Time to redefine prolonged third stage of labor? A systematic review and meta-analysis of the length of the third stage of labor and adverse maternal outcome after vaginal birth.

OBJECTIVE: This study aimed (1) to assess the association between the length of the third stage of labor and adverse maternal outcome after vaginal birth and (2) to evaluate whether earlier manual placenta removal reduces the risk of adverse outcome. DATA SOURCES: PubMed, MEDLINE, Embase, ClinicalTrials.gov, the Cochrane Library, Journals@Ovid, and the World Health Organization International Clinical Trials Registry were searched from January 1, 2000, to June 13, 2023. STUDY ELIGIBILITY CRITERIA: All studies that assessed adverse maternal outcome, defined as any maternal complication after vaginal birth, concerning the length of the third stage of labor and the timing of manual placenta removal were included. METHODS: The included studies were evaluated using the Conducting Systematic Reviews and Meta-Analyses of Observational Studies of Etiology methodology. Pooled odds ratios with 95% confidence intervals were calculated. Heterogeneity (I2 test) was assessed, subgroup analyses were performed, and 95% prediction intervals were calculated. RESULTS: To meet the first objective, 18 cohort studies were included. The assessed cutoff values for the length of the third stage of labor were 15, 30, and 60 minutes. Women with a third stage of labor of ≥15 minutes had an increased risk of postpartum hemorrhage compared with those with a third stage of labor of <15 minutes (odds ratio, 5.55; 95% confidence interval, 1.74-17.72). For women without risk factors for postpartum hemorrhage, the odds ratio was 2.20 (95% confidence interval, 0.75-6.49). Among women with a third stage of labor of ≥60 minutes vs women with a third stage of labor of <60 minutes, the odds ratio was 3.72 (95% confidence interval, 2.36-5.89). The incidence of red blood cell transfusion was higher for a third stage of labor of ≥30 minutes than for a third stage of labor of <30 minutes (odds ratio, 3.23; 95% confidence interval, 2.26-4.61). Of note, 3 studies assessed the timing of placenta removal and the risk of adverse maternal outcome. However, the results could not be pooled because of the different outcome measures. Moreover, 1 randomized controlled trial (RCT) reported a significantly higher incidence of hemodynamic compromise in women with manual placenta removal at 15 minutes than in women with manual placenta removal at 10 minutes (30/156 [19.2%] vs 10/156 [6.4%], respectively), whereas 2 observational studies reported a lower risk of bleeding among women without manual placenta removal. CONCLUSION: Although the risk of adverse maternal outcome after vaginal birth increases when the third stage of labor exceeds 15 minutes, there is no convincing supporting evidence that reducing the length of the third stage of labor by earlier manual removal of the placenta can reduce the incidence of adverse maternal outcome.

Fetal sex and the relative reactivity of human umbilical vein and arteries are key determinants in potential beneficial effects of phosphodiesterase inhibitors.

Intrauterine growth restriction (IUGR) is a common complication of pregnancy. We previously demonstrated that IUGR is associated with an impaired nitric oxide (NO)-induced relaxation in the human umbilical vein (HUV) of growth-restricted females compared to appropriate for gestational age (AGA) newborns. We found that phosphodiesterase (PDE) inhibition improved NO-induced relaxation in HUV, suggesting that PDEs could represent promising targets for therapeutic intervention. This study aimed to investigate the effects of PDE inhibition on human umbilical arteries (HUAs) compared to HUV. Umbilical vessels were collected in IUGR and AGA term newborns. NO-induced relaxation was studied using isolated vessel tension experiments in the presence or absence of the nonspecific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX). PDE1B, PDE1C, PDE3A, PDE4B, and PDE5A were investigated by Western blot. NO-induced vasodilation was similar between IUGR and AGA HUAs. In HUAs precontracted with serotonin, IBMX enhanced NO-induced relaxation only in IUGR females, whereas in HUV IBMX increased NO-induced relaxation in all groups except IUGR males. In umbilical vessels preconstricted with the thromboxane A2 analog U46619, IBMX improved NO-induced relaxation in all groups to a greater extent in HUV than HUAs. However, the PDE protein content was higher in HUAs than HUV in all study groups. Therefore, the effects of PDE inhibition depend on the presence of IUGR, fetal sex, vessel type, and vasoconstrictors implicated. Despite a higher PDE protein content, HUAs are less sensitive to IBMX than HUV, which could lead to adverse effects of PDE inhibition in vivo by impairment of the fetoplacental hemodynamics.NEW & NOTEWORTHY The effects of phosphodiesterase inhibition on the umbilical circulation depend on the presence of intrauterine growth restriction, the fetal sex, vessel type, and vasoconstrictors implicated. The human umbilical vascular tone regulation is complex and depends on the amount and activity of specific proteins but also probably on the subcellular organization mediating protein interactions. Therefore, therapeutic interventions using phosphodiesterase inhibitors to improve the placental-fetal circulation should consider fetal sex and both umbilical vein and artery reactivity.

