Untangling the independent effect of endometriosis, adenomyosis, and ART-related factors on maternal, placental, fetal, and neonatal adverse outcomes: results from a systematic review and meta-analysis.

BACKGROUND: Women with endometriosis may constitute a group at a particularly increased risk of pregnancy-related complications. Furthermore, women selected for assisted reproductive technology (ART) are exposed to additional endocrinological and embryological factors that have been associated with adverse pregnancy outcomes. OBJECTIVE AND RATIONALE: This study aimed to investigate the independent effect of endometriosis, adenomyosis, and various ART-related factors on adverse maternal, placental, fetal, and neonatal outcomes. SEARCH METHODS: Published randomized controlled trials, cohort studies, and case-control studies were considered eligible. PubMed, MEDLINE, ClinicalTrials.gov, Embase, and Scopus were systematically searched up to 1 March 2024. This systematic review and meta-analysis was performed in line with the PRISMA and the MOOSE reporting guidelines. To thoroughly investigate the association between endometriosis/adenomyosis and adverse pregnancy outcomes, sub-analyses were conducted, whenever possible, according to: the method of conception (i.e. ART and non-ART conception), the endometriosis stage/phenotype, the coexistence of endometriosis and adenomyosis, any pre-pregnancy surgical treatment of endometriosis, and the form of adenomyosis. The odds ratio (OR) with 95% CI was used as effect measure. The quality of evidence was assessed using the GRADE approach. OUTCOMES: We showed a higher risk of placenta previa in women with endometriosis compared to controls (34 studies, OR 2.84; 95% CI: 2.47, 3.26; I2 = 83%, moderate quality). The association was observed regardless of the method of conception and was particularly strong in the most severe forms of endometriosis (i.e. rASRM stage III-IV endometriosis and deep endometriosis (DE)) (OR 6.61; 95% CI: 2.08, 20.98; I2 = 66% and OR 14.54; 95% CI: 3.67, 57.67; I2 = 54%, respectively). We also showed an association, regardless of the method of conception, between endometriosis and: (i) preterm birth (PTB) (43 studies, OR 1.43; 95% CI: 1.32, 1.56; I2 = 89%, low quality) and (ii) cesarean section (29 studies, OR 1.52; 95% CI: 1.41, 1.63; I2 = 93%, low quality). The most severe forms of endometriosis were strongly associated with PTB. Two outcomes were associated with adenomyosis both in the main analysis and in the sub-analysis that included only ART pregnancies: (i) miscarriage (14 studies, OR 1.83; 95% CI: 1.53, 2.18; I2 = 72%, low quality) and (ii) pre-eclampsia (7 studies, OR 1.70; 95% CI: 1.16, 2.48; I2 = 77%, low quality). Regarding ART-related factors, the following associations were observed in the main analysis and confirmed in all sub-analyses conducted by pooling only risk estimates adjusted for covariates: (i) blastocyst stage embryo transfer (ET) and monozygotic twinning (28 studies, OR 2.05; 95% CI, 1.72, 2.45; I2 = 72%, low quality), (ii) frozen embryo transfer (FET) and (reduced risk of) small for gestational age (21 studies, OR 0.59; 95% CI, 0.57, 0.61; P < 0.00001; I2 = 17%, very low quality) and (increased risk of) large for gestational age (16 studies, OR 1.70; 95% CI, 1.60, 1.80; P < 0.00001; I2 = 55%, very low quality), (iii) artificial cycle (AC)-FET and pre-eclampsia (12 studies, OR 2.14; 95% CI: 1.91-2.39; I2 = 9%, low quality), PTB (21 studies, OR 1.24; 95% CI 1.15, 1.34; P < 0.0001; I2 = 50%, low quality), cesarean section (15 studies, OR 1.59; 95% CI 1.49, 1.70; P < 0.00001; I2 = 67%, very low quality) and post-partum hemorrhage (6 studies, OR 2.43; 95% CI 2.11, 2.81; P < 0.00001; I2 = 15%, very low quality). WIDER IMPLICATIONS: Severe endometriosis (i.e. rASRM stage III-IV endometriosis, DE) constitutes a considerable risk factor for placenta previa and PTB. Herein, we recommend against superimposing on this condition other exposure factors that have a strong association with the same obstetric adverse outcome or with different outcomes which, if coexisting, could determine the onset of an ominous obstetric syndrome. Specifically, we strongly discourage the use of AC regimens for FET in ovulatory women with rASRM stage III-IV endometriosis or DE. We also recommend single ET at the blastocyst stage in this high-risk population. REGISTRATION NUMBER: CRD42023401428.

