Aspirin pharmacokinetics and pharmacodynamics through gestation.

BACKGROUND: Low dose aspirin is recommended for prevention of preeclampsia, however there is not consensus on the appropriate dose. Pregnancy specific changes have the potential to impact the pharmacology of aspirin in pregnancy, however there are very limited studies on aspirin pharmacokinetics in pregnancy and none linking pharmacokinetics (PK, drug dose and drug level) to pharmacodynamics (PD, drug dose and physiologic response) in pregnancy. As a result, we do not have a good understanding of the pharmacologic response to aspirin in pregnancy, which has important implications for clinical efficacy. We sought to describe the PK and PD of aspirin through pregnancy and to identify individual covariates that impacted aspirin PK/PD. OBJECTIVE: We sought to describe the PK and PD of aspirin through pregnancy (first and third trimester), to identify covariates that significantly impact aspirin PK and to identify the relationship between aspirin PK and PD. STUDY DESIGN: This is a prospective study of patients at high risk for preeclampsia recommended to take 81 mg aspirin daily. This study involved 3 visits as follows: (1) baseline, first trimester (10-16 weeks of gestation) 6-hour PK visit, done before initiation of aspirin; (2) follow-up 1: 2 to 4 weeks after aspirin initiation; and (3) follow-up 2: third trimester 6-hour PK visit (28-32 weeks of gestation). The following were assessed at each visit: weight or body mass index, platelet function analysis-100 (Siemens), urinary thromboxane B2, serum thromboxane B2, and plasma salicylic acid. The PK visits consisted of blood work done at baseline (predose), administration of 81 mg nonenteric coated aspirin, and then plasma blood level of salicylic acid assessed at 30 minutes and then hourly 1 to 6 hours after dose. Pearson correlation and multivariable regression were used to identify associations between parameters and identify relevant covariates. Log-adjusted values were used for regression analysis. P<.05 was considered statistically significant. RESULTS: Nineteen participants were included with first trimester data, and 16 with third trimester data. There was no statistically significant change in mean PK parameters between the first and third trimester, although there was a trend to lower peak concentration in the third than in the first trimester (P=.08). In multivariable regression, baseline obesity and current body mass index as a continuous measures were negatively associated with log-adjusted peak salicylic acid concentration (-0.28 [-0.46 to -0.11], P=.003 and -0.02 [-0.03 to -0.009], P=.001, respectively) and log-adjusted plasma salicylic acid area under the curve 0 to 6 hours postdose (-0.25 [-0.45 to 0.05], P=.02, -0.04 [-0.07 to -0.01], P=.008 respectively). There was a significant decrease in urinary thromboxane 2 to 4 weeks after aspirin initiation compared with baseline, which correlated with a concomitant increase in platelet function analysis-100 closure time. In multivariable regression model, there was a strong association between plasma salicylic acid concentration (area under the curve 0-6 hours postdose) and urinary thromboxane (B=-3.12 [-5.38 to -1.04], P=.006), and with urinary thromboxane suppression and platelet inhibition, platelet function analysis-100 (-0.23 [-0.31 to -0.14], P<.001). With progressive thromboxane suppression, platelet inhibition (platelet function analysis-100 closure time) increased. Individual comorbidities, including weight, hypertension, and pregestational diabetes (Type I or II), also impacted aspirin response. CONCLUSION: We have demonstrated the relationship between individual factors, plasma concentrations of salicylic acid, thromboxane suppression, and platelet inhibition at a single dose (81 mg) of aspirin taken through pregnancy. Our findings suggest that dose modification of aspirin in pregnancy may help to achieve the optimal response. Our results may be used to facilitate computational modeling to identify optimal dosing, taking into consideration individual factors.

Eligibility, Utilization, and Effectiveness of 17-Alpha Hydroxyprogesterone Caproate in a Statewide Population-Based Cohort of Medicaid Enrollees.

OBJECTIVE: The primary objective was to estimate the initiation and adherence rates of 17 α-hydroxyprogesterone caproate (17OHPC) among eligible mothers in a statewide population-based cohort of Medicaid enrollees. The secondary objectives were to (1) determine the association of maternal sociodemographic and clinical characteristics with 17OHPC utilization and (2) assess the real-world effectiveness of 17OHPC on recurrent preterm birth prevention and admission to neonatal intensive care unit (NICU). STUDY DESIGN: This is a retrospective cohort study using a linked, longitudinal administrative dataset of birth certificates and medical assistance claims. Medicaid-enrolled mothers in Pennsylvania were included in this study if they had at least one singleton live birth from 2014 to 2016 following at least one spontaneous preterm birth. Maternal Medicaid claims were used to ascertain the use of 17OHPC from various manufacturers, including compounded formulations. Propensity score matching was used to create a covariate balance between 17OHPC treatment and comparison groups. RESULTS: We identified 4,781 Medicaid-covered 17OHPC-eligible pregnancies from 2014 to 2016 in Pennsylvania, 3.4% of all Medicaid-covered singleton live births. The population-based initiation rate was 28.5% among eligible pregnancies. Among initiators, 50% received ≥16 doses as recommended, while 10% received a single dose only. The severity of previous spontaneous preterm birth was the strongest predictor for the initiation and adherence of 17OHPC. In the matched treatment (n = 1,210) and comparison groups (n = 1,210), we found no evidence of 17OHPC effectiveness. The risks of recurrent preterm birth (relative risk [RR] 1.10, 95% confidence interval [CI] 0.97-1.24) and births admitted to NICU (RR 1.00, 95% CI 0.84-1.18) were similar in treated and comparison mothers. CONCLUSION: The 17OHPC-eligible population represented 3.4% of singleton live births. Less than one-third of eligible mothers initiated treatment. Among initiators, 50% were treatment adherent. We found no difference in the risk of recurrent preterm birth or admission to NICU between treatment and comparison groups. KEY POINTS: · About 3.4% of singleton live births were eligible for 17OHPC.. · About 30% of eligible mothers initiated treatment.. · We found no association of 17OHPC with recurrent preterm birth..

