data at baseline, time of misoprostol (0-hour), 8-hour and 24 hours using real-time electronic surveys, and at follow-up. RESULTS: Between June 2019 and March 2020, we screened 251 patients and randomized 40-20 each to hfTENS or sham-with one postrandomization exclusion and two patients lost to follow-up. Baseline characteristics were similar. Median maximum pain scores at 8 hours were 7.0 (interquartile range 3.0) and 10.0 (interquartile range 3.0) for hfTENS and sham, respectively. The distribution of these scores was lower among hfTENS users compared with sham (mean rank 15.17 vs 22.63, P=.036). High-frequency TENS users also experienced a significant reduction in posttreatment pain score (-2.0 [interquartile range 2.5] vs 0 [interquartile range 1.5], P=.008). We found no statistically significant differences in use of additional analgesia, distribution of maximum pain scores at 24 hours, side effects, or measures of acceptability. CONCLUSION: High-frequency TENS reduced maximum pain scores within 8 hours of misoprostol and reduced pain scores immediately after treatment compared with placebo. High-frequency TENS offers an effective nonpharmacologic option for pain management during medication abortion. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03925129.

Two prophylactic pain management regimens for medical abortion ≤63 days' gestation with mifepristone and misoprostol: A multicenter, randomized, placebo-controlled trial.

OBJECTIVE: To determine if either prophylactic tramadol 50 mg or ibuprofen 400 mg/metoclopramide 10 mg result in lower maximal pain compared to placebo in women ≤63 days' gestation having a mifepristone-misoprostol medical abortion. STUDY DESIGN: We conducted a randomized, placebo-controlled trial in Nepal, South Africa, and Vietnam. Participants seeking medical abortion received active treatment or placebo, taken at time of misoprostol and repeated 4 hours later. All had access to additional analgesia. The primary outcome was mean maximum pain score within 8 hours. Participants self-assessed maximum pain using an 11-point numeric rating scale recorded in paper diaries; we analyzed these data using intention-to-treat analysis. Secondary outcomes included use of additional analgesia, side effects, and satisfaction. RESULTS: We enrolled 563 patients between June 2016 and October 2017; 5 participants failed to follow up. Mean adjusted maximum pain scores within 8 hours in both active arms were lower than placebo (tramadol: n = 188, 6.78 (95% confidence interval [CI] 6.46, 7.11); ibuprofen/metoclopramide: n = 187, 6.43 (95% CI 6.10, 6.75); placebo: n = 188, 7.42 (95% CI 7.10, 7.74); p = 0.0001). Additional analgesia was used by 97 (52.2%) participants in the tramadol group, 80 (43.0%) in the ibuprofen/metoclopramide group, and 103 (55.7%) in the placebo group, p = 0.04. More dizziness (p = 0.004), headache (p = 0.03), and vomiting (p < 0.001) occurred in the tramadol group. More participants reported experienced pain was the same or less than expected in the ibuprofen/metoclopramide group (p = 0.05); overall abortion satisfaction did not differ by group (p = 0.44). CONCLUSIONS: Compared with placebo, tramadol or ibuprofen/metoclopramide co-administered with misoprostol and repeated 4 h later resulted in lower mean maximum pain scores that failed to achieve clinical significance. Women who received ibuprofen/metoclopramide were least likely to use additional analgesia and reported fewer side effects. IMPLICATIONS: Given that tramadol, ibuprofen, and metoclopramide are inexpensive, globally available; and, ibuprofen and metoclopramide are included on the World Health Organization Essential Medicines List, these medicines could be considered for prophylactic pain management during medical abortion.

Could second-trimester medical abortion be offered as a day service? Assessing the feasibility of a 1-day outpatient procedure using pooled data from six clinical studies.

OBJECTIVES: Current service delivery models for second-trimester medical abortion typically include routine inpatient admission and overnight stays. To assess the feasibility of a day-service model, we evaluated outpatient administration of abortion medications and analyzed the proportion of clients who could avoid an overnight stay. We also examined additional key elements of medical abortion care to evaluate the practicality of this model. STUDY DESIGN: We pooled data from six clinical studies of second-trimester medical abortion conducted by Gynuity over the past 10 years. We include 868 individuals receiving mifepristone-misoprostol abortion between 13 and 22 weeks' gestation. RESULTS: At 8 h post misoprostol initiation, 309/521 (59.3%) participants at 13-18 weeks' gestation had a successful abortion; by 10 h, 382/521 (73.3%) were successful. Taking the mifepristone at home lowered neither the efficacy of the method nor satisfaction with the experience. Nonphysician providers played a significant role in the provision of care. Needed interventions were relatively rare; serious complications were very rare. CONCLUSIONS: Our findings support the provision of second-trimester medical abortion in a day-clinic setting, especially at ≤18 weeks' gestation. Such a model could increase access to quality care in many settings. IMPLICATIONS: Second-trimester medical abortion can safely and effectively be offered as a day service. Nonphysician providers are well suited to provide the majority of care. Developing guidelines for a 1-day model could increase access to quality care in many settings worldwide.