First Trimester Placental Biomarkers for Pregnancy Outcomes.

The placenta plays a key role in several adverse obstetrical outcomes, such as preeclampsia, intrauterine growth restriction and gestational diabetes mellitus. The early identification of at-risk pregnancies could significantly improve the management, therapy and prognosis of these pregnancies, especially if these at-risk pregnancies are identified in the first trimester. The aim of this review was to summarize the possible biomarkers that can be used to diagnose early placental dysfunction and, consequently, at-risk pregnancies. We divided the biomarkers into proteins and non-proteins. Among the protein biomarkers, some are already used in clinical practice, such as the sFLT1/PLGF ratio or PAPP-A; others are not yet validated, such as HTRA1, Gal-3 and CD93. In the literature, many studies analyzed the role of several protein biomarkers, but their results are contrasting. On the other hand, some non-protein biomarkers, such as miR-125b, miR-518b and miR-628-3p, seem to be linked to an increased risk of complicated pregnancy. Thus, a first trimester heterogeneous biomarkers panel containing protein and non-protein biomarkers may be more appropriate to identify and discriminate several complications that can affect pregnancies.

Special Issue "Ovarian Cancer: Advances on Pathophysiology and Therapies".

Ovarian cancer is a gynecologic cancer with a high mortality rate, and its incidence has increased significantly over the past 50 years [...].

Dietary Patterns and Fertility.

Diet has a key role in the reproductive axis both in males and females. This review aims to analyze the impacts of different dietary patterns on fertility. It appears that the Mediterranean diet has a predominantly protective role against infertility, while the Western diet seems to be a risk factor for infertility. Moreover, we focus attention also on dietary patterns in different countries of the World (Middle Eastern diet, Asian diet). In particular, when analyzing single nutrients, a diet rich in saturated fatty acids, cholesterol, animal proteins, and carbohydrates with high glycemic index is highly associated with male and female infertility. Finally, we evaluate the effects of vegetarian, vegan, and ketogenic diets on fertility, which seem to be still unclear. We believe that comprehension of the molecular mechanisms involved in infertility will lead to more effective and targeted treatments for infertile couples.

Update on long-term cardiovascular risk after pre-eclampsia: a systematic review and meta-analysis.

BACKGROUND/INTRODUCTION: There is a need for further studies on the cardiovascular risk of women experiencing pre-eclampsia (PE). PURPOSE: To update the literature regarding the association between a history of PE and subsequent cardiovascular diseases, including cardiovascular death, coronary heart diseases, heart failure, and stroke, focusing on the trend in the effect size (ES) estimates over time. METHODS AND RESULTS: Following PRISMA guidelines, from inception to May 2023, we performed a systematic review of PubMed, MEDLINE, Scopus, and EMBASE. Randomized, cohort, or case-control studies in English were included if fulfiling the following criteria:(i) The association between PE and subsequent cardiovascular disease was adjusted for clinically relevant variables, (ii) the presence of a control group, and (iii) at least 1 year of follow-up. Pooled adjusted ESs and 95% confidence intervals (CIs) were used as effect estimates and calculated with a random-effect model. Twenty-two studies met the inclusion criteria. PE was associated with a higher risk of cardiovascular death (ES 2.08, 95% CI 1.70-2.54, I2 56%, P < 0.00001), coronary artery diseases (ES 2.04, 95% CI 1.76-2.38, I2 87%, P < 0.00001), heart failure (ES 2.47, 95% CI 1.89-3.22, I2 83%, P < 0.00001), and stroke (ES 1.75, 95% CI 1.52-2.02, I2 72%, P < 0.00001) after adjusting for potential confounders. This risk is evident in the first 1-to-3 years of follow-up and remains significant until 39 years of follow-up. CONCLUSIONS: Compared to women who experienced a normal pregnancy, those suffering from PE have about double the risk of lifetime cardiovascular disease.