Vaginal progesterone vs intramuscular 17-hydroxyprogesterone caproate for prevention of recurrent preterm birth: a randomized controlled trial.

BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality, and previous preterm birth is one of the strongest risk factors for preterm birth. National and international obstetrical societies have different recommendations regarding progesterone formulation for the prevention of recurrent preterm birth. OBJECTIVE: This study aimed to determine whether vaginal progesterone is superior to 17-hydroxyprogesterone caproate in the prevention of recurrent preterm birth in patients with singleton pregnancies who had a previous spontaneous preterm birth. STUDY DESIGN: This was an open-label multicenter pragmatic randomized controlled trial at 5 US centers of patients with singleton pregnancies at <24 weeks of gestation who had a previous spontaneous preterm birth randomized 1:1 to either 200 mg vaginal progesterone suppository nightly or 250 mg intramuscular 17-hydroxyprogesterone caproate weekly from 16 to 36 weeks of gestation. Based on the estimated recurrent preterm birth rate of 36% with 17-hydroxyprogesterone caproate, 95 participants were needed in each arm to detect a 50% reduction in preterm birth rate with vaginal progesterone, with 80% power and 2-sided alpha of 0.05. The primary outcome was preterm birth at <37 weeks of gestation. Prespecified secondary outcomes included preterm birth at <34 and <28 weeks of gestation, mean gestational age at delivery, neonatal morbidity and mortality, and measures of adherence. Analysis was by intention to treat. The chi-square test and Student t test were used as appropriate. P<.05 was considered significant. RESULTS: Overall, 205 participants were randomized; 94 participants in the vaginal progesterone group and 94 participants in 17-hydroxyprogesterone caproate group were included. Although gestational age at enrollment was similar, those assigned to vaginal progesterone initiated therapy earlier (16.9±1.4 vs 17.8±2.5 weeks; P=.001). Overall continuation of assigned formulation until delivery was similar (73% vs 69%; P=.61). There was no significant difference in preterm birth at <37 (31% vs 38%; P=.28; relative risk, 0.81 [95% confidence interval, 0.54-1.20]), <34 (9.6% vs 14.9%; P=.26; relative risk, 0.64 [95% confidence interval, 0.29-1.41]), or <28 (1.1% vs 4.3%; P=.37; relative risk, 0.25 [95% confidence interval, 0.03-2.20]) weeks of gestation. Participants in the vaginal progesterone group had a later mean gestational age at delivery than participants in the 17-hydroxyprogesterone caproate group (37.36±2.72 vs 36.34±4.10 weeks; mean difference, 1.02 [95% confidence interval, 0.01-2.01]; P=.047). CONCLUSION: Vaginal progesterone did not reduce the risk of recurrent preterm birth by 50% compared with 17-OHPC; however, vaginal progesterone may lead to increased latency to delivery. This trial was underpowered to detect a smaller, but still clinically significant, difference in the efficacy of preterm birth prevention. Patient factors that impact adherence and ability to obtain medication in a timely fashion should be included in counseling on progesterone selection.

Cervical Length Ultrasound for the Evaluation of Preterm Labor: A Survey of National Use and Review of Evidence.

OBJECTIVE: The objective of this study was to survey national utilization of cervical length (CL) ultrasound on labor and delivery (L&D) for the evaluation of preterm labor (PTL) and identify provider attitudes and barriers to utilization. STUDY DESIGN: Survey was emailed to Obstetrics and Gynecology Residency and Maternal-Fetal Medicine Fellowship program and advertised via links on obstetric-related Facebook interest groups. The survey was open from August 4, 2020 to January 4, 2021. Characteristics between respondents who did and did not report the use of CL ultrasound for PTL evaluation were compared with chi-square analysis. RESULTS: There were 214 respondents across 42 states. One hundred and thirty-four respondents (63%) reported any use of CL in the evaluation of PTL and eighty (37%) denied it. There was a significant difference in practice location, practice type, delivery volume, and region between those who did and did not utilize CL ultrasound on L&D. Those who did use CL ultrasound were more likely to report no barriers to use (40 vs. 4%, p < 0.001). The most common barriers involved the availability of transvaginal ultrasound (31%), sterilization of transvaginal ultrasound probe (32%), limited availability of persons able to perform/interpret CL imaging (38%). Nineteen percent believed CL ultrasound had little/no utility in clinical practice. Those who did not use CL ultrasound in the evaluation of PTL were significantly more likely to report the feeling that there was little/no utility of CL ultrasound in clinical practice (37 vs. 7%, p < 0.001) and to report transvaginal ultrasound availability as barriers to use (63 vs. 12%, p < 0.001). CONCLUSION: CL ultrasound is used nationally in PTL evaluation. However, significant barriers limit widespread adoption. These barriers can be addressed through the dissemination of information and practice guidelines, addition of CL ultrasound education in residency training and through CME opportunities after training, and providing support/resources/access for those looking to add this tool to their practice environment. KEY POINTS: · In a national survey, 63% of obstetricians endorsed any use of cervical length (CL) ultrasound for preterm labor evaluation on labor and delivery.. · The most common barriers involved the availability of transvaginal ultrasound (31%), sterilization of transvaginal ultrasound probe (32%), limited availability of persons able to perform/interpret CL imaging (38%).. · Those who did not use CL ultrasound in the evaluation of PTL were significantly more likely to report the feeling that there was little/no utility of CL ultrasound in clinical practice and to report transvaginal ultrasound availability as barriers to utilization.. · Barriers to utilization of CL ultrasound for preterm labor evaluation can be addressed through practice guidelines, ultrasound education, and support for equipment/training necessary for use..