Feasibility of a hospital outpatient day procedure for medication abortion at 13-18 weeks gestation: Findings from Nepal.

OBJECTIVES: To evaluate the safety, acceptability and feasibility of a one-day outpatient medication abortion service at gestations 13-18 weeks. STUDY DESIGN: Open-label prospective study in which participants received mifepristone 200 mg orally to swallow at home or at the clinic followed 24 h later by misoprostol 400 mcg buccally. They presented to the outpatient clinic 24-48 h after mifepristone for misoprostol 400 mcg buccally every three hours (no maximum dose). The primary outcome was successful abortion without transfer to overnight inpatient care. Secondary outcomes included time to abortion from initial misoprostol dose, safety, additional interventions and side effects. RESULTS: We enrolled 230 women from December 2017 to November 2018. Approximately nine of ten (n = 206, 89.6%) achieved a successful abortion without transfer to overnight care. Twenty-four were transferred to overnight inpatient care; of these 18 were to manage a complication, five for incomplete abortion and two by choice. Among these 24, three women experienced an SAE. The median time to successful abortion from time of the first misoprostol dose was 7.2 h (range: 0.75-92.3), with an average of three misoprostol doses. Most participants expelled the fetus and the placenta at or around the same time; median time between fetal and placental expulsion was 15 minutes (range: 0-4.5 h). Fifteen participants (6.6%) received more than five misoprostol doses and were transferred to inpatient care. Administration of more than five doses of misoprostol was associated with nulliparity. Provision of antibiotics (27.9%, n = 64), manual removal of placenta (15.3%, n = 35), uterotonics (4.4%, n = 10) and surgical interventions (4.4%, n = 10) were also reported. About one in four participants experienced nausea, vomiting and chills; fever was infrequent (2.5%, n = 5). CONCLUSIONS: For gestations 13-18 weeks, an outpatient day process for medication abortion is safe, effective and feasible. IMPLICATIONS: Medication abortion in 13 - 18 weeks need not be limited to inpatient care; nine of ten cases can be managed as an outpatient day service.

Abortion care for adolescents.

Over 800,000 pregnancies occur among adolescents annually in the United States. The majority of teen pregnancies are unintended and one-third of these pregnancies end in abortion. As in older reproductive age women, medical and surgical abortions are safe and well tolerated by adolescents. Short-term morbidity is uncommon and no long-term adverse health or psychologic sequelae are associated with uncomplicated abortion. Adolescents encounter unique barriers in accessing abortion services that delay care and increase the cost and complexity of abortion. Clinicians function as a key resource for accurate information and support for adolescents with undesired pregnancies.

A systematic review and meta-analysis of venous thrombosis risk among users of combined oral contraception.

BACKGROUND: Combined oral contraceptives (COCs) containing various progestogens could be associated with differential risks for venous thromboembolism (VTE). OBJECTIVE: To evaluate the comparative risks of VTE associated with the use of low-dose (less than 50 µg ethinyl estradiol) COCs containing different progestogens. SEARCH STRATEGY: PubMed and the Cochrane Library were searched from database inception through September 15, 2016, by combining search terms for oral contraception and venous thrombosis. SELECTION CRITERIA: Studies reporting VTE risk estimates among healthy users of progestogen-containing low-dose COCs were included. DATA COLLECTION AND ANALYSIS: A random-effects model was used to generate pooled adjusted risk ratios and 95% confidence intervals; subgroup and sensitivity analyses assessed the impact of monophasic-COC use and study-level characteristics. MAIN RESULTS: There were 22 articles included in the analysis. The use of COCs containing cyproterone acetate, desogestrel, drospirenone, or gestodene was associated with a significantly increased risk of VTE compared with the use of levonorgestrel-containing COCs (pooled risk ratios 1.5-2.0). The analysis restricted to monophasic COC formulations with 30 µg of ethinyl estradiol yielded similar findings. After adjustment for study characteristics, the risk estimates were slightly attenuated. CONCLUSIONS: Compared with the use of levonorgestrel-containing COCs, the use of COCs containing other progestogens could be associated with a small increase in risk for VTE.