Prep-for-Labor: Overview of FIGO's labor and delivery triage bundles of care to optimize maternal and newborn outcomes.

Childbirth is an intense event in which decisions may need to be made in seconds to guarantee the health of both mother and newborn. Despite health systems and care approaches varying widely according to real-life scenarios, availability of facilities, beliefs, resources, staff, and geography, among others, optimal outcomes should be ensured worldwide. Triaging low-risk pregnancies from high-risk pregnancies is the first step to ensure proper allocation of resources. From this need, we developed FIGO's Prep-For-Labor triage methods, a series of 2-minute labor and delivery bundles of care, with special regard given to low- and middle-income countries and rural settings. Around 80% of women, once properly triaged, can pursue vaginal delivery with minimal intervention, while those at risk can either be managed on site or transferred promptly to an advanced care site. FIGO's bundles of care and good practice recommendations for labor and delivery and immediate newborn triage cover four clinical scenarios: (1) preterm labor; (2) induced or spontaneous labor at term; (3) cesarean delivery; and (4) newborn care. From rapid triage of the mother (low vs high risk) to the list of required equipment, description of skilled staff, and coordination of resources, the recommendations for care are introduced across these four areas in this overview article. Implementing the proposed management steps described in each summary can improve maternal and neonatal outcomes.

FIGO good practice recommendations for cesarean delivery: Prep-for-Labor triage to minimize risks and maximize favorable outcomes.

Cesarean delivery is an abdominal surgical procedure performed for child delivery when the vaginal route is not feasible or desired due to maternal/fetal indications. All childbirth facilities should be able to safely perform a cesarean, which is not the current reality. For planned cesarean delivery, the facility must be prepared for the patient. In contrast, for unplanned arrivals at the facility, FIGO's Prep-for-Labor triage method allows rapid decision-making on whether cesarean delivery can be safely performed on site or whether transfer to an advanced care center is needed. A checklist of staff/tools for safe on-site cesarean delivery is provided to enable timely decision-making. Maternal complications following cesarean are three-fold higher than vaginal delivery. To prevent nonmedically indicated cesarean by favoring vaginal delivery, up-to-date safe and effective guidance is provided, defining labor, second stage length, and status before an arrested labor is confirmed. Whether cesarean delivery is planned or emergency, the Misgav Ladach simplified procedure is proposed as it is suitable for both low- and high-risk cases, including twins, thereby reducing both operative morbidity and postoperative recovery. A trial of labor after first cesarean (TOLAC) should be pursued when feasible, for which the indications, contraindications, safeguards, and steps of safe labor induction are delineated. Implementation of these good practice recommendations will improve childbirth by reducing excessive nonindicated cesareans, while precisely defining the resources and postoperative care required for safe performance on site. Enabling safe childbirth by cesarean and TOLAC, even at sites with low rates currently, will significantly improve maternal and fetal outcomes.

FIGO good practice recommendations for induced or spontaneous labor at term: Prep-for-Labor triage to minimize risks and maximize favorable outcomes.