Is Maternal Methadone Dose Associated with the Severity of Neonatal Abstinence Syndrome?

OBJECTIVE: The aim of the study is to assess the correlation between maternal methadone dose and severity of neonatal abstinence syndrome (NAS) in infants that required pharmacological treatment for NAS. STUDY DESIGN: This is a retrospective analysis of 574 infants ≥35 weeks' gestation exposed to methadone in utero, born between August 2006 and May 2018, and who required pharmacological therapy for NAS. Indicators of NAS severity (duration of morphine treatment, maximum morphine dose, use of phenobarbital, and length of hospitalization) were compared between infants exposed to high (≥200 mg), intermediate (100-199 mg), and low doses (<100 mg) of methadone. Logistic and linear regression models were used to adjust for the covariates. RESULTS: Median (interquartile range) duration of medical treatment with morphine was higher in infants exposed to higher doses of methadone (low dose 23 [14-37] days, intermediate dose 31 [18-45] days, and high dose 35 [20-48] days, p < 0.001). Higher methadone doses were also predictive of longer duration of hospitalization, higher maximum morphine dose, and increased likelihood of treatment with phenobarbital. The association between maternal methadone dose and the severity of NAS persisted in multivariable regression models. CONCLUSION: Infants exposed to higher methadone doses displayed more severe NAS, as indicated by longer durations of treatment, higher maximum morphine dose, longer duration of hospitalization, and increased likelihood of phenobarbital use. KEY POINTS: · Methadone maintenance therapy is used during pregnancy to control maternal withdrawal symptoms.. · Relationship between maternal methadone dose and severity of NAS is not adequately investigated.. · Increased doses of methadone during pregnancy correlate with increased severity of NAS..

Society for Maternal-Fetal Medicine Special Statement: COVID-19 research in pregnancy: progress and potential.

The COVID-19 global pandemic has broad implications for obstetrical care and perinatal outcomes. As we approach the 2-year mark into an unprecedented international pandemic, this review presents the progress and opportunities for research related to COVID-19 and pregnancy. Research is the basis for evidence-based clinical guidelines, and we aim to provide the structure and guidance for framing COVID-19-related obstetrical research. This structure will pertain not only to this pandemic but future ones as well.

Utility of follow-up cervical length screening in low-risk women with a cervical length of 26 to 29 mm.

BACKGROUND: In women with a previous preterm birth, a protocol for serial cervical length screening has been studied and recommended for the identification and treatment of a short cervix. Cervical length screening along with vaginal progesterone has been suggested for low-risk women with singleton pregnancies to treat a short cervix and reduce preterm birth. However, specific protocols for single vs serial ultrasound measuring cervical length in this population are not established. Cost-effectiveness of universal cervical length screening depends on the cost of screening; follow-up of borderline measurements can contribute to increased costs with uncertain benefit. OBJECTIVE: This study aimed to determine the utility of follow-up cervical length screening in otherwise low-risk women with singleton pregnancies with a midtrimester cervical length measurement of 26 to 29 mm through the assessment of the rate of short cervix (≤25 mm) on follow-up ultrasound and subsequent delivery outcomes. STUDY DESIGN: This was a 2-year retrospective cohort study at a single urban institution of women with singleton pregnancies with no previous spontaneous preterm birth and an initial transvaginal ultrasound cervical length measurement of 26 to 29 mm identified during universal cervical length screening at time of anatomy ultrasound (18 0/7 to 22 6/7 weeks' gestation). The primary outcome was the rate of short cervix (defined as ≤25 mm on transvaginal ultrasound) on follow-up ultrasound at <24 weeks' gestation. Secondary outcomes included the rate of spontaneous preterm birth (<37 and <34 weeks' gestation). RESULTS: During the study period, there were 2801 women with singleton pregnancies at 18 0/7 to 22 6/7 weeks' gestation with transvaginal ultrasound cervical length screening at time of anatomy scan. Among those women, 201 had a cervical length of 26 of 29 mm, and 184 (7%) had no previous spontaneous preterm birth and were included in the study. Furthermore, 144 women (78%) had a follow-up cervical length completed before 24 weeks' gestation. The mean follow-up interval was 1.5±0.6 weeks. Overall, the percentage of short cervix (≤25 mm) on follow-up was 15% (n=21). Baseline characteristics were similar, but the initial cervical length measurement was shorter in women who subsequently developed a short cervix (26.7±0.8 vs 27.8±1.0; P<.01). Delivery outcomes were available for 126 patients. The rate of spontaneous preterm birth at <37 weeks' gestation in women with an initial cervical length 26 to 29 mm and subsequent short cervix was significantly higher than the rate of spontaneous preterm birth in a historical cohort of low risk women with an initial cervical length >25 mm (16% vs 3%; P=.03). The rate of spontaneous preterm birth at <34 weeks' gestation in women with a subsequent short cervix was 11% (2 of 19). CONCLUSION: Here, approximately 15% of low-risk women with singleton pregnancies with a midtrimester cervical length measurement of 26 to 29 mm will experience cervical shortening of ≤25 mm before 24 weeks' gestation. Compared to women with singleton pregnancies without a history of preterm birth, the rate of spontaneous preterm birth (16%) in women with an initial cervical length of 26 to 29 mm and a subsequent cervical shortening of ≤25 mm is significantly higher. A total of 111 follow-up ultrasounds measuring cervical length would be required to prevent 1 early preterm birth at <34 weeks' gestation.

