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
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) [1]. 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) [2]. 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 220/7 to 236/7 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) [3]. 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'.)
Elimination of perinatal HIV transmission with ART (September 2022)
Antiretroviral therapy (ART) has played a significant role in reducing the number of perinatal HIV transmissions over the past few decades. In a new analysis of 14,630 females with HIV, among the 5482 who conceived on ART and had a suppressed viral load at time of delivery, there were no perinatal HIV transmissions [4]. This study further supports the efficacy ART initiation prior to conception, when possible, and maintenance of viral suppression during pregnancy for the prevention of perinatal HIV transmission. (See "Antiretroviral selection and management in pregnant women with HIV in resource-rich settings", section on 'HIV viremia and risk of infant infection'.)
Dolutegravir not associated with adverse birth outcomes (September 2022)
Dolutegravir is a preferred antiretroviral drug for the treatment of HIV. Initial results from a surveillance study of birth outcomes in Botswana suggested a possible increased risk of neural tube defects among infants born to mothers who conceived while taking dolutegravir-based antiretroviral therapy (ART); however, subsequent data has been reassuring. In a follow-up analysis of the Botswana study, with nearly 30,000 births with ART exposure at the time of conception recorded, there was no difference in the incidence of neural tube defects with dolutegravir (used in 6000 pregnancies) versus other antiretrovirals [5]. In another observational study of over 1000 females on ART during pregnancy, dolutegravir use was not associated with adverse birth outcomes (preterm birth, low birth weight, small gestational age) [4]. Given these results, we continue to recommend dolutegravir in females of childbearing age and those who are pregnant. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Fetal safety'.)
False-positive syphilis screening in pregnancy (September 2022)
Screening for syphilis is a routine prenatal test; however, false positives can be more common than true positives. In a study including over 75,000 pregnancies, 183 of the 221 positive initial screening tests were false positives, and the rate did not differ between traditional algorithms and reverse algorithms [6]. These findings support the importance of confirmatory testing when initial screening for syphilis in pregnant patients yields a positive test (algorithm 1). (See "Syphilis in pregnancy", section on 'False-positive serologic tests in pregnancy'.)
No difference in outcomes with lower glycemic thresholds for diagnosing gestational diabetes (September 2022)
Use of lower rather than higher glycemic criteria for diagnosis of gestational diabetes mellitus (GDM) increases the number of patients diagnosed, but may not improve maternal or newborn outcome. In a randomized trial including over 4000 participants undergoing GDM screening, those diagnosed by standard thresholds for the 75 gram oral glucose tolerance test (GTT) (table 1) had similar maternal and newborn outcomes as those diagnosed by higher thresholds (fasting plasma glucose ≥99 mg/dL [≥5.5 mmol/L] or two-hour glucose ≥162 mg/dL [≥9.0 mmol/L]) [7]. However, the lower thresholds resulted in more patients diagnosed with GDM, more inductions, and more use of health services and pharmacotherapy. These findings suggest that the optimum glucose thresholds for diagnosis of GDM by the 75 gram oral GTT still need to be determined. (See "Gestational diabetes mellitus: Screening, diagnosis, and prevention", section on '75 gram oral glucose tolerance test'.)
Change in fibroid volume across gestation (September 2022)
The effect of pregnancy on fibroid volume has been unclear because of the lack of prospective longitudinal data from a large diverse obstetric population. To address this gap, a prospective cohort study performed six obstetric ultrasounds at timed intervals between 10 and 41 weeks of gestation in nearly 2800 patients at 12 clinical sites in the United States [8]. Change in total fibroid volume was affected by initial volume: increasing by 2 percent per week in patients with initially small volumes (diameter ≤1 cm), no or minimal change in those with initially medium volumes (diameter 1 to <3 cm), and decreasing by 2 percent per week in those with initially large volumes (diameter ≥3 cm). Change in volume was also affected by maternal age, race/ethnicity, parity, and miscarriage history. These findings will be useful in counseling patients with fibroids about what to expect during pregnancy. (See "Uterine fibroids (leiomyomas): Issues in pregnancy", section on 'Change in volume during pregnancy and postpartum'.)
Lack of efficacy of vaginal progesterone in patients with prior spontaneous preterm birth (September 2022)
In 2021, the American College of Obstetricians and Gynecologists endorsed offering either vaginal progesterone or intramuscular hydroxyprogesterone caproate supplementation to patients with a singleton pregnancy and a prior spontaneous preterm birth (sPTB) to reduce the risk of recurrence. However, a 2022 meta-analysis limited to trials assessing use of vaginal progesterone for preventing recurrent sPTB in this population found that reductions in sPTB were not statistically significant after restriction to trials at low risk of bias and adjustment for small-study effects [9]. We offer hydroxyprogesterone caproate to patients with a singleton pregnancy and history of sPTB and offer vaginal progesterone to patients with a short cervix in the current pregnancy. However, the efficacy of any progesterone supplement for prevention of sPTB remains controversial. (See "Progesterone supplementation to reduce the risk of spontaneous preterm labor and birth", section on 'Patients with singleton pregnancy and a short cervix or previous spontaneous preterm birth'.)