The goal of induced or spontaneous labor is childbirth by vaginal delivery. Delivery after 37 weeks is desirable and associated with favorable maternal and newborn outcomes. Delivery facilities should have suitable staff and resources on site for antenatal services and delivery care. FIGO's Prep-for-Labor triage method provides rapid diagnostic tools that help define patients as high or low risk to determine whether transfer to a higher-level center is needed. There is often a disconnect between a facility's designation and its ability to achieve safe deliveries. For preplanned labor induction, the designated clinical facility must have the right set-up and prenatal records available to achieve a successful outcome. However, this is often not the case if a patient arrives in labor or needs an induction and the facility has limited patient information and resources, thus requiring rapid management decisions. The practical guidance checklist in this article defines maternal and/or fetal risk factors and delineates approaches and safe practices for labor induction and management, including when antenatal information is limited to maximize safe delivery practices. Guidelines on using the Bishop score (>6 or <6) to manage labor are presented. Evidence supporting successful safe labor induction at 41-42 weeks of gestation in low-risk cases is described. This practice will increase the rate of spontaneous labor and delivery, minimizing intervention and thereby diverting limited clinical resources to those patients in need. In the right setting, this could lead to around 80% of women delivering spontaneously, which remains a desired goal.

Before Is Better: Innovative Multidisciplinary Preconception Care in Different Clinical Contexts.

CONTEXT: Implementation of pre-conception care units is still very limited in Italy. Nowadays, the population's awareness of the reproductive risks that can be reduced or prevented is very low. Purpose and main findings: We presented a new personalized multidisciplinary model of preconception care aimed at identifying and possibly reducing adverse reproductive events. We analyzed three cohorts of population: couples from the general population, infertile or subfertile couples, and couples with a previous history of adverse reproductive events. The proposal involves a deep investigation regarding family history, the personal histories of both partners, and reproductive history. PRINCIPAL CONCLUSIONS: Preconception care is still neglected in Italy and under-evaluated by clinicians involved in natural or in vitro reproduction. Adequate preconception counseling will improve maternal and fetal obstetrical outcomes.

Recurrent pregnancy loss: a male crucial factor-A systematic review and meta-analysis.

BACKGROUND: Recurrent pregnancy loss (RPL), defined as two or more failed clinical pregnancies, affects 1%-3% of couples trying to conceive. Nowadays up to 50% of cases remain idiopathic. In this context, paternal factors evaluation is still very limited. The aim is to address the topic of the male factor in RPL with a broad approach, analyzing collectively data on sperm DNA fragmentation (SDF) and semen parameters. We systematically searched in Pubmed/MEDLINE and Google Scholar from inception to February 2023. A protocol has been registered on PROSPERO (ID number CRD42022278616). PRISMA guidelines were followed. METHODS: Pooled results from 20 studies revealed a higher DNA fragmentation rate in the RPL group compared to controls (mean difference [MD] 9.21, 95% CI 5.58-12.85, p < 0.00001, I2 98%). Age, body mass index (BMI), smoking, and alcohol intake were not associated with DNA fragmentation. Subgroup analysis by different SDF assays (TUNEL and COMET at a neutral pH vs. indirect assessment with other assays) and ethnicity did not highlight different results (p = 0.25 and 0.44). RESULTS: Results pooled from 25 studies showed a significant difference comparing RPL and control groups regarding ejaculation volume (MD -0.24, 95% CI -0.43; -0.06, p 0.01, I2 66%), total sperm number (MD -10.03, 95% CI -14.65; -5.41, p < 0.0001, I2 76%), total sperm motility (MD -11.20, 95% CI -16.15; -6.25, p < 0.0001, I2 96%), progressive sperm motility (MD -7.34, 95% CI -10.87; -3.80, p < 0.0001, I2 97%), and normal sperm morphology (MD -5.99, 95% CI -9.08; -2.90, p 0.0001, I2 98%). A sub-analysis revealed that Asian and Africans, but not white-European RPL men had lower progressive sperm motility compared to controls. CONCLUSION: In conclusion, current review and meta-analysis findings suggested that SDF and some specific semen parameters were associated with RPL in a multi-ethnic evaluation. This effort opens future direction on a growing awareness of, first, how the male factor plays a key role and, second, how appropriate would be to establish a direct dialogue between the gynecologist and the urologist. PATIENT SUMMARY: We performed a systematic review and meta-analysis on the male component of RPL. We found that sperm DNA fragmentation and some specific sperm parameters are significantly associated with RPL.

