What's new in obstetrics and gynecology

The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.

PRENATAL OBSTETRICS

Malaria prevention regimens and pregnancy outcomes in East Africa (March 2023)

Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is important for reducing malaria-associated adverse birth outcomes, but dihydroartemisinin-piperaquine (DP) is a promising alternative in areas with SP resistance. A randomized trial of nearly 4700 pregnant women without human immunodeficiency virus (HIV) infection in East Africa randomly assigned participants to receive IPTp with: SP alone, DP alone, or DP with azithromycin [1]. Compared with SP alone, DP resulted in a 41 percent reduction in clinical malaria but a higher composite rate of adverse pregnancy outcomes (low birth weight, small for gestational age, preterm birth, death: 28 versus 23 percent). Thus, while DP-IPTp may have superior antimalarial effects in areas with SP resistance, SP-IPTp may have other benefits on pregnancy outcomes. Further study of malaria prevention tools in areas with SP resistance is needed. (See "Malaria in pregnancy: Prevention and treatment", section on 'Intermittent preventive treatment in pregnancy (IPTp)'.)

Intrauterine transfusion for alpha thalassemia major (March 2023)

Alpha thalassemia major (ATM; loss of all four alpha globin genes) is usually incompatible with live birth unless intrauterine transfusions (IUT) are performed. In a series of 19 pregnancies with prenatally diagnosed ATM, all 14 fetuses treated with >2 IUT survived to delivery, while the 5 fetuses who did not receive IUT died in utero or shortly after birth [2]. Earlier initiation of IUT correlated with higher neurodevelopmental scores. For patients electing to proceed with fetal therapy, IUT should be initiated as soon as technically possible (18 weeks at most fetal treatment centers). (See "Alpha thalassemia major: Prenatal and postnatal management", section on 'Intrauterine transfusions'.)

Timing of aspirin discontinuation in preeclampsia prophylaxis (March 2023)

The optimal time to discontinue aspirin use for preventing preeclampsia is unclear, and practice varies. In a randomized trial in Spain, patients at high risk of preterm preeclampsia based on a first-trimester screening algorithm began aspirin 150 mg daily before 14 weeks of gestation [3]. Blood angiogenic factors were measured at 24 to 28 weeks, and those at low preeclampsia risk based on these results discontinued aspirin prophylaxis. The rates of preterm and term preeclampsia and most adverse outcomes were not significantly different for the two groups, but the early discontinuation group had less minor antepartum bleeding (7.6 versus 12.3 percent). These findings warrant further study. They are not generalizable to populations such as the United States, where angiogenic factor testing is unavailable, a lower dose of aspirin (81 mg) is commonly used, and the population is more diverse. (See "Preeclampsia: Prevention", section on 'Dose'.)

ART selection during pregnancy (February 2023)

The United States Department of Health and Human Services issued new recommendations on the selection and continuation of antiretroviral therapy (ART) during pregnancy [4]. The major practical changes include:

● Atazanavir and raltegravir are no longer preferred ART agents during pregnancy but are reasonable alternative agents if preferred agents cannot be used.

● Patients who become pregnant while on the injectable cabotegravir-rilpivirine regimen can now continue the regimen throughout pregnancy with frequent viral load monitoring (every one to two months).

● For patients who acquire HIV despite using cabotegravir as part of an HIV pre-exposure prophylaxis (PrEP) regimen, ritonavir-boosted darunavir is preferred over dolutegravir for ART initiation during pregnancy.

Our approach is consistent with these recommendations, which take into account a patient's preferences regarding use of ART that have less data on pregnancy and also consider the effect of newer ART agents used in PrEP. (See "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings", section on 'Selecting the third drug'.)

Removal of X-waiver requirement to prescribe buprenorphine for opioid use disorder (February 2023)

Previously, in order to prescribe buprenorphine for opioid use disorder (OUD) in the United States, clinicians had to apply for a federally required DATA Waiver (X-Waiver). In January 2023, the Consolidated Appropriations Act of 2023 removed this requirement and allowed clinicians with schedule III authority on their Drug Enforcement Administration (DEA) registration to prescribe buprenorphine for OUD treatment if permitted by applicable state law [5]. We believe this change will encourage buprenorphine prescribing and thus prevent opioid overdose. (See "Acute opioid intoxication in adults", section on 'Prevention of recurrent opioid overdose'.)