Nonoral combined hormonal contraceptives and thromboembolism: a systematic review.

BACKGROUND: Combined hormonal contraceptives (CHCs), containing estrogen and progestin, are associated with an increased risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) compared with nonuse. Few studies have examined whether nonoral formulations (including the combined hormonal patch, combined vaginal ring and combined injectable contraceptives) increase the risk of thrombosis compared with combined oral contraceptives (COCs). OBJECTIVES: The objectives were to examine the risk of VTE and ATE among women using nonoral CHCs compared to women using COCs. METHODS: We searched the PubMed database for all English language articles published from database inception through May 2016. We included primary research studies that examined women using the patch, ring or combined injectables compared with women using levonorgestrel-containing or norgestimate-containing COCs. Outcomes of interest included VTE (deep venous thrombosis or pulmonary embolism) or ATE (acute myocardial infarction or ischemic stroke). We assessed the quality of each individual piece of evidence using the system developed by the United States Preventive Services Task Force. RESULTS: Eight studies were identified that met inclusion criteria. Of seven analyses from six studies examining VTE among patch users compared with levonorgestrel- or norgestimate-containing COC users, two found a statistically significantly elevated risk among patch users (risk estimates 2.2-2.3), one found an elevated risk that did not meet statistical significance (risk estimate 2.0), and four found no increased risk. Of three studies examining VTE among ring users compared with levonorgestrel COC users, one found a statistically significantly elevated risk among patch users (risk estimate 1.9) and two did not. Two studies did not find an increased risk for ATE among women using the patch compared with norgestimate COCs. We did not identify any studies examining combined injectable contraceptives. CONCLUSION: Limited Level II-2 good to fair evidence demonstrated conflicting results on whether women using the patch or the ring have a higher risk of VTE than women using COCs. Evidence did not demonstrate an increased risk of ATE among women using the patch. Overall, any potential elevated risk likely represents a small number of events on a population level. Additional studies with standard methodology are needed to further clarify any associations and better understand mechanisms of hormone-induced thrombosis among users of nonoral combined hormonal contraception.

Combined hormonal contraceptive (CHC) use among obese women and contraceptive effectiveness: a systematic review.

OBJECTIVE: To evaluate from the literature whether combined hormonal contraception (CHC), including combined oral contraception pills (COCs), transdermal patch, vaginal ring or combined injectables, have different effectiveness or failure rates by body weight or body mass index (BMI). STUDY DESIGN: We searched PubMed and the Cochrane Library databases for all articles in all languages published between inception and February 2016, for evidence relevant to body weight or BMI, CHC use and contraceptive effectiveness. The quality of each individual study was assessed using the system for evaluating evidence developed by the United States Preventive Services Task Force. RESULTS: From 2874 articles, we identified 15 reports for inclusion, all of fair to poor quality. Fourteen studies measured the association of obesity status and contraceptive failure among COC users. Three fair quality and one poor quality study reported increased COC failure among a heterogeneous population of overweight and obese women compared with normal weight women, while eight fair quality and two poor quality studies did not find an association. Two fair quality studies reported on contraceptive transdermal patches. One pooled analysis described a higher proportion of pregnancies among women using the patch who weighed ≥90 kg; another secondary analysis suggested BMI>30 was associated with increased failure. No studies directly compared contraceptive effectiveness using the combined vaginal ring or combined injectable. CONCLUSION: Current available evidence addressing the risk of CHC failure in obese compared to normal weight women is limited to fair and poor quality studies. Studies of COCs show mixed results, though absolute differences in COC failure by body weight and BMI are small. Based on limited evidence, it appears that increasing body weight and BMI may contribute to decreasing contraceptive patch effectiveness.

The safety of subcutaneously administered depot medroxyprogesterone acetate (104mg/0.65mL): A systematic review.