Depression, Stress and Anxiety among Women and Men Affected by Recurrent Pregnancy Loss (RPL): A Systematic Review and Meta-Analysis.

The aim of the present study is to perform a systematic review and meta-analysis on depression, stress and anxiety in women who experienced recurrent pregnancy loss (RPL) compared to controls and to men who experienced RPL. The pooled results showed a higher level of moderate/severe depression among women who experienced RPL compared to controls (5359 women, random effects model, odds ratio (OR) 3.77, 95% Confidence Interval (CI) 2.71-5.23, p < 0.00001, I2 0%). Anxiety and stress levels were also higher among women experiencing RPL compared to controls. The pooled results showed a higher level of moderate/severe depression in women who experienced RPL compared to men who underwent the same experience (113/577 (19.5%) women versus 33/446 (7%) men versus random effects model, OR 4.63; 95% CI 2.95-7.25, p < 0.00001 I2 0%). Similarly, higher levels of stress and anxiety in women experiencing RPL compared to men experiencing RPL were described. Women who experienced RPL showed higher rates of moderate-severe depression, stress and anxiety compared to both controls and men who experienced RPL. Healthcare professionals should implement screening for anxiety and depression and social support for both partners and support them in dealing with RPL according to sex-specific responses to this stressful event.

Ovarian Cancer: Advances in Pathophysiology and Therapies.

We are pleased to present this Special Issue of the International Journal of Molecular Sciences, entitled "Ovarian Cancer: Advances in Pathophysiology and Therapies" [...].

HLA-G and Recurrent Pregnancy Loss.

Placentation is an immunological compromise where maternal immune system cells and trophoblastic cells interact to reach an equilibrium condition. Although the cross talk between the two systems is complex and not completely understood, Human Leukocyte Antigen G (HLA-G), expressed on trophoblastic cell surfaces, seems to be one of the main molecules involved in the modulation of both local and systemic maternal immune response. The prevalence of recurrent pregnancy loss (RPL), probably underestimated, is 5% of all women who achieve pregnancy, and about 40-60% percent of RPL cases are unexplained. There is an immunological analogy between allograft rejection and miscarriage, and the purpose of this review is to describe how the HLA-G pathway alterations are involved in disrupting the immunologic balance and in increasing the risk of recurrent pregnancy loss.

Endometrial Microbiota and Immune Tolerance in Pregnancy.

Recent studies have demonstrated that the uterus has its own microbiota. However, there is no consensus on endometrial microbiota composition, thus its role in the healthy uterine environment is still a frontier topic. Endometrial receptivity is key to embryo implantation, and in this specific context immunological tolerance against fetal antigens and the tightly regulated expression of inflammatory mediators are fundamental. According to recent evidence, endometrial microbiota may interact in a very dynamic way with the immune system during the peri-conceptional stage and later during pregnancy. For this reason, a condition of dysbiosis might lead to adverse pregnancy outcomes. The aim of this review is to summarize the evidence on the molecular mechanisms by which the endometrial microbiota may interact with the immune system. For this purpose, the link between dysbiosis and reproductive disorders, such as infertility, recurrent pregnancy loss (RPL), and preterm birth, will be discussed. In conclusion, the most recent findings from molecular analyses will be reported to illustrate and possibly overcome the intrinsic limitations of uterine microbiota detection (low endometrial biomass, high risk of contamination during sampling, and lack of standardization).

Celiac Disease Predisposition and Genital Tract Microbiota in Women Affected by Recurrent Pregnancy Loss.