Improving Utilization of Aspirin for Prevention of Preeclampsia in a High-Risk Urban Cohort: A Prospective Cohort Study.

OBJECTIVE: This study aimed to evaluate the utilization of aspirin for preeclampsia prevention before and after implementation of a screening tool during nuchal translucency (NT) ultrasound. STUDY DESIGN: One-year prospective cohort study of patients at high risk for preeclampsia after the implementation of a screening tool (postscreen) administered to all patients at check in for NT (11-13 weeks) ultrasound. Prospective cohort was compared with one-year retrospective cohort (prescreen) the year prior (2017). All patients who presented for NT ultrasound in both cohorts were evaluated for the presence of one or more risk factor for preeclampsia with screening tool collected prospectively and chart review retrospectively. Provider recommendation for aspirin determined by documentation in prenatal record. Primary outcome was rate of provider recommendation for aspirin pre versus post screening tool, compared by Chi-square test and adjusted for potential confounders with multiple regression analysis. RESULTS: Pre- (n = 156) and postscreen (n = 136) cohorts were similar except for race and multifetal gestation. Prescreen, rate of provider recommendation for aspirin was 74%. Of those with prior preeclampsia, 96% were recommended aspirin, compared with 64% of patients with other risk factors (p < 0.001). Postscreen, provider recommendation of aspirin improved to 95% (p < 0.001). Rate of preeclampsia/gestational hypertension were similar between cohorts; however, there was a reduced adjusted risk in overall preterm birth <37 weeks (adjusted odds ratio [aOR] = 0.50 [0.25-0.99]) and preterm birth <34 weeks (aOR = 0.33 [0.13-0.88]) postscreening tool implementation. CONCLUSION: Prior to implementation of a simple screening questionnaire, approximately 25% of high risk patients did not receive the recommendation of aspirin for preeclampsia prevention. High-risk patients who lack a history of preeclampsia were less likely to be advised of aspirin prophylaxis. Use of a simple universal screening tool at time of NT ultrasound significantly improved utilization of aspirin for preeclampsia prevention and may improve patient outcomes. KEY POINTS: · Despite recommendations, aspirin use for preeclampsia prevention is suboptimal.. · High-risk patients who lack a history preeclampsia were less likely to be advised of aspirin use.. · A simple universal screening tool can significantly improve aspirin utilization..

Impact of the ACOG guideline regarding low-dose aspirin for prevention of superimposed preeclampsia in women with chronic hypertension.

BACKGROUND: Patients with chronic hypertension are at increased risk for superimposed preeclampsia. The 2016 American College of Obstetricians and Gynecologists guideline recommended initiating 81 mg of daily aspirin for all pregnant women with chronic hypertension to prevent superimposed preeclampsia. OBJECTIVE: (1) To evaluate the rates of implementation of the 2016 American College of Obstetricians and Gynecologists guideline over time; and (2) to evaluate the effectiveness of aspirin for the prevention of superimposed preeclampsia and other adverse maternal and neonatal outcomes in women with chronic hypertension before and after this guideline. STUDY DESIGN: This is a retrospective study of women with chronic hypertension who delivered at Thomas Jefferson University Hospital from January 2014 through June 2018. This cohort of women with chronic hypertension was divided into 2 groups, before and after the American College of Obstetricians and Gynecologists recommendation published in September 2016. Daily 81 mg of aspirin was initiated between 12 and 16 weeks. We excluded multiple gestations and incomplete records. The primary outcome was incidence of superimposed preeclampsia, and secondary outcomes were incidence of superimposed preeclampsia with or without severe features, small for gestational age, and preterm birth <37 weeks. Subgroup analysis based on risk stratification was evaluated in women with chronic hypertension requiring antihypertensive medication, history of preeclampsia, and pregestational diabetes. RESULTS: We identified 457 pregnant women with chronic hypertension, 203 in the post-American College of Obstetricians and Gynecologists group and 254 in the pre-American College of Obstetricians and Gynecologists group. Aspirin 81 mg was offered to 142 (70%) in the post-American College of Obstetricians and Gynecologists group and 18 (7.0%) in the pre-American College of Obstetricians and Gynecologists group. Maternal demographics were not significantly different. The overall incidence of superimposed preeclampsia was not significantly different: 87 (34.3%) vs 72 (35.5%), P=.79, in the pre- and post-American College of Obstetricians and Gynecologists guideline groups, respectively. Superimposed preeclampsia with severe features significantly increased: 32 (12.6%) vs 9 (4.4%), P<.01, whereas superimposed preeclampsia without severe features significantly decreased: 55 (21.7%) vs 63 (31.0%), P=.03. There were no significant differences in small for gestational age neonates or preterm birth <37 weeks incidences between groups. There were no significant differences in the subgroup analysis based on the severity of chronic hypertension requiring antihypertensive medication, history of preeclampsia, or pregestational diabetes. CONCLUSION: After the adoption of the American College of Obstetricians and Gynecologists guidelines in 70% of the cohort, superimposed preeclampsia, small for gestational age, and preterm birth were not significantly decreased after implementation of aspirin 81 mg initiated between 12 and 16 weeks of gestation.

