Vaginal progesterone as luteal phase support in natural cycle frozen-thawed embryo transfer (ProFET): protocol for a multicentre, open-label, randomised controlled trial.

INTRODUCTION: Vaginal progesterone supplementation is frequently given to patients receiving frozen embryo transfer (FET) in the natural cycle aiming to increase the chance of pregnancy and live birth. To date, only a few studies have investigated if progesterone supplementation is beneficial in these cycles and the level of evidence for progesterone supplementation is very low. METHODS AND ANALYSIS: The ProFET trial is a multicentre, open-label, randomised controlled trial powered for this investigation, including 1800 women with regular menstrual cycles (24-35 days), aged 18-43 years planned for natural cycle-FET receiving a single blastocyst for transfer. Participants are randomised (1:1:1) to either luteal phase progesterone for 3 weeks, luteal phase progesterone for 7 weeks or no luteal phase progesterone. The participating study centres consist of 12 in vitro fertilisation-clinics in Sweden and 1 in Iceland. The primary outcome is to investigate if luteal phase support (LPS) by vaginal progesterone increases the chance of a live birth per randomised patient in a natural FET cycle compared with no LPS. ETHICS AND DISSEMINATION: The trial was approved by the Swedish Ethical Review Authority (ID 2020-06774, 2021-02822 and 2022-01502-02) and the Swedish Medical Products Agency (ID nr 5.1-2020-102613). All participants are required to provide written informed consent. The outcome of this study will be disseminated to the public through broadcasts, newspapers and presentations at scientific congresses as well as publications in international scientific journals. TRIAL REGISTRATION NUMBER: NCT04725864.

The Association Between High Birth Weight and Long-Term Outcomes-Implications for Assisted Reproductive Technologies: A Systematic Review and Meta-Analysis.

Background: Studies have shown that the prevalence of children born with high birth weight or large for gestational age (LGA) is increasing. This is true for spontaneous pregnancies; however, children born after frozen embryo transfer (FET) as part of assisted reproductive technology (ART) also have an elevated risk. In recent years, the practice of FET has increased rapidly and while the perinatal and obstetric risks are well-studied, less is known about the long-term health consequences. Objective: The aim of this systematic review was to describe the association between high birth weight and LGA on long-term child outcomes. Data Sources: PubMed, Scopus, and Web of Science were searched up to January 2021. Exposure included high birth weight and LGA. Long-term outcome variables included malignancies, psychiatric disorders, cardiovascular disease, and diabetes. Study Selection: Original studies published in English or Scandinavian languages were included. Studies with a control group were included while studies published as abstracts and case reports were excluded. Data Extraction: The methodological quality, in terms of risk of bias, was assessed by pairs of reviewers. Robins-I (www.methods.cochrane.org) was used for risk of bias assessment in original articles. For systematic reviews, AMSTAR (www.amstar.ca) was used. For certainty of evidence, we used the GRADE system. The systematic review followed PRISMA guidelines. When possible, meta-analyses were performed. Results: The search included 11,767 articles out of which 173 met the inclusion criteria and were included in the qualitative analysis, while 63 were included in quantitative synthesis (meta-analyses). High birth weight and/or LGA was associated with low to moderately elevated risks for certain malignancies in childhood, breast cancer, several psychiatric disorders, hypertension in childhood, and type 1 and 2 diabetes. Conclusions: Although the increased risks for adverse outcome in offspring associated with high birth weight and LGA represent serious health effects in childhood and in adulthood, the size of these effects seems moderate. The identified risk association should, however, be taken into account in decisions concerning fresh and frozen ART cycles and is of general importance in view of the increasing prevalence in high birthweight babies.

The association between the number of oocytes retrieved for IVF, perinatal outcome and obstetric complications.