Romiplostim for ITP during pregnancy (February 2023)

Initial therapies for immune thrombocytopenia (ITP) during pregnancy (glucocorticoids and intravenous immune globulin [IVIG]) are usually effective and considered safe. In contrast, data on thrombopoietin receptor agonists (TPO-RAs) has been lacking. In a new study involving 92 pregnancies with romiplostim exposure, adverse pregnancy outcomes were similar to the general population [6]. In pregnant individuals, we generally reserve TPO-RAs for refractory ITP or for those who cannot take glucocorticoids or IVIG. Individuals who become pregnant while taking a TPO-RA should have an individualized risk assessment. (See "Thrombocytopenia in pregnancy", section on 'ITP therapies'.)

Screening for alcohol use during pregnancy (February 2023)

Although universal screening for alcohol use during pregnancy is advised, evidence suggests that screening and follow-up care remain suboptimal. An analysis of 2017 and 2019 United States Behavioral Risk Factor Surveillance Systems data noted that approximately 20 percent of pregnant patients were not asked about alcohol consumption at their most recent visit and, of those who were asked and reported alcohol use, only 16 percent were advised to stop or reduce their consumption [7]. We advise continued education for both patients and clinicians about the risks of alcohol use during pregnancy and encourage universal screening for pregnant persons. (See "Alcohol intake and pregnancy", section on 'Screening during pregnancy'.)

Cerebral palsy and maternal injury during pregnancy (January 2023)

The underlying causes of cerebral palsy (CP) are often unknown, though several perinatal risk factors have been identified (eg, prematurity, hypoxic-ischemic injury, intrauterine infections). In a large cohort study that included over 2 million children, those with in utero exposure to accidental maternal injury requiring emergency department or inpatient care had a higher prevalence of CP compared with unexposed children (3.6 versus 2.5 per 1000 children, respectively) [8]. CP risk correlated with severity of maternal injury. These findings highlight the importance of prevention efforts to reduce the risk of severe injury during pregnancy (correct use of seat belts and airbags). (See "Cerebral palsy: Epidemiology, etiology, and prevention", section on 'Antenatal infection or injury'.)

First trimester treatment of malaria with artemisinin derivatives (December 2022)

Artemisinin combination therapy (ACT) has become the preferred treatment for uncomplicated malaria in most patients, but use for treatment of chloroquine-resistant malaria in the first trimester has been avoided because of limited safety data. However, in a 2022 meta-analysis of prospective data from >700 pregnancies with confirmed first trimester exposure to ACT and >1000 pregnancies with confirmed first trimester exposure to non-ACTs, adverse pregnancy outcomes occurred less often among those who received ACT, although the result was not statistically significant (5.7 versus 8.9 percent; adjusted hazard ratio [aHR] 0.71, 95% CI 0.49-1.03) [9]. Artemether-lumefantrine accounted for 70 percent of the ACT exposures and was associated with a lower risk of adverse pregnancy outcome compared with oral quinine (4.8 versus 9.2 percent; aHR 0.58, 95% CI 0.36-0.92). Based on these data, we now suggest artemether-lumefantrine for treatment of chloroquine-resistant malaria during the first trimester. (See "Malaria in pregnancy: Prevention and treatment", section on 'Drug safety'.)

Suture choice for cerclage (October 2022)

Cerclage is performed with either a monofilament or braided suture, depending on the surgeon's preference. In the first randomized trial comparing these two types of sutures in 2000 patients undergoing history- or ultrasound-indicated transvaginal cerclage, the frequency of pregnancy loss (miscarriage and perinatal mortality) was similar in both groups (monofilament 8.0 percent, braided 7.6 percent) [10]. The type of cerclage (Shirodkar or MacDonald) was at the discretion of the surgeon. These findings support the current standard of care in which the choice of suture is based on the surgeon's preference. (See "Transvaginal cervical cerclage", section on 'Technique'.)