Predictors of Early Preterm Birth Despite Vaginal Progesterone Therapy in Singletons with Short Cervix.

OBJECTIVE: This study aimed to identify the incidence of and risk factors for early preterm birth (PTB) (delivery <34 weeks) in women without prior PTB and current short cervix (≤20 mm) prescribed vaginal progesterone. STUDY DESIGN: Retrospective cohort study of singletons without prior PTB diagnosed with short cervix (≤20 mm) between 180/7 and 236/7 weeks. Women who accepted vaginal progesterone and had delivery outcomes available were included. Demographic/obstetric history, cervical length, and pregnancy characteristics compared between women with early PTB versus delivery ≥34 weeks. Multiple logistic regression analysis used to identify predictors; odds ratio for significant factors used to generate a risk score. Risk score and risk of early PTB assessed with receiver operating characteristic curve (ROCC). Perinatal outcomes compared by risk score. RESULTS: Among 109 patients included, 29 (27%) had a spontaneous PTB <34 weeks. In univariate analysis, only gestational age at ultrasound, presence funneling, and mean cervical length were significantly different between those with and without early sPTB. With multiple logistic regression analysis, only gestational age at diagnosis (odds ratio [OR]: 0.66; 95% confidence interval [CI]: 0.46-0.96; p = 0.028) and index cervical length (OR: 0.84; 95% CI: 0.76-0.93; p = 0.001) remained significantly associated with early PTB. ROCC for the risk score incorporating cervical length and gestational age was predictive of early PTB with an AUC of 0.76 (95% CI: 0.67-0.86; p < 0.001). A high-risk score was predictive of early PTB with a sensitivity of 79%, specificity of 75%, positive predictive value of 54%, and negative predictive value of 91%. Women with a high-risk score had worse perinatal outcomes compared with those with low-risk score. CONCLUSION: A total of 27% of patients with short cervix prescribed vaginal progesterone will have a sPTB < 34 weeks. Patients at high risk for early PTB despite vaginal progesterone therapy may be identified using gestational age and cervical length at diagnosis of short cervix. Given the narrow window for intervention after diagnosis of short cervix, this has important implications for clinical care.

Pharmacokinetics of vaginal progesterone in pregnancy.

BACKGROUND: Characterization of pharmacokinetics is lacking for vaginal progesterone in pregnancy. Dosing of vaginal progesterone for preterm birth prevention has been empirical. Owing to pregnancy-related changes in vaginal and uterine blood flow, hepatic metabolism, renal clearance, and endogenously elevated serum progesterone, studies outside of pregnancy may not be applicable. The lack of the pharmacokinetics profile of vaginally administered progesterone in pregnancy limits the ability to define the exposure-response relationship needed to optimize dosing, which has implications for its use in research and clinical care regarding management of short cervix, prevention of recurrent preterm birth, and prevention of recurrent miscarriage. OBJECTIVE: This was a study to establish the feasibility of using serum progesterone to establish basic pharmacokinetic parameters of vaginal progesterone in pregnancy for preterm birth prevention. STUDY DESIGN: This is a prospective study of 6 low-risk singletons at 18 0/7 to 23 6/7 weeks' gestation with body mass index 20-40. Exclusion criteria were current vaginitis, abnormal Pap smear, prescription medication use, cervical length ≤25 mm, prior preterm birth, and contraindication to progesterone. Participants received a single dose of 200 mg micronized vaginal progesterone and serum progesterone levels were evaluated every 2 hours from 0 to 12 hours and then 24 hours post dose. Primary outcome was concentration/time profile of serum progesterone. RESULTS: Median (range) maternal age was 27 (21.5-33.3) years, median body mass index was 26.5 (23.3-29.0) kg/m2, and median gestational age was 22.9 (21.0-23.4) weeks. Median baseline serum progesterone was 47 (40-52) ng/mL, median peak concentration was 54 (48-68) ng/mL, and median time to peak was 12 (4-15) hours. There was a trend in rising serum progesterone over baseline with a median change in peak concentration of 11 ng/mL and interquartile range of 2-22. Median percent change from baseline was an increase by 24% (interquartile range, 4%-53%). However, there was no clear elimination phase and the median area under the curve was 112 ng*h/mL with an interquartile range of -43 to 239. CONCLUSION: Unlike in nonpregnant individuals, administration of vaginal progesterone in pregnant individuals only minimally impacts systemic exposure. There is a limited trend of rising serum progesterone over baseline levels, with significant inter-individual variability. Serum progesterone is unlikely to be a good candidate for establishing pharmacokinetics or dosing of vaginal progesterone in pregnancy for preterm birth prevention.