CONTEXT: Depot medroxyprogesterone acetate (DMPA), a progestogen-only contraceptive injectable, has traditionally been formulated as a crystalline suspension delivered intramuscularly (IM) at a dose of 150mg/1.0mL. A new, lower dose formulation of DMPA (104mg/0.65mL) has been developed for subcutaneous administration (SC). Given its increasing global availability and public health relevance, DMPA-SC was prioritized for inclusion as a new method referenced in the World Health Organization (WHO) Medical Eligibility Criteria for Contraceptive Use (MEC), 5th Edition. OBJECTIVE: This systematic review evaluated the published peer-reviewed literature regarding the safety of DMPA-SC among women with various characteristics or medical conditions. Results of this review informed the decision-making of a WHO Guideline Development Group in order to include recommendations on contraceptive eligibility within the revised MEC. METHODS: We searched PubMed and Cochrane Library databases to identify all relevant evidence published in peer-reviewed journals regarding the safety of DMPA-SC when used by women of reproductive age, particularly those with select characteristics or conditions specified in the MEC, from inception through June 2015. The quality of each individual study was assessed using the system for grading evidence developed by the United States Preventive Services Task Force. RESULTS: Fourteen studies met criteria for inclusion. Ten reported results relevant to DMPA users of varying age or with obesity, endometriosis or HIV; four compared the safety of DMPA-SC and DMPA-IM when used by general populations of healthy women. A randomized trial evaluating changes in bone mineral density among adult DMPA-SC and DMPA-IM users demonstrated no differences at 2years of follow-up. Limited evidence reported no consistent differences in weight change or bleeding patterns according to age; however, adolescents (<18years) were not included in any studies. Similar contraceptive efficacy, weight change, bleeding patterns and occurrence of other adverse effects among obese and nonobese DMPA-SC users were observed. Women with endometriosis using DMPA-SC over 6months had minimal decreases in bone mineral density, weight gain, few serious adverse events and experienced improved pain symptoms. Women living with HIV tolerated injection of DMPA-SC with rare complications. DMPA-SC and DMPA-IM also show therapeutic equivalence and similar effects on weight gain, changes in bleeding patterns and reports of other adverse effects when these different delivery systems were used by general populations of women. CONCLUSION: Evidence for use of DMPA-SC by women with select conditions and characteristics including age, obesity, endometriosis or HIV demonstrates that this method can generally be used safely in these contexts. Further, DMPA-SC and DMPA-IM appear to be therapeutically equivalent with similar safety profiles when used by healthy women.

Combined hormonal contraceptive use among women with known dyslipidemias: a systematic review of critical safety outcomes.

CONTEXT: Dyslipidemias represent a spectrum of lipid disorders that are important risk factors for cardiovascular disease. In addition, elevated triglycerides are known to be associated with pancreatitis. Though less clear, it is possible that dyslipidemias may also contribute to risk for venous thromboembolism (VTE). Ethinyl estradiol and progestogen, contained within combined hormonal contraception, are known to impact lipid metabolism. OBJECTIVES: To evaluate from the literature whether use of combined hormonal contraception (CHC), including combined oral contraception (COC) pills, transdermal patch, vaginal ring or injectables, modifies the relative risk of acute myocardial infarction (MI), stroke, VTE or pancreatitis among women with known dyslipidemias and to determine if existing lipid abnormalities worsen with CHC use. METHODS: PubMed and the Cochrane Library databases were searched for all articles in all languages published between inception and September 2014 relevant to dyslipidemia, CHC use and serious adverse events (MI, stroke, VTE or pancreatitis). The quality of each individual study was assessed using the system for grading evidence developed by the United States Preventive Services Task Force. RESULTS: From 306 articles identified by our search strategy, 3 articles met inclusion criteria. In a poor-quality case-control study, women with hypercholesterolemia but no COC use had an increased risk of MI (adjusted odds ratio [adj OR] 3.3, 95% confidence interval [CI] 1.6-6.8), as did women who used COCs but did not have hypercholesterolemia (adj OR 2.0, 95% CI 1.4-2.8), compared with non-COC users without hypercholesterolemia; women with both COC use and hypercholesterolemia had an adjusted OR of 24.7 (95% CI 5.6-108.5) compared with women with neither risk factor. A poor-quality cohort study examined COC users and reported that women with dyslipidemia had increased risk for VTE [crude risk ratio (RR) 1.39, 95% CI 1.04-1.85] and transient ischemic attacks or cerebrovascular accidents (CVAs) (RR 1.76, 95% CI 1.51-2.06) compared to those without dyslipidemia. Another poor-quality cohort study provided direct evidence on changes in lipid levels among COC users with dyslipidemia. A minority of women with elevated total cholesterol or triglyceride levels at baseline showed normal results (25% and 28%, respectively) after 6 cycles of COC use. No evidence regarding risks associated with use of other CHC methods was identified. No evidence was identified for the outcome of pancreatitis. CONCLUSION: Limited data from poor-quality observational studies suggest that women with known dyslipidemias using CHC may be at increased risk for MI and may experience a minimal increase in risk for CVA or VTE. No evidence was identified on risk for pancreatitis in this context. The impact of CHC exposure on the status of lipid abnormalities over time, an intermediate marker for disease, is also unclear. Given the significant limitations of this body of evidence, the importance of access to effective contraception and theoretical concerns raised about the use of CHCs by women with known dyslipidemias, additional rigorous studies are needed to best estimate true associations. Contraceptive decision making should include consideration of both the known and theoretical risks of a given CHC method, safety and acceptability of alternative contraceptive methods, and risks associated with unintended pregnancy.