Antenatal corticosteroids for anticipated preterm birth before 23 weeks (October 2022)

The value of antenatal corticosteroids (ACS) in pregnancies between 21 and 23 weeks of gestation is controversial. In an observational cohort study including over 400 infants born at 22^0/7 to 23^6/7 weeks of gestation, administration of a complete course of ACS was associated with higher survival to discharge compared with no ACS (54 versus 36 percent); however, most survivors had major morbidity when evaluated at 36 weeks postmenstrual age (survival without major morbidity: 27 percent with ACS, 10 percent without ACS) [11]. Shared decision-making (parents, obstetrical and neonatal staff) is particularly important at this gestational age when parents are faced with a decision affecting their child's survival and quality of life. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery", section on '22+0 to 22+6 weeks'.)

INTRAPARTUM AND POSTPARTUM OBSTETRICS

Extending low molecular weight heparin until closer to delivery (March 2023)

Some obstetricians replace low molecular weight (LMW) heparin with unfractionated heparin at 36 to 37 weeks of gestation to improve the patient's chances of receiving neuraxial anesthesia for labor and delivery, if desired. However, an analysis of data from the Highlow trial of LMW heparin prophylaxis in pregnancy found that most patients were eligible for neuraxial anesthesia at the unplanned onset of labor, including 82 percent of patients on low-dose and 61 percent of patients on intermediate-dose LMW heparin [12]. Numbers of eligible patients were higher for planned labor (93 and 81 percent). These results support extended use of LMW heparin prophylaxis to 38 to 39 weeks or even until onset of labor in many individuals. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Switch to unfractionated heparin'.)

Prophylactic antibiotics before vaginal birth (February 2023)

Antibiotic prophylaxis to reduce the risk of postpartum maternal infection is standard practice before cesarean birth but not for laboring patients planning to give birth vaginally. However, in a randomized trial among nearly 30,000 patients ≥28 weeks of gestation in early labor planning a vaginal birth in seven low- and middle-income countries (LMIC), a single 2-gram oral dose of azithromycin reduced the composite risk of maternal sepsis or death compared with placebo (1.6 versus 2.4 percent) [13]. Neonatal sepsis and death rates were unchanged. A similar trial in different LMIC reported a reduction in maternal sepsis that was not statistically significant (0.1 versus 0.2 percent) [14]. Based on these findings, we would consider use of azithromycin prophylaxis in LMIC with clinical settings that mirror the first trial's setting, but not in other countries or clinical settings. (See "Labor and delivery: Management of the normal first stage", section on 'Interventions unlikely to be beneficial'.)

Feeding and antiretroviral prophylaxis for infants born to mothers with HIV (February 2023)

The United States Department of Health and Human Services (DHHS) issued updated guidelines on breastfeeding and antiretroviral prophylaxis for infants born to mothers with HIV [4]:

●Patients who are virologically suppressed and have been on ART consistently through at least the third trimester and at delivery can now consider breastfeeding after discussing the risks and benefits with their clinician. The guidelines continue to strongly recommend against breastfeeding for individuals without virologic suppression.

●Formula-fed infants who are at very low risk of HIV acquisition (full-term and born to mothers who maintained viral suppression on at least 10 consecutive weeks of ART during pregnancy and delivery without adherence concerns) can receive only 2 weeks of zidovudine instead of the previously recommended 4 to 6 weeks. For breastfed infants who are at low risk of HIV acquisition at birth, the guidelines recommend six weeks of zidovudine.

We are in agreement with these recommendations. (See "Intrapartum and postpartum management of pregnant women with HIV and infant prophylaxis in resource-rich settings", section on 'Breastfeeding'.)

Maximum oxytocin dose in labor (January 2023)

Although many labor and delivery units limit the maximum oxytocin infusion dose to no more than 40 milliunits per minute during labor with a live fetus in the third trimester, doses as high as 90 milliunits per minute were used without adverse maternal or fetal effects in a recent trial [15]. Given these and previous data of the variability in uterine response to the medication, we favor titrating the oxytocin dose according to the oxytocin responsiveness of the individual patient, primarily based on their contraction and fetal heart rate patterns, without regard to an arbitrary maximum dose. (See "Induction of labor with oxytocin", section on 'Dose titration'.)