Predicting asymptomatic cervical dilation in pregnant patients with short mid-trimester cervical length: A secondary analysis of a randomized controlled trial.

INTRODUCTION: Second trimester asymptomatic cervical dilation is a significant risk factor for early preterm birth. The objective of this study is to evaluate whether transvaginal ultrasound cervical length (CL) predicts asymptomatic cervical dilation on physical exam in women with short cervix (CL ≤25 mm) and no prior preterm birth. MATERIAL AND METHODS: Secondary analysis of a randomized trial on pessary in asymptomatic singletons without prior preterm birth diagnosed with CL ≤25 mm between 18+0/7 and 23+6/7  weeks. Participants had transvaginal ultrasound and physical cervical exam and were randomized to pessary or no pessary with all patients with cervical length ≤20 mm offered vaginal progesterone. The primary outcome was to determine whether CL was predictive of asymptomatic physical cervical dilation ≥1 cm using receiver operating characteristic curve. RESULTS: In all, 119 women were included. Based on receiver operating characteristic curve, CL ≤11 mm was best predictive of cervical dilation ≥1 cm, with 75% sensitivity, 80% specificity, and area under the curve 0.73 (0.55-0.91), P = 0.009. Cervical length ≤11 mm had increased incidence of cervical dilation ≥1 cm on physical exam (30% vs 3%, odds ratio 12.29 (3.05-49.37) P < 0.001) with a negative predictive value of 97%. Patients with ≥1 cm dilation had increased preterm birth <37 weeks (75% vs 39%, P = 0.03) compared to those not dilated. Women with a CL ≤11 mm had increased preterm birth <37 weeks (77% vs 31%, P < 0.001), preterm birth <34 weeks (63% vs 22%, P < 0.001), and lower birthweight (1552 ± 1047 vs 2560 ± 1072 g, P < 0.001) compared to women with CL >11 mm. CONCLUSIONS: Among singletons without prior preterm birth diagnosed with short cervix (≤25 mm), CL ≤11 mm may identify a subgroup of patients at high risk for asymptomatic cervical dilation and poor perinatal outcome. Physical exam should be considered and adjunctive preterm birth prevention measures should be studied in singletons with CL ≤11 mm.

Prior Uterine Evacuation and the Risk of Short Cervical Length: A Retrospective Cohort Study.

OBJECTIVES: To determine whether a prior uterine evacuation procedure is associated with an increased risk of short cervical length (≤20 mm) in women without prior spontaneous preterm birth. METHODS: This work was a retrospective cohort study from January 2012 to December 2014 of singletons without prior spontaneous preterm birth with cervical length screening between 18 weeks and 23 weeks 6 days. Women with a prior miscarriage/abortion were excluded if management (medical, surgical, or expectant) was not specified. Prior uterine evacuation was defined as dilation and curettage or dilation and evacuation of a spontaneous or induced abortion. The primary outcome was the risk of short cervical length (≤20 mm) among women with and without 1 of more prior uterine evacuations at any gestational age, assessed by the odds ratio and adjusted odds ratio for confounders. RESULTS: Of 2672 women included, 714 (27%) had at least 1 prior uterine evacuation. The overall incidence of short cervical length in the cohort was 1% (n = 27). Women with at least 1 prior uterine evacuation were more likely to be African American (64% versus 41%; P < .001), smoke (14% versus 8%; P < .001), have a higher body mass index (mean ± SD, 28.1 ± 7.1 versus 26.8 ± 7.1 kg/m2 ; P < .001), and have had prior full-term delivery (60% versus 41%; P < .001). Women with at least 1 prior uterine evacuation had a significantly higher incidence of short cervical length (2% versus 0.7%; P = .003; odds ratio, 2.99 [95% confidence interval, 1.40-6.40]). After adjustment for confounders, prior uterine evacuation remained a source of increased risk of short cervical length (adjusted odds ratio, 2.63 [95% confidence interval, 1.19-5.80]). CONCLUSIONS: Although the overall incidence of short cervical length is low (1%-2%), women with at least 1 prior uterine evacuation have at least a 2-fold increased risk of a short second-trimester cervical length compared to women without a prior uterine evacuation.

Interventions for treating hyperemesis gravidarum.