Prenatal cell-free screening results and maternal malignancy (August 2022)
In pregnant patients with a malignancy, noninvasive fetal aneuploidy screening with cell-free DNA (cfDNA) may detect circulating cfDNA from the tumor in addition to the usual placental and maternal cfDNA. In a study including over 168,000 pregnant patients who underwent prenatal genome-wide cfDNA screening, malignancy-suspicious results (ie, multiple chromosome imbalances) led to a new diagnosis of malignancy in 16 patients [10]. The appropriate clinical evaluation of malignancy-suspicious prenatal cfDNA results is unclear, in part because the results have no correlation with the tissue of origin of the malignancy. Patients undergoing prenatal fetal aneuploidy screening with a cfDNA test should be aware of the possibility of this rare incidental finding. (See "Prenatal screening for common aneuploidies using cell-free DNA", section on 'False-positive cfDNA test results'.)
Interpregnancy interval and adverse pregnancy outcomes (August 2022)
A short or long interpregnancy interval appears to increase the risk for some adverse pregnancy outcomes, but it is challenging to analyze because of multiple confounding variables. A recent study including over 700,000 consecutive first- and second-live born sibling pairs was able to control for several such variables since 99% of the mothers were of Han Chinese ethnicity and <35 years of age and a matched-sibling analysis accounted for adverse outcomes of the first sibling [11]. This study confirmed previous data that short (<6 months) or longer (≥36 months) interpregnancy intervals are associated with greater odds of adverse birth outcomes, such as preterm birth and low birth weight, compared with an 18- to 23-month interval. We recommend that most patients should strive for an interpregnancy interval of 18 to 24 months. (See "Interpregnancy interval: Optimizing time between pregnancies", section on 'Limitations of available data'.)
High prevalence of anemia in pregnancy (July 2022)
Nonphysiologic anemia in pregnancy can have serious adverse consequences for the mother and child and disproportionally affects some populations. The main cause is iron deficiency. A new report from the United States Special Supplemental Nutrition Program for Women, Infants, and Children documented a slight increase in pregnancy-associated anemia from 2008 to 2018 [12]. Nearly 50 percent of Black gravidas had anemia in the third trimester, a rate twice as high as in non-Black gravidas. This and previous studies highlight the importance of screening and treating iron deficiency in pregnancy. (See "Anemia in pregnancy", section on 'Epidemiology'.)
INTRAPARTUM AND POSTPARTUM OBSTETRICS
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 [13]. 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'.)
Maternal mortality in the United States (November 2022)
While maternal mortality rates have been decreasing globally, the rate in the United States has been increasing, and the causes of such deaths have shifted over time. In a report by the Centers for Disease Control and Prevention (CDC) including over 1000 maternal deaths from 2017 to 2019, mental health conditions (eg, suicide, opioid use disorder) were the most common cause (23 percent of deaths), and over 80 percent of all maternal deaths were considered preventable [14]. 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 maternal mortality, 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 [15]. 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 2)
●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 2)
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 newborn infants" and "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns" and "Escalation of care for term and late preterm newborns with unconjugated hyperbilirubinemia".)
OFFICE GYNECOLOGY
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 [16]. 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 [17]. 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 [18]. 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'.)
Progestogens and risk of venous thromboembolism (September 2022)
Historically, estrogens but not progestogens were avoided in patients at increased risk of venous thromboembolism (VTE) who desired contraception or experienced abnormal uterine bleeding. In a case-control study that matched >21,000 reproductive-age patients with acute VTE with patients without prior VTE, current use of depot medroxyprogesterone acetate (DMPA), norethindrone acetate, or MPA was associated with an increased risk of VTE compared with non-use; the levonorgestrel-releasing intrauterine device and oral norethindrone were not associated with increased risk [19]. Study limitations included potential bias from patient selection and treatment indication. When counseling any patient about use of DMPA or high dose oral progestogens, we discuss the possibly increased risk of VTE and consider the patient's other potential risk factors for VTE when making treatment decisions. (See "Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits", section on 'Cardiovascular and thromboembolic risk'.)
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) [20]. We include this information when counseling patients. (See "Assisted reproductive technology: Infant and child outcomes", section on 'Cancer risk'.)