Blood loss at delivery in placenta accreta spectrum (January 2023)

A meta-analysis of 20 studies evaluating red blood cell (RBC) use in nearly 1100 patients with placenta accreta spectrum (PAS) found that, on average, five RBC units were transfused per patient at delivery [16]. In the largest study (338 patients), a median of two units were transfused but the range was 0 to 108 units. These findings illustrate the variability in blood loss and the potential for horrific hemorrhage in PAS. They also highlight the importance of notifying the blood bank and ensuring that adequate blood products are available at delivery in these cases. (See "Placenta accreta spectrum: Management", section on 'Components of preoperative planning'.)

Dose of LMW heparin for VTE prevention in pregnancy (November 2022)

Low molecular weight (LMW) heparin is used for venous thromboembolism (VTE) prophylaxis during pregnancy and postpartum, but optimal dosing has been unclear. The Highlow trial evaluated dosing in 1110 pregnant individuals with a prior VTE receiving LMW heparin for VTE prophylaxis from the first trimester to six weeks postpartum [17]. Compared with weight-adjusted intermediate dosing, those assigned to daily fixed low-dose (60 mg) LMW heparin had a slightly higher rate of VTE (1 percent in both groups antepartum, 2 versus 1 percent postpartum); the difference did not reach statistical significance. Bleeding risk was 4 percent in each group. While we continue to perform an individualized risk assessment for each patient, this trial provides reassurance for the efficacy of fixed low-dose LMH heparin, especially antenatally. (See "Use of anticoagulants during pregnancy and postpartum", section on 'LMW heparin'.)

Pregnancy-related death in the United States (November 2022)

In a report by the Centers for Disease Control and Prevention (CDC) including over 1000 pregnancy-related deaths from 2017 to 2019 (ie, maternal death during pregnancy and up to one year postpartum), mental health conditions (eg, suicide, opioid use disorder) accounted for 23 percent and were the most common cause; over 80 percent of all of the deaths were considered preventable [18]. By comparison, cardiovascular conditions were the most common cause in a previous CDC report. Based on these and other data, the CDC has expanded its efforts to eliminate preventable causes of pregnancy-related death, but additional initiatives are needed. (See "Overview of maternal mortality", section on 'United States'.)

Updated guidance on neonatal hyperbilirubinemia (October 2022)

The American Academy of Pediatrics (AAP) has updated its clinical practice guidance on management of hyperbilirubinemia in term and late preterm newborns ≥35 weeks of gestation [19]. Key changes from earlier guidelines include:

●Initial newborn screening can be performed either with a laboratory test (ie, total serum bilirubin [TSB]) or transcutaneous bilirubin (TcB) device; abnormal TcB results require confirmation with TSB

●Guidance for follow-up after newborn bilirubin screening has been updated (table 1)

●Higher treatment TSB thresholds are used for initiating phototherapy (figure 1A-B) and exchange transfusion (figure 2A-B)

●New guidance is provided for "escalation of care" to rapidly address dangerously high bilirubin concentrations (algorithm 1)

We generally agree with the updated AAP guidance. Importantly, since the new treatment thresholds are higher than in previous guidelines, delays in starting phototherapy are more likely to result in dangerously high TSB levels. Thus, when treatment is indicated, it should begin promptly. (See "Screening for hyperbilirubinemia in term and late preterm newborns" and "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns" and "Escalation of care for term and late preterm newborn infants with unconjugated hyperbilirubinemia".)

OFFICE GYNECOLOGY

Combination medical therapy not superior to methotrexate alone for treating ectopic pregnancy (March 2023)

Ectopic pregnancy is usually treated with surgery or methotrexate (MTX) alone, but use of MTX with another medication (eg, gefitinib, mifepristone) has been described. In a randomized trial comparing a single dose of MTX plus seven days of either gefitinib or placebo in over 300 patients with tubal ectopic pregnancy, both groups had similar rates of surgical intervention, time to pregnancy resolution, subsequent doses of MTX, and serious complications [20]. However, more patients in the gefitinib group experienced diarrhea and rash. In our practice, we do not use combination medical therapy because MTX alone is effective, and combination therapy increases side effects and cost. (See "Ectopic pregnancy: Methotrexate therapy", section on 'Role of combined drug therapy'.)