BACKGROUND: Hyperemesis gravidarum is a severe form of nausea and vomiting in pregnancy affecting 0.3% to 1.0% of pregnancies, and is one of the most common indications for hospitalization during pregnancy. While a previous Cochrane review examined interventions for nausea and vomiting in pregnancy, there has not yet been a review examining the interventions for the more severe condition of hyperemesis gravidarum. OBJECTIVES: To assess the effectiveness and safety, of all interventions for hyperemesis gravidarum in pregnancy up to 20 weeks' gestation. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register and the Cochrane Complementary Medicine Field's Trials Register (20 December 2015) and reference lists of retrieved studies. SELECTION CRITERIA: Randomized controlled trials of any intervention for hyperemesis gravidarum. Quasi-randomized trials and trials using a cross-over design were not eligible for inclusion.We excluded trials on nausea and vomiting of pregnancy that were not specifically studying the more severe condition of hyperemesis gravidarum. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed the eligibility of trials, extracted data and evaluated the risk of bias. Data were checked for accuracy. MAIN RESULTS: Twenty-five trials (involving 2052 women) met the inclusion criteria but the majority of 18 different comparisons described in the review include data from single studies with small numbers of participants. The comparisons covered a range of interventions including acupressure/acupuncture, outpatient care, intravenous fluids, and various pharmaceutical interventions. The methodological quality of included studies was mixed. For selected important comparisons and outcomes, we graded the quality of the evidence and created 'Summary of findings' tables. For most outcomes the evidence was graded as low or very low quality mainly due to the imprecision of effect estimates. Comparisons included in the 'Summary of findings' tables are described below, the remaining comparisons are described in detail in the main text.No primary outcome data were available when acupuncture was compared with placebo, There was no clear evidence of differences between groups for anxiodepressive symptoms (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.73 to 1.40; one study, 36 women, very low-quality evidence), spontaneous abortion (RR 0.48, 95% CI 0.05 to 5.03; one study, 57 women, low-quality evidence), preterm birth (RR 0.12, 95% CI 0.01 to 2.26; one study, 36 women, low-quality evidence), or perinatal death (RR 0.57, 95% CI 0.04 to 8.30; one study, 36 women, low-quality evidence).There was insufficient evidence to identify clear differences between acupuncture and metoclopramide in a study with 81 participants regarding reduction/cessation in nausea or vomiting (RR 1.40, 95% CI 0.79 to 2.49 and RR 1.51, 95% CI 0.92 to 2.48, respectively; very low-quality evidence).In a study with 92 participants, women taking vitamin B6 had a slightly longer hospital stay compared with placebo (mean difference (MD) 0.80 days, 95% CI 0.08 to 1.52, moderate-quality evidence). There was insufficient evidence to demonstrate a difference in other outcomes including mean number of episodes of emesis (MD 0.50, 95% CI -0.40 to 1.40, low-quality evidence) or side effects.A comparison between metoclopramide and ondansetron identified no clear difference in the severity of nausea or vomiting (MD 1.70, 95% CI -0.15 to 3.55, and MD -0.10, 95% CI -1.63 to 1.43; one study, 83 women, respectively, very low-quality evidence). However, more women taking metoclopramide complained of drowsiness and dry mouth (RR 2.40, 95% CI 1.23 to 4.69, and RR 2.38, 95% CI 1.10 to 5.11, respectively; moderate-quality evidence). There were no clear differences between groups for other side effects.In a single study with 146 participants comparing metoclopramide with promethazine, more women taking promethazine reported drowsiness, dizziness, and dystonia (RR 0.70, 95% CI 0.56 to 0.87, RR 0.48, 95% CI 0.34 to 0.69, and RR 0.31, 95% CI 0.11 to 0.90, respectively, moderate-quality evidence). There were no clear differences between groups for other important outcomes including quality of life and other side effects.In a single trial with 30 women, those receiving ondansetron had no difference in duration of hospital admission compared to those receiving promethazine (MD 0.00, 95% CI -1.39 to 1.39, very low-quality evidence), although there was increased sedation with promethazine (RR 0.06, 95% CI 0.00 to 0.94, low-quality evidence) .Regarding corticosteroids, in a study with 110 participants there was no difference in days of hospital admission compared to placebo (MD -0.30, 95% CI -0.70 to 0.10; very low-quality evidence), but there was a decreased readmission rate (RR 0.69, 95% CI 0.50 to 0.94; four studies, 269 women). For other important outcomes including pregnancy complications, spontaneous abortion, stillbirth and congenital abnormalities, there was insufficient evidence to identify differences between groups (very low-quality evidence for all outcomes). In other single studies there were no clear differences between groups for preterm birth or side effects (very low-quality evidence).For hydrocortisone compared with metoclopramide, no data were available for primary outcomes and there was no difference in the readmission rate (RR 0.08, 95% CI 0.00 to 1.28;one study, 40 women).In a study with 80 women, compared to promethazine, those receiving prednisolone had increased nausea at 48 hours (RR 2.00, 95% CI 1.08 to 3.72; low-quality evidence), but not at 17 days (RR 0.81, 95% CI 0.58 to 1.15, very low-quality evidence). There was no clear difference in the number of episodes of emesis or subjective improvement in nausea/vomiting. There was insufficient evidence to identify differences between groups for stillbirth and neonatal death and preterm birth. AUTHORS' CONCLUSIONS: On the basis of this review, there is little high-quality and consistent evidence supporting any one intervention, which should be taken into account when making management decisions. There was also very limited reporting on the economic impact of hyperemesis gravidarum and the impact that interventions may have.The limitations in interpreting the results of the included studies highlights the importance of consistency in the definition of hyperemesis gravidarum, the use of validated outcome measures, and the need for larger placebo-controlled trials.

Cervical Length Screening in Asymptomatic Women at High Risk and Low Risk for Spontaneous Preterm Birth.

Cervical length (CL) screening should be offered to singletons because there are interventions for those with a short CL. A transvaginal ultrasound (TVU) is the "gold standard" for CL. In singletons with prior spontaneous preterm birth, serial TVU CL screening is recommended between 16 and 23 6/7 weeks. Universal TVU CL screening between 18 and 24 weeks may be considered for low-risk singletons with the administration of vaginal progesterone for TVU CL≤20 mm; alternatively, transabdominal ultrasound CL screening may be considered with reflux to TVU CL screening for a transabdominal ultrasound CL<35 mm or inadequate visualization. CL screening is not recommended in multiples.