Vaginal estrogen therapy in patients with a history of breast cancer (August 2022)
Low-dose vaginal estrogen is an effective treatment for moderate to severe symptoms of genitourinary syndrome of menopause (GSM) unresponsive to nonhormonal management (vaginal moisturizers, lubricants), but its safety in patients with breast cancer is unclear. In a study of postmenopausal patients with a history of early estrogen-positive breast cancer treated with aromatase inhibitors (AI), those who used vaginal estrogen after the breast cancer diagnosis had a higher risk of breast cancer recurrence compared with nonusers (adjusted hazard ratio 1.39, 95% CI 1.04-1.85) [21]. This association was not seen in patients treated with tamoxifen. While there are several limitations to this study, these data support our general practice of prescribing vaginal estrogen for management of GSM in patients with breast cancer treated with tamoxifen but not those treated with AI. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment", section on 'Patients with breast cancer'.)
Treatment of recurrent vulvovaginal candidiasis (July 2022)
Patients with recurrent vulvovaginal candidiasis (RVVC, defined as ≥3 culture-confirmed episodes in ≤12 months) who do not respond to oral fluconazole therapy have had few other treatment options. In an industry-sponsored trial comparing treatment and maintenance with either oteseconazole (a novel azole) or fluconazole/placebo in 185 females with active RVVC, fewer patients receiving oteseconazole experienced ≥1 culture-confirmed candidiasis episodes during the 48-week maintenance phase compared with fluconazole/placebo (5 versus 42 percent, respectively) [22]. Where available, oteseconazole is a therapeutic option for patients with culture-confirmed RVVC who do not respond to fluconazole therapy and who are not pregnant, attempting pregnancy, or lactating. (See "Candida vulvovaginitis: Treatment".)
Levonorgestrel dose for emergency contraception in individuals with obesity (June 2022)
Because levonorgestrel (LNG) emergency contraception (EC) appears to be less effective in individuals with obesity, doubling the LNG EC dose has been proposed to improve efficacy in this population. However, in a randomized pharmacodynamic trial comparing usual (1.5 mg) versus double-dose (3 mg) LNG EC in 70 individuals with obesity and a dominant follicle ≥15 mm on ultrasound, the proportion of individuals that achieved at least five days with no evidence of rupture was not significantly different between groups, and the time to follicle rupture was also similar for both groups [23]. As there was no clear reduction or delay in ovulation, we use the 1.5 mg LNG EC dose for all individuals but counsel those with obesity that other options (eg, copper intrauterine device) are more effective. (See "Emergency contraception", section on 'Impact of body weight'.)
Anti-D immune globulin prophylaxis for pregnancy loss or termination (June 2022)
Although RhD status has historically been assessed in all pregnant individuals experiencing pregnancy loss or termination to select candidates for anti-D immune globulin (RhIG) prophylaxis, the risk of alloimmunization in D-negative individuals appears to be negligible before 12 weeks of gestation. In a change from prior practice, the World Health Organization, National Abortion Federation, and Society of Family Planning now recommend against testing/RhIG prophylaxis of D-negative individuals before 12 weeks [24-26]. UpToDate contributors vary as to whether they follow the new or historic approach, but there is consensus to offer RhIG prophylaxis to unsensitized D-negative individuals ≥12 weeks of gestation experiencing pregnancy loss or termination. (See "Overview of pregnancy termination", section on 'Alloimmunization prevention' and "Pregnancy loss (miscarriage): Description of management techniques", section on 'Prevention of alloimmunization'.)
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, stroke, 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) [27]. While rates of Parkinson disease were similar between groups overall, risk was elevated in those with oophorectomy prior to age 43 years (HR 5.0). 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'.)
GYNECOLOGIC ONCOLOGY
Use of risk scoring systems in patients with an adnexal mass (September 2022)
For patients with an adnexal mass, risk scoring systems (eg, adnexal [ADNEX] model, Risk of Malignancy Algorithm [ROMA], Risk of Malignancy Index [RMI]) may be used to help differentiate between benign and malignant masses; however, the optimal system is unclear. In a systematic review comparing the accuracy of ADNEX, ROMA, and RMI for predicting epithelial ovarian carcinoma (EOC) in both pre- and postmenopausal patients with an adnexal mass on imaging, ADNEX had higher sensitivity but lower specificity than both ROMA and RMI [28]. The choice of test must be individualized and balance the risk of a missed diagnosis of EOC with that of unnecessary testing and surgery. These tests should not be used alone to decide whether to proceed with surgical exploration for an adnexal mass and have not been studied for ovarian cancer screening. (See "Serum biomarkers for evaluation of an adnexal mass for epithelial carcinoma of the ovary, fallopian tube, or peritoneum", section on 'Comparison of methods'.)
OTHER GYNECOLOGY
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 3). 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 [29]. (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 [30]. (See "Overview of ovulation induction", section on 'Cancer risks'.)