Safety of the progesterone-releasing vaginal ring (PVR) among lactating women: A systematic review.

CONTEXT: Lactation causes a delay in ovulation in the postpartum period, and therefore a delay in the resumption of menses. However, return to fertility is variable in the postpartum period and is contingent upon numerous factors. The postpartum period is therefore a critical time to initiate effective contraception in order to support the numerous beneficial health outcomes of optimal pregnancy spacing. Breastfeeding women have an unmet need for highly effective birth control methods that do not interfere with lactation and that are safe for their infants. The progesterone-releasing vaginal ring (PVR) releases a natural progesterone that suppresses ovulation and is specifically designed for breastfeeding women in the first postpartum year. OBJECTIVE: To review the published peer-reviewed literature regarding the safety and effectiveness of the PVR used for contraception among lactating women, as well as the safety for their infants. Results of this review informed the decisions of the Guideline Development Group to include recommendations on contraceptive eligibility for the PVR within the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 5th Edition. METHODS: We searched the PubMed, Popline, and LILACS bibliographic databases for articles published in any language from database inception through October 1, 2014. We reviewed the literature for evidence regarding the safety of the PVR among breastfeeding women using the method, as well as for their infants. The US Preventive Services Task Force system was applied to assess the quality of the evidence. RESULTS: Seven articles met our criteria for inclusion in this review. All studies were of a prospective cohort design. All studies consistently showed that use of the PVR among breastfeeding women compares favorably to other methods of contraception with regard to effectiveness, does not compromise a woman's breastfeeding performance, and does not adversely affect infant growth during the first year postpartum. CONCLUSION: The PVR is a safe and highly effective method of contraception for use among breastfeeding women. It should be offered to women who plan to breastfeed in the context of postpartum contraceptive counseling.

Proinflammatory cytokine genes are constitutively overexpressed in the heart in experimental systemic lupus erythematosus: a brief communication.

The heart is one of a number of organs that may be affected in systemic lupus erythematosus (SLE), a prototypic autoimmune disease. Potential anatomical sites of involvement include the myocardium, pericardium, endocardium, valves, conduction system and blood vessels that subserve the heart. Typically, the severity of cardiovascular disease in lupus correlates with the degree of systemic inflammation, which is mirrored by the level of C-reactive protein (CRP) in the plasma. C-reactive protein, in turn is regulated by proinflammatory cytokines, such as interleukins (ILs) 1beta and 6. These cytokines have been found in functionally and/or structurally damaged areas of the heart and have been implicated in disease pathogenesis. It has been assumed that the source of these putatively pathogenetically relevant cytokines in the compromised heart is infiltrating mononuclear cells. This study tests the hypothesis that cardiomyocytes per se may contribute to proinflammatory cytokine production in the setting of systemic inflammation. Using as the experimental model MRL/MpJ-Tnfrs6(lpr) (MRL-lpr/lpr) mice, which spontaneously manifest an autoimmune syndrome that has clinical features of SLE, we show that ventricular homogenates and ventricular cardiomyocytes constitutively overexpress genes encoding the proinflammatory cytokines IL-1beta, IL-6, IL-10, and gamma interferon. The results suggest the possibility that proinflammatory cytokines emanating from the heart may actually contribute to the high levels of CRP that appear to aid in predicting subsequent cardiac events. Viewed in this setting, CRP becomes a footprint of an ongoing pathogenic process mediated, in part, by the heart muscle itself.