Preconception counseling and care in the setting of HIV: clinical characteristics and comorbidities.

OBJECTIVE: To describe the demographic and clinical characteristics of HIV-infected individuals and HIV-affected couples who were referred for preconception counseling (PCC) at a large urban US-based HIV clinic. METHODS: Electronic medical records were reviewed for HIV-infected individuals and HIV-affected couples. Medical, reproductive, surgical, psychosocial, and family history data were abstracted. Univariate analyses were done. RESULTS: There were 8 single HIV-infected women and 100 HIV-affected couples who underwent PCC. HIV-infected women were older (mean age 35 years versus 32 years, P = 0.06), were more likely to smoke (23% versus 0%, P < 0.01), and had more medical comorbidities (57% versus 33%, P = 0.04) than HIV-uninfected women. The majority of couples were serodiscordant (77%), and of these couples, 32% had a detectable plasma viral load and 33% report inconsistent condom use. CONCLUSIONS: HIV-infected women have a number of medical and psychosocial issues, including those related to HIV that may increase the risk of adverse pregnancy outcomes and HIV perinatal and sexual transmission. PCC is an important intervention to optimize maternal management to improve perinatal outcomes and minimize transmission risks.

Pregnancy as an Opportunity for Hepatitis C Virus Elimination and Eradication.

Since the development of highly effective direct-acting antivirals, the WHO has set a goal of hepatitis C virus (HCV) elimination by 2030. Key to this strategy is increased screening and treatment. Pregnancy and the postpartum period represent a unique time when underserved populations have increased contact with the healthcare system. We propose using antenatal care to maximize case identification, treatment, and prevention. Pregnant individuals are an ideal sentinel population for HCV surveillance. Universal screening in pregnancy can provide population-level data. Once cases are identified, pregnancy presents an opportunity for intervention. Although not currently WHO approved, clinical trials are examining treatment during pregnancy. In the interim, identification of infection during pregnancy allows for optimization of the treatment cascade postpartum. Pregnancy can be used as a time for prevention. Taking advantage of patient engagement and existing infrastructure, pregnancy presents an opportunity to intervene in the fight for HCV eradication.

Azithromycin dosing and preterm premature rupture of membranes treatment (ADAPT): a randomized controlled Phase I trial.

BACKGROUND: Seven days of antibiotics are recommended in the setting of preterm premature rupture of membranes to promote latency. Azithromycin has generally replaced a 7-day course of erythromycin in current clinical practice. Azithromycin clears from plasma quickly and concentrates in local tissue, which is why daily dosing is not always needed, and local tissue, rather than plasma, concentrations are used to determine dosing. On the basis of limited pharmacokinetic studies in pregnancy, a 1-time dose of 1 g azithromycin may not maintain local (amniotic fluid) drug concentrations above minimum inhibitory concentrations for common genitourinary pathogens (50-500 ng/mL). OBJECTIVE: We aimed to compare the pharmacokinetics of 1-time vs daily dosing of azithromycin in the setting of preterm prelabor rupture of membranes. STUDY DESIGN: This is a randomized clinical trial of singletons with preterm prelabor rupture of membranes randomized to 1 g oral azithromycin once or 500 mg oral azithromycin daily for 7 days. The primary outcome was amniotic fluid azithromycin concentrations over 8 days. Secondary outcomes included plasma azithromycin trough concentrations. Plasma was collected at 1-4 hours and 12-24 hours after the first dose and then every 24 hours through 8 days. Amniotic fluid was collected opportunistically throughout the day noninvasively with Always Flex foam pads. We aimed to enroll 20 participants to achieve n=5 still pregnant through 8 days in each group. Continuous variables were compared using the Mann-Whitney U test, and the relationship between azithromycin concentration and time was assessed using linear regression. RESULTS: The study was halted after 6 enrolled because of lagging enrollment, with 3 in each group. The mean gestational age of enrollment was 27.1±1.7 weeks in the 1 g group and 31.0±1.4 weeks in the 500 mg daily group. One participant in each group had latency to delivery >7 days. Regarding amniotic fluid azithromycin concentration, there was a difference in change in amniotic fluid azithromycin concentration over time between groups (P<.001). The amniotic fluid concentration of azithromycin was relatively stable in the 1 g once group (B,-0.07; 95% confidence interval, -0.44 to 0.31; P=.71), whereas amniotic fluid concentration (ng/mL) increased over time (hours) in the 500 mg daily group (B, 1.3; 95% confidence interval, 0.7-1.9; P<.001). By ≥96 hours, median amniotic fluid levels of azithromycin were lower in the 1 g once group (median, 11; interquartile, 7-56) compared with 500 mg daily (median, 46; interquartile, 23-196), with a median difference of -27 (interquartile,-154 to -1; P=.03). In plasma, there was higher azithromycin concentration during the first 24 hours with 1 g once vs 500 mg daily (median difference, 637 ng/mL; 101-1547; P=.01); however, by ≥96 hours plasma azithromycin declined and was virtually undetectable in the 1 g once group, whereas trough plasma levels in the 500 mg remained elevated (median difference -207 ng/mL; interquartile, -271 to -155; P=.03). CONCLUSION: Approximately 500 mg daily dosing of azithromycin maintains higher amniotic fluid concentrations and more consistently greater than common minimum inhibitory concentrations over 8 days compared with 1 g once in the setting of PPROM. El resumen está disponible en Español al final del artículo.