Abortion restriction and rates of suicide (January 2023)

While pregnancy termination does not appear to be a risk factor for suicidal ideation or behavior, increased abortion restriction may be one. In a report by the Centers for Disease Control and Prevention (CDC), increasing enforcement of laws restricting access to abortion was associated with more than a fivefold increase in rates of suicide among females ages 20 to 34 years [21]. These data are consistent with other published outcomes that suggest abortion restriction is associated with adverse health outcomes. (See "Unsafe abortion", section on 'Other health consequences of abortion restriction'.)

FDA changes to mifepristone REMS restrictions (January 2023)

Mifepristone (a progesterone receptor antagonist used for management of some abortions and pregnancy loss) is available in the United States with Risk Evaluation and Mitigation Strategy (REMS) restrictions; only mifepristone REMS-registered health care providers can prescribe the drug and, until 2023, only registered mail-order pharmacies and provider clinics could dispense the drug. In January 2023, the US Food and Drug Administration (FDA) expanded access by allowing mifepristone prescriptions from a registered prescriber to be filled and dispensed by mifepristone-registered retail pharmacies [22]. Depending on state abortion bans and restrictions, this expansion may increase patient access to mifepristone, especially those seeking alternative methods to in-person care. (See "Overview of pregnancy termination", section on 'REMS restrictions'.)

Association between tamoxifen and endometrial pathology in patients with breast cancer (January 2023)

Tamoxifen, a selective estrogen receptor modulator, is used as adjuvant therapy or chemoprevention for selected patients with hormone-sensitive breast cancer or at increased risk for breast cancer; however, it is associated with an increased risk for uterine pathology. In one of the largest studies, a retrospective study including over 78,000 premenopausal patients (mean age 42 years) with breast cancer in Korea who were followed for an average of six years, those treated with versus without tamoxifen had higher rates of uterine disease (32 versus 7 per 1000 person-years), including (in descending order of frequency) endometrial polyps, endometrial hyperplasia, endometrial cancer, and other uterine cancers (rare) [23]. We discuss these risks with all patients when counseling about the use of tamoxifen. (See "Abnormal uterine bleeding and uterine pathology in patients on tamoxifen therapy", section on 'Risks and management of uterine pathology'.)

Ibrexafungerp for recurrent vulvovaginal candidiasis (December 2022)

Treatment of recurrent vulvovaginal candidiasis (RVVC) has mainly consisted of long-term use of azole drugs such as fluconazole. In a phase 3 trial evaluating extended treatment with either ibrexafungerp, a novel triterpenoid antifungal, or placebo after initial fluconazole treatment in patients with RVVC, more patients receiving extended ibrexafungerp remained without evidence of RVVC four weeks from final dose (65 versus 53 percent). Based on this trial, the US Food and Drug Administration recently approved RVVC as a new indication for use of ibrexafungerp [24]. Although the duration of treatment benefit and efficacy against non-Candida species are not yet known, ibrexafungerp offers patients with RVVC another treatment option. (See "Candida vulvovaginitis: Treatment", section on 'Triterpenoid extended treatment'.)

Genomic endometrial testing does not improve live birth rates with IVF (December 2022)

Use of gene expression to evaluate endometrial receptivity and optimize timing of embryo transfer has been proposed to improve live birth rates during in vitro fertilization cycles, particularly for patients with prior unsuccessful implantations. However, a multicenter randomized trial evaluating outcomes of euploid blastocyst transfers based on endometrial receptivity testing or standard timing practices reported similar live birth rates for the two groups [25]. These findings add to the observational evidence that routine use of genomic endometrial receptivity testing does not improve live birth rates. (See "In vitro fertilization: Procedure", section on 'Endometrial preparation for frozen-thawed embryo transfer'.)