The incidence of Idiopathic Recurrent Pregnancy Loss (RPL) is doubled in patients suffering from Celiac Disease (CD) compared to healthy populations. CD genetic components are HLA class II genes known as HLA-DQ2 and DQ8. Genetically susceptible women can remain asymptomatic even though they are exposed to a doubled risk of RPL compared to the general population. Furthermore, CD has been associated with microbiota alterations. The aim of this study is to evaluate endometrial and vaginal microbiota in HLA-DQ2/DQ8 positive and negative RPL patients compared to healthy pregnant women. Endometrial and vaginal microbiota of 3 subgroups were evaluated: 15 HLA-DQ2/DQ8 positive RPL women, 25 HLA DQ2/DQ8 negative RPL women (for a total of 40 RPL women) and 7 healthy fertile controls with previous uncomplicated pregnancies (all HLA-DQ2/DQ8 negative). The 2 RPL subgroups (HLA-DQ2/DQ8 positive and negative) showed a different endometrial and vaginal composition in the Lactobacillacae family compared to controls: Lactobacillus acidophilus was absent both in the vaginal and endometrial samples of RPL women, while Lactobaciluus iners, which can favor a less stable vaginal microbiota, was found only in RPL women (26.4% in HLA DQ2/DQ8 positive and 22.1% HLA DQ2/DQ8 negative) in both the vaginal and endometrial districts. In conclusion, both HLA DQ2/DQ8 positive-RPL and HLA DQ2/DQ8 negative-RPL women showed different endometrial and vaginal microbiota composition compared to healthy controls.

Antinuclear antibodies positivity in women in reproductive age: From infertility to adverse obstetrical outcomes - A meta-analysis.

This systematic review and meta-analysis were designed to identify possible correlations between isolated serum antinuclear antibody (ANA) and (i) infertility in the context of in-vitro fertilization (IVF), (ii) idiopathic recurrent pregnancy losses (RPL), and (iii) second/ third trimester pregnancy complications. We performed a systematic review and meta-analysis of the literature in PubMed Library database from inception to March 2022 following PRISMA guidelines. Our pooled results showed a lower pregnancy rate among ANA-positive women undergoing IVF/ICSI compared to ANA-negative women undergoing the same procedures (279/908 versus 1136/2347, random effect, odds ratio -OR- 0.50, 95% confidence interval -CI- 0.38-0.67, p 0.00001, I2 = 58%). We also reported a higher miscarriage rate among ANA-positive compared to ANA-negative women (48/223 versus 109/999, random effect, OR: 3.25 95% CI: 1.57-6.76, p = 0.002, I2 = 61%) and a lower implantation rate (320/1489 versus 1437/4205, random effect, OR: 0.51, 95% CI: 0.36-0.72, p = 0.0001, I2 = 78%). Regarding RPL, pooled results demonstrated a higher prevalence of ANA-positivity in RPL women compared to controls (698/2947 versus 240/3145, random effect, OR: 3.22, 95% CI: 2.12-4.88, p 0.00001, I2 77%), either using > 2 or > 3 pregnancy losses threshold for defining RPL. Heterogeneity of reporting outcome did not allow a quantitative analysis and led to no clear demonstration of an effect of serum ANA on the incidence of stillbirth, preeclampsia and hypertensive disorders. In conclusion, the unfavorable effect of serum ANA was observed in women following IVF. Similarly, ANA were associated with the risk of RPL, while data were unconclusive in terms of late pregnancy complications.

Sperm human papillomavirus infection and risk of idiopathic recurrent pregnancy loss: insights from a multicenter case-control study.