STUDY QUESTION: Is there an association between the number of oocytes retrieved for IVF, and perinatal and obstetric outcomes? SUMMARY ANSWER: No significant association was found between the number of oocytes retrieved and perinatal outcomes, while an association was found for placenta praevia and male gender. WHAT IS KNOWN ALREADY: Previous studies have shown that between 6 and 15 oocytes retrieved is optimal for the live birth rate in fresh cycles. In a recent study, we showed that the cumulative live birth rate, including fresh and all cryopreservation cycles following one OPU, increases by the number of oocytes retrieved, up to approximately 20 oocytes. However, there was also an increase in serious side effects such as severe ovarian hyperstimulation syndrome (OHSS). A few studies, with contradictory results, have investigated whether the number of oocytes retrieved might also be associated with negative obstetric and perinatal outcomes. STUDY DESIGN, SIZE, DURATION: A retrospective population-based registry study including all singleton babies born after fresh IVF cycles from 2002 to 2015 (n = 27 359) in Sweden. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on treatment characteristics from the Medical Birth/IVF Registry and the Swedish National Quality Registry of Assisted Reproduction, including all fresh IVF cycles performed in public or private infertility clinics during the study period and resulting in singleton deliveries, were cross-linked to the Medical Birth Registry and the National Patient Registry for maternal and neonatal outcome. Data on educational level, ethnicity and paternal age were obtained through cross-linking to Statistics Sweden. Oocyte donation cycles were excluded. Main perinatal outcome variables were preterm birth (PTB <37 gestational weeks), very PTB (<32 gestational weeks), small for gestational age (SGA: <2 SD), peri/neonatal death and major birth defects. Main obstetric outcome variables were hypertensive disorders of pregnancy and placenta praevia. Univariable and multivariable analyses were used to explore the association between the number of oocytes retrieved and outcome variables. Adjustments were performed for maternal age, parity, smoking, BMI, cause of infertility, maternal educational level, maternal country of birth, treatment period, embryo stage, fertilization method (IVF/ICSI), number of embryos transferred, OHSS and vanishing twin. MAIN RESULTS AND THE ROLE OF CHANCE: The number of oocytes retrieved was analyzed as a continuous variable as well as categorized as <10, 10-14, 15-19 and >20 oocytes. A number of between four and nine oocytes was used as a reference. Single embryo transfer was performed in 20 910 (76.4%) of the cycles. Blastocyst transfer was performed in 3478 (12.7%) and cleavage stage embryo transfer was performed in 23 881 (87.3%) of the cycles. No significant association was observed between the number of oocytes retrieved (continuous variable) and PTB (adjusted odds ratio [AOR] 1.002, 95% CI 0.994-1.011), very PTB (AOR 1.013, 95% CI 0.994-1.032), SGA (AOR 0.998, 95% CI 0.988-1.009), peri/neonatal death (AOR 1.008, 95% CI 0.975-1.043) or major birth defects (AOR 1.009, 95% CI 0.998-1.020). Concerning obstetric outcomes, a significant association was found for placenta praevia (AOR 1.021, 95% CI 1.005-1.037) while no association was found for hypertensive disorders of pregnancy (AOR 0.991, 95% CI 0.981-1.001). Furthermore, a significant association was detected between the number of oocytes retrieved and the secondary outcome variable gender distribution, with a higher rate of males after >20 oocytes (AOR 1.126, 95% CI 1.014-1.249). LIMITATIONS, REASONS FOR CAUTION: As in all observational studies, unknown confounders may affect outcomes. WIDER IMPLICATIONS OF THE FINDINGS: These results are reassuring, indicating that there is no association between adverse neonatal outcomes and the number of oocytes retrieved. The association between the number of oocytes and placenta praevia was significant, though weak. The finding of an association with gender should be interpreted with caution. STUDY FUNDING/COMPETING INTEREST(S): Financial support was received through Sahlgrenska University Hospital (ALFGBG-70 940) and the Hjalmar Svensson Research Foundation. None of the authors declares any conflict of interest.

Can de novo stress incontinence after anterior wall repair be predicted?

OBJECTIVE: To locate preoperatively continent women with pelvic organ prolapse at risk of developing incontinence after surgery by means of reducing the prolapse preoperatively with a speculum and a pessary. DESIGN: Prospective observational cohort study. SETTING: Departments of Obstetrics and Gynecology at Northern Alvborgs County Hospital, Varbergs Hospital, and Sahlgrenska University Hospital, Sweden, between 2000 and 2004. POPULATION: Patients scheduled for anterior wall repair with no history of incontinence. METHODS: Data were collected using a questionnaire, a voiding diary, a gynecological examination including staging of prolapse with the Pelvic Organ Quantification System and clinical testing preoperatively and one year after vaginal repair. The first test included a cough test while the prolapse was reduced with a speculum. The second test was performed with the patient undergoing a standardized quantification test and a 48-hour pad test after reducing the prolapse with a pessary. Postoperatively, clinical testing was repeated one year after surgery without any device in place. MAIN OUTCOME MEASURES: Reported symptoms of leakage during movement or coughing. RESULTS: Seventy-four patients were included. Before surgery, six (8.1%) women tested positive during the speculum test and seven (9.5%) during the pessary test. Eight women (10.8%) were found to have subjective urinary stress incontinence after 1 year. This was only confirmed in four women during stress testing. The positive predictive values for subjective stress incontinence of the speculum and the pessary tests were 42.9% (95%CI 12.0-76.9) and 33.3% (95%CI -4.4 to +71.5), respectively. The negative predictive values of the tests were 92.5% (95%CI 90.3-1.00) and 91.1% (95%CI 88.5-99.7). CONCLUSIONS: The tested preoperative methods predicting de novo subjective stress incontinence after anterior wall repair did not show sufficient positive predictive values to be clinically useful.

Hazardous alcohol users during pregnancy: psychiatric health and personality traits.

BACKGROUND: We examined alcohol use disorders, psychiatric symptoms and personality traits in women reporting alcohol use during pregnancy. METHODS: In a pilot cohort (n=139), subjects were screened for alcohol use disorders, and assessed for psychopathology, personality traits, and alcohol use during the first trimester. Those reporting consumption exceeding a conservative threshold for harmful use were offered a diagnostic psychiatric interview. The main findings of the pilot study were replicated using a large sample of women in the third trimester (n=715), who were screened for alcohol use disorders, had their consumption during pregnancy assessed, and were assessed for personality traits. RESULTS: In the pilot cohort, only a minority of women who consumed significant amounts of alcohol during pregnancy fulfilled alcohol dependence criteria, or had scores on the Alcohol Use Disorder Identification Test typically associated with such a diagnosis. Psychiatric morbidity was also unremarkable as assessed by self-reported symptom intensity. The distinguishing feature was high novelty seeking. The results were robustly confirmed in the replication study. CONCLUSIONS: Most women with significant alcohol consumption during pregnancy do not seem to be alcohol dependent. Instead, use during pregnancy may reflect impulsive personality traits, and be correlated with additional risk behaviors.