Use of GLP1 receptor agonists in early pregnancy and reproductive safety: a multicentre, observational, prospective cohort study based on the databases of six Teratology Information Services.

OBJECTIVES: Glucagon-like peptide 1 receptor agonists (GLP1-RA) are indicated for the treatment of type 2 diabetes and more recently for weight loss. The aim of this study was to assess the risks associated with GLP1-RA exposure during early pregnancy. DESIGN: This multicentre, observational prospective cohort study compared pregnancy outcomes in women exposed to GLP1-RA in early pregnancy either for diabetes or obesity treatment with those in two reference groups: (1) women with diabetes exposed to at least one non-GLP1-RA antidiabetic drug during the first trimester and (2) a reference group of overweight/obese women without diabetes, between 2009 and 2022. SETTING: Data were collected from the databases of six Teratology Information Services. PARTICIPANTS: This study included 168 pregnancies of women exposed to GLP1-RA during the first trimester, alongside a reference group of 156 pregnancies of women with diabetes and 163 pregnancies of overweight/obese women. RESULTS: Exposure to GLP1-RA in the first trimester was not associated with a risk of major birth defects when compared with diabetes (2.6% vs 2.3%; adjusted OR, 0.98 (95% CI, 0.16 to 5.82)) or to overweight/obese (2.6% vs 3.9%; adjusted OR 0.54 (0.11 to 2.75)). For the GLP1-RA group, cumulative incidence for live births, pregnancy losses and pregnancy terminations was 59%, 23% and 18%, respectively. In the diabetes reference group, corresponding estimates were 69%, 26% and 6%, while in the overweight/obese reference group, they were 63%, 29% and 8%, respectively. Cox proportional cause-specific hazard models indicated no increased risk of pregnancy losses in the GLP1-RA versus the diabetes and the overweight/obese reference groups, in both crude and adjusted analyses. CONCLUSIONS: This study offers reassurance in cases of inadvertent exposure to GLP1-RA during the first trimester of pregnancy. Due to the limited sample size, larger studies are required to validate these findings.

Contribution of fetal blood sampling to determining the prognosis of congenital cytomegalovirus infections: a case-cohort study in Switzerland.

BACKGROUND: Cytomegalovirus is responsible for the most common congenital infection, affecting 0.5% to 1.0% of live births in Europe. Congenital cytomegalovirus infection can be diagnosed during pregnancy by viral DNA amplification in the amniotic fluid, but the prognosis of fetuses without severe brain abnormalities remains difficult to establish on the basis of prenatal imaging alone. OBJECTIVE: To identify predictors of moderate to severe symptomatic cytomegalovirus infection among fetal blood parameters and to propose an algorithm on the basis of these parameters and on prenatal imaging that would provide the best positive and negative predictive values. STUDY DESIGN: Fetal blood sampling at 21-28 weeks gestation was performed in fetuses with congenital cytomegalovirus infection confirmed by amniocentesis after maternal infection in the first-trimester or periconceptional period. We compared the levels of hemoglobin, thrombocytes, γ-glutamyl transpeptidase, aspartate aminotransferase, alanine aminotransferase, ß2-microglobulin, immunoglobulins G and M, and cytomegalovirus DNA viral loads in amniotic fluid and fetal blood between those with moderate to severe symptomatic infection and those with asymptomatic to mild infection (median follow-up of 36 months for live births). RESULTS: Among 58 fetuses included, 25 (43%) had a moderate to severe symptomatic infection: 16 with severe cerebral abnormalities, 5 with multiple signs or symptoms at birth, 2 with bilateral sensorineural hearing loss, and 2 with neurodevelopmental delay. The values of thrombocytes, aspartate aminotransferase, ß2 microglobulin, Immunoglobulin M, and cytomegalovirus viral loads differed significantly between fetuses with moderate to severe symptomatic infection and those with asymptomatic to mild infection. The optimal strategy to predict moderate to severe symptomatic infection was to first perform fetal brain imaging, followed by fetal blood sampling with the following cutoffs: thrombocytes <120,000/mL, viremia ≥5 log10/mL, and ß2 microglobulin ≥12 mg/L). This recursive algorithm had a negative predictive value of 100% for moderately to severely symptomatic infection. CONCLUSION: The combination of thrombocytes, ß2-microglobulin, and cytomegalovirus viral load in fetal blood can be used for prognosis determination, particularly in cytomegalovirus-infected fetuses without severe brain abnormalities at the time of prenatal diagnosis. Future studies should evaluate whether these parameters remain useful in infected fetuses who have been treated with valacyclovir before fetal blood sampling.