OBJECTIVE: To test the hypothesis claiming an association between human papilloma virus (HPV) sperm infection and idiopathic recurrent pregnancy loss (RPL). DESIGN: Multicenter retrospective case-control study. SETTING: Three university hospitals. PATIENT(S): Cases included men belonging to couples affected by first trimester idiopathic RPL. Controls included men belonging to couples with proven fertility and no history of pregnancy loss; RPL was defined as the previous loss of 2 or more pregnancies. Couples were defined as "fertile" if they achieved a full-term pregnancy within the year before enrollment in the study. All participants conceived without assistance. MAIN OUTCOME MEASURE(S): The association between HPV DNA sperm infection, as identified using polymerase chain reaction, and RPL. RESULTS: The HPV DNA sperm infection was detected in 23 of 117 cases (20%; 95% confidence interval [CI]: 13%, 28%) and in 3 of 84 controls (4%; 95% CI; 1%, 10%) (P<.001). A comparison across baseline characteristics and multiple regression analysis did not identify any potentially confounding factors. Multivariate regression models showed a significant association between HPV DNA sperm infection and RPL (adjusted odds ratio, 7.44; 95% CI: 2.08, 26.58; P=.002 [Model 1]; adjusted odds ratio, 8.96; 95% CI: 2.41, 33.44; P=.001 [Model 2]). CONCLUSIONS: The prevalence of HPV sperm infection was significantly higher in couples affected by RPL than in their fertile counterparts. Notably, the semen sample was infected by HPV in approximately 1 out of 5 patients.

Screening for Low-Tract Genital Infections in Women with Threatened Preterm Labor: Which Role?

OBJECTIVES: The aim of this study was to evaluate the possible relationship between cultural specimens and preterm birth in women admitted for threatened preterm labor. Preterm birth is the leading cause of neonatal mortality and antenatal hospitalization; several risk factors including intrauterine infections have been identified, but its real causes remain poorly understood. DESIGN: This is a retrospective, multicenter, cohort study including 250 women admitted for threatened preterm labor. Methods, Participants/Materials, Setting: All women admitted for threatened preterm labor, i.e., presenting with cervical changes and uterine activity before 37 weeks at the obstetrics unit of the hospitals of Modena, Monza, Carate, and Vimercate were included in the study. We excluded twin pregnancies and cases with preterm premature rupture of membranes at admission. Data about maternal history, pregnancy complications, cervical length, vaginal swabs, and urine culture at admission and gestational age at delivery were collected from clinical records in order to compare the incidence of preterm birth according to some known risk factors, cervical length, and microbiological test at admission. RESULTS: 250 women were included in the study; preterm birth at less than 37 weeks occurred in 44.4% women admitted for threatened preterm labor. The incidence of preterm birth was not different between those with a positive or a negative vaginal swab (48.3 vs. 38.4%, p = 0.22) or positive versus negative urine culture (31.8 vs. 42.1%, p = 0.23) at admission. A shorter cervical length at admission was found in women with subsequent preterm birth (17 vs. 19.5 mm, p = 0.03). Cervical length <15 mm (OR 1.82, 95% CI: 1.03-3.23, p = 0.039) predicted the risk of preterm birth. Furthermore, only the history of a previous preterm birth (p = 0.02) and a previous uterine curettage (p = 0.045) was associated with preterm birth. LIMITATIONS: The observational and retrospective nature of the study and its small sample size are important limitations of the study. Moreover, women were not systematically or randomly assigned to the screening for vaginal or urinary infections. CONCLUSIONS: There is no evidence that the search for vaginal or urinary infections in women admitted for threatened preterm labor is helpful to identify those at increased risk of preterm birth. Although several studies have explored the role of screening for bacterial vaginosis in asymptomatic women and some studies evaluated vaginal or urinary infections in women with preterm birth, none of them focused on the possible role of microbiological specimens as a predictive tool in women admitted for threatened PTL. No association was found in our study, but prospective randomized controlled trials are required to confirm the results of this observation.

Neurocognitive sequelae of antenatal corticosteroids in a late preterm rabbit model.