Disparities in infant mortality after assisted reproductive technology (November 2022)

Existing racial and ethnic disparities in infant health outcomes appear to be increased for children conceived with assisted reproductive technology (ART). In a study in the United States comparing infant mortality in singleton births between 2016 and 2017, non-Hispanic Black children had double the risk of infant death compared with non-Hispanic White children when conceived naturally, but four times greater risk when conceived by ART [26]. Further study is warranted as these differences could not be accounted for by available maternal demographic data and underlying medical conditions alone. (See "Assisted reproductive technology: Infant and child outcomes", section on 'Stillbirth and perinatal mortality'.)

Infertility treatment and pediatric cancer risk (September 2022)

The risk of cancer in children conceived with assisted reproductive technology (ART, such as in vitro fertilization) has been debated, in part because it is difficult to separate the impact of the treatment from that of the underlying fertility disorder. In a recent cohort study including over 2.3 million parent-child triads followed for a median of 6 years, conception with ART was associated with an increased risk of pediatric cancer compared with non-ART conception in subfertile patients or unassisted (natural) conception, but the absolute increase was small (65 cases per million person-years) [27]. We include this information when counseling patients. (See "Assisted reproductive technology: Infant and child outcomes", section on 'Cancer risk'.)

GYNECOLOGIC SURGERY

Association of premenopausal oophorectomy with parkinsonism (November 2022)

Bilateral oophorectomy in premenopausal patients is associated with increased risk of serious long-term health consequences, including all-cause mortality, cardiovascular disease, and cognitive impairment; its association with parkinsonism is less clear. In a cohort study of almost 5500 age-matched premenopausal patients, those with a history of oophorectomy compared with no oophorectomy had increased rates of examination or medical record-confirmed parkinsonism (hazard ratio [HR] 1.59) [28]. While rates of Parkinson disease were similar between groups overall, risk was elevated in those with oophorectomy prior to age 43 years (HR 5). Despite its limitations, this study further supports our practice to suggest ovarian conservation to premenopausal patients undergoing hysterectomy for benign indications. (See "Elective oophorectomy or ovarian conservation at the time of hysterectomy", section on 'Cognitive function and neurologic disease'.)

OTHER GYNECOLOGY

Assisted reproductive technology outcomes in euthyroid women with thyroid peroxidase (TPO) antibodies (March 2023)

A 2022 meta-analysis of observational studies showed higher rates of adverse assisted reproductive technology (ART) outcomes in euthyroid women with, compared to without, thyroid peroxidase (TPO) antibodies, although the findings were limited by the low quality of the evidence [29]. In a subsequent retrospective study of 449 TPO antibody-positive and 2945 antibody-negative Chinese women undergoing in vitro fertilization or intracytoplasmic sperm injection, there was no difference in oocyte retrieval, fertilization, embryo utilization, blastocyst formation, pregnancy rate, or live birth rate between the two groups [30]. Although the new study was larger than most previous studies and attempted to control for numerous potential confounding factors, it was retrospective in design and has similar limitations as previous observational studies. The association between thyroid autoimmunity and adverse ART outcomes remains uncertain. (See "Overview of thyroid disease and pregnancy", section on 'Pregnancy outcomes'.)

CDC updates opioid prescribing guidelines (November 2022)

The United States Centers for Disease Control and Prevention (CDC) has published a new guideline for prescribing opioids for acute, subacute, and chronic pain, updating their 2016 guideline (table 2). The guideline is intended for clinicians who prescribe opioids to outpatients ≥18 years of age and does not apply to pain related to sickle cell disease, cancer, palliative care, or end of life care [31]. (See "Use of opioids in the management of chronic non-cancer pain", section on 'Opioid therapy in the context of the opioid epidemic'.)

Use of ovulation induction drugs does not affect colon cancer risk (September 2022)

Ovulation induction drugs are used for anovulatory infertility. While these drugs increase circulating estradiol levels, no increased risk of estrogen-sensitive cancers, such as breast and ovarian cancers, has been observed. In addition, the risk of colon cancer, which may also be impacted by hormonal factors, does not appear to affected. This was demonstrated in a population-based cohort study of nearly 150,000 women where no significant change in colon cancer risk was observed with the use of clomiphene citrate, exogenous gonadotropins, human chorionic gonadotropin, or gonadotropin-releasing hormone agonists [32]. (See "Overview of ovulation induction", section on 'Cancer risks'.)