Cytomegalovirus infection during pregnancy: cross-sectional survey of knowledge and prevention practices of healthcare professionals in French-speaking Switzerland.

BACKGROUND: Lack of Cytomegalovirus (CMV) knowledge among healthcare professionals has been proven to be the main threat to pregnant women's awareness, preventing them from reducing the risk of infection. The aims of this study were to assess the knowledge and practices of French-speaking Swiss perinatal professionals in terms of CMV prevention, as well as the sociodemographic-professional factors that influence them. METHODS: This observational study used a cross-sectional design to collect data-via an anonymous electronic questionnaire in French distributed to gynecologists-obstetricians, general practitioners and midwives via various channels: e-mails and social networks of partner centers, professional associations, and conferences. The 41-item questionnaire collected data on sociodemographic and professional characteristics, general CMV knowledge, national recommendation knowledge and prevention practices. Univariable and multivariable analyses were performed. RESULTS: A total of 110 gynecologist-obstetricians, 5 general practitioners and 226 midwives participated in the study. While more than 80% of practitioners were familiar with protective hygiene measures, significant gaps were highlighted concerning the transmission routes, as well as the signs of short- and long-term congenital CMV infection. Regarding practice, 63.3% of participants provided information on CMV to their patients, mainly during the first antenatal visit. Among those who did not, lack of knowledge and forgetfulness were the two main reasons cited. Concerning systematic screening, 45.7% of participants offered it to their patients, and 37.3% only offered it to "at risk" groups. The existence of national guidelines on CMV was known by 62.0% of participants. Multivariable analysis revealed that working as a gynecologist-obstetrician was independently associated with higher score of preventive practices, while performing ultrasound or preconception consultations was independently associated with a higher score of general CMV knowledge, and working in a university hospital was independently associated with a higher score of Swiss recommendation knowledge. A level of training higher than the basic medical or midwifery diploma and participation in fetal medicine symposia both promote a higher score of CMV knowledge and prevention practices in line with current recommendations. CONCLUSION: This study confirms the significant gaps in CMV knowledge among French-speaking Swiss caregivers along with the heterogeneity of their prevention practices. To raise awareness among pregnant women and reduce the burden of congenital CMV infections, improving professional knowledge through access to specific training and standardizing practices should be a national priority.

Improving Data Collection in Pregnancy Safety Studies: Towards Standardisation of Data Elements in Pregnancy Reports from Public and Private Partners, A Contribution from the ConcePTION Project.

INTRODUCTION AND OBJECTIVE: The ConcePTION project aims to improve the way medication use during pregnancy is studied. This includes exploring the possibility of developing a distributed data processing and analysis infrastructure using a common data model that could form a foundational platform for future surveillance and research. A prerequisite would be that data from various data access providers (DAPs) can be harmonised according to an agreed set of standard rules concerning the structure and content of the data. To do so, a reference framework of core data elements (CDEs) recommended for primary data studies on drug safety during pregnancy was previously developed. The aim of this study was to assess the ability of several public and private DAPs using different primary data sources focusing on multiple sclerosis, as a pilot, to map their respective data variables and definitions with the CDE recommendations framework. METHODS: Four pregnancy registries (Gilenya, Novartis; Aubagio, Sanofi; the Organization of Teratology Information Specialists [OTIS]; Aubagio, Sanofi; the Dutch Pregnancy Drug Register, Lareb), two enhanced pharmacovigilance programmes (Gilenya PRIM, Novartis; MAPLE-MS, Merck Healthcare KGaA) and four Teratology Information Services (UK TIS, Jerusalem TIS, Zerifin TIS, Swiss TIS) participated in the study. The ConcePTION primary data source CDE includes 51 items covering administrative functions, the description of pregnancy, maternal medical history, maternal illnesses arising in pregnancy, delivery details, and pregnancy and infant outcomes. For each variable in the CDE, the DAPs identified whether their variables were: identical to the one mentioned in the CDE; derived; similar but with a divergent definition; or not available. RESULTS: The majority of the DAP data variables were either directly taken (85%, n = 305/357, range 73-94% between DAPs) or derived by combining different variables (12%, n = 42/357, range 0-24% between DAPs) to conform to the CDE variables and definitions. For very few of the DAP variables, alignment with the CDE items was not possible, either because of divergent definitions (1%, n = 3/357, range 0-2% between DAPs) or because the variables were not available (2%, n = 7/357, range 0-4% between DAPs). CONCLUSIONS: Data access providers participating in this study presented a very high proportion of variables matching the CDE items, indicating that alignment of definitions and harmonisation of data analysis by different stakeholders to accelerate and strengthen pregnancy pharmacovigilance safety data analyses could be feasible.