BACKGROUND: Late preterm birth is associated with short-term respiratory and adaptive problems. Although antenatal corticosteroids seem to reduce the respiratory burden, this may come at the cost of adverse neuropsychological outcomes later in life. This impact has not been investigated. OBJECTIVE: Herein, we investigate what the short- and long-term neurodevelopmental effects of a single course of betamethasone in simulated late preterm birth. STUDY DESIGN: Time-mated pregnant does received 0.1 mg/kg betamethasone (n=8) or 1 mL saline intramuscular (n=6) at the postconceptional ages of 28 and 29 days. The antenatal corticosteroid dose and scheme were based on previous studies and were comparable with routine clinical use. Cesarean delivery was done on postconceptional age 30 days (term=31 days), and new-born rabbits were foster-cared for 28 days and were thereafter cared for in group housing. Neonatal lung function testing and short-term neurobehavioral testing was done. Open field, spontaneous alternation, and novel object recognition tests were subsequently performed at 4 and 8 weeks of age. On postnatal day 1 and at 8 weeks, a subgroup was euthanized and transcardially perfuse fixated. Ex vivo high-resolution Magnetic Resonance Imaging was used to calculate the Diffusion Tensor Imaging-derived fractional anisotropy and mean diffusivity. Fixated brains underwent processing and were serial sectioned, and a set of 3 coronal sections underwent anti-NeuN, Ki67, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. RESULTS: Antenatal corticosteroid exposure was associated with improved neonatal lung function, yet resulted in a long-term growth deficit that coincided with a persistent neurobehavioral deficit. We demonstrated lower neonatal motor scores; a persistent anxious behavior in the open field test with more displacements, running, and self-grooming episodes; persistent lower alternation scores in the T-Maze test; and lower discriminatory indexes in the novel object recognition. On neuropathological assessment, antenatal corticosteroid exposure was observed to result in a persistent lower neuron density and fewer Ki67+ cells, particularly in the hippocampus and the corpus callosum. This coincided with lower diffusion tensor imaging-derived fractional anisotropy scores in the same key regions. CONCLUSION: Clinical equivalent antenatal corticosteroid exposure in this late preterm rabbit model resulted in improved neonatal lung function. However, it compromised neonatal and long-term neurocognition.

Mode of birth in women with low-lying placenta: protocol for a prospective multicentre 1:3 matched case-control study in Italy (the MODEL-PLACENTA study).

INTRODUCTION: The term placenta praevia defines a placenta that lies over the internal os, whereas the term low-lying placenta identifies a placenta that is partially implanted in the lower uterine segment with the inferior placental edge located at 1-20 mm from the internal cervical os (internal-os-distance). The most appropriate mode of birth in women with low-lying placenta is still controversial, with the majority of them undergoing caesarean section. The current project aims to evaluate the rate of vaginal birth and caesarean section in labour due to bleeding by offering a trial of labour to all women with an internal-os-distance >5 mm as assessed by transvaginal sonography in the late third trimester. METHODS AND ANALYSIS: The MODEL-PLACENTA is a prospective, multicentre, 1:3 matched case-control study involving 17 Maternity Units across Lombardy and Emilia-Romagna regions, Italy. The study includes women with a placenta located in the lower uterine segment at the second trimester scan. Women with a normally located placenta will be enrolled as controls. A sample size of 30 women with an internal-os-distance >5 mm at the late third trimester scan is needed at each participating Unit. Since the incidence of low-lying placenta decreases from 2% in the second trimester to 0.4% at the end of pregnancy, 150 women should be recruited at each centre at the second trimester scan. A vaginal birth rate ≥60% in women with an internal-os-distance >5 mm will be considered appropriate to start routinely admitting to labour these women. ETHICS AND DISSEMINATION: Ethical approval for the study was given by the Brianza Ethics Committee (No 3157, 2019). Written informed consent will be obtained from study participants. Results will be disseminated by publication in peer-reviewed journals and presentation in international conferences. TRIAL REGISTRATION NUMBER: NCT04827433 (pre-results stage).