Identifying hazardous alcohol consumption during pregnancy: implementing a research-based model in real life.

AIMS: It has been repeatedly demonstrated that hazardous alcohol use during pregnancy is rarely detected in regular antenatal care, and that detection can be markedly improved using systematic screening. A major challenge is to translate research-based strategies into regular antenatal care. Here, we examined whether a screening strategy using the Alcohol Use Disorder Test (AUDIT) and time-line follow-back (TLFB) could be implemented under naturalistic conditions and within available resources; and whether it would improve detection to the extent previously shown in a research context. METHODS: Regular midwives at a large antenatal care clinic were randomized to receive brief training and then implement AUDIT and TLFB ("intervention"); or to a waiting-list control group continuing to deliver regular care ("control"). In the intervention-condition, AUDIT was used to collect data about alcohol use during the year preceding pregnancy, and TLFB to assess actual consumption during the first trimester. Data were collected from new admissions over 6 months. RESULTS: Drop out was higher among patients of the intervention group than control midwives, 14% (23/162) versus 0% (0/153), and p<0.0001. A one-day training session combined with continuous expert support was sufficient to implement systematic screening with AUDIT and TLFB largely within resources of regular antenatal care. The use of these instruments identified patients with hazardous consumption during the year preceding pregnancy i.e. AUDIT score 6 or higher (17%, 23/139), and patients with ongoing consumption exceeding 70 g/week and/or binge consumption according to TLFB (17%, 24/139), to a significantly higher degree than regular antenatal screening (0/162). The AUDIT- and TLFB-positive populations overlapped partially, with 36/139 subjects screening positive with either of the instrument and 11/139 were positive for both. CONCLUSIONS: We confirm previous findings that alcohol use during pregnancy is more extensive in Sweden than has generally been realized. Systematic screening using AUDIT and TLFB detects hazardous use in a manner which regular antenatal care does not. This remains true under naturalistic conditions, following minimal training of regular antenatal care staff, and can be achieved with minimal resources. The proposed strategy appears attractive for broad implementation.

Unexpectedly high prevalence of alcohol use among pregnant Swedish women: failed detection by antenatal care and simple tools that improve detection.

OBJECTIVE: We examined the use of alcohol during early pregnancy in urban Swedish women, the ability of Swedish antenatal care to identify alcohol-related risk pregnancies and the utility of some potential tools for improving its performance. METHOD: Women attending regular antenatal care were randomized to regular assessment only (control, n = 156) or intensified screening (intervention, n = 147). In the intervention group, alcohol use was determined using the Timeline Followback (TLFB) interview, alcohol use habits with the Alcohol Use Disorder Inventory Test (AUDIT), and biomarkers for alcohol use were analyzed. Data were typically obtained in pregnancy week 12. RESULTS: In the intervention group as a whole, average absolute alcohol consumption during the first 6 weeks of pregnancy was low but highly variable (mean [SD] = 24.9 [50.5] g/week; 4.8 [6.0] episodes for the entire 6 week period); 22 women (15%) drank at levels exceeding 70 g/week during any 2 or more weeks and/or in a heavy episodic drinking pattern, 60 g/episode, on 2 or more episodes. The AUDIT had a moderate sensitivity (54%) to identify these subjects. Biomarkers identified subjects with somatic illness rather than high alcohol consumption. In the control group, only 4 (3%) were identified as using alcohol, indicating a probable underestimation of alcohol use by regular antenatal screening procedures (p = .0001). CONCLUSIONS: An unexpected proportion of pregnant women in urban Sweden consume alcohol at levels likely to produce adverse effects. Regular antenatal care did not identify most of these risk pregnancies. The TLFB identified pregnant women with risk use of alcohol during pregnancy who were only partly identified by analyzing prepregnancy alcohol use patterns with the AUDIT. Elevated laboratory markers likely indicated somatic illness rather than harmful drinking.

Fetus at risk: prevalence of alcohol consumption during pregnancy estimated with a simple screening method in Swedish antenatal clinics.

AIMS: Maternal alcohol consumption is a major health hazard for the fetus. Sweden has an extensive system of public antenatal care clinics, whose mission is to detect and prevent this type of health hazards. However, very few cases of alcohol consumption during pregnancy are detected. The aim of this study was to examine the prevalence of hazardous or harmful alcohol consumption during pregnancy in a consecutive series of Swedish pregnant females. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: The Alcohol Use Disorders Identification Test (AUDIT) was used to collect anonymous data from consecutive pregnant subjects admitted during 1 year to an antenatal clinic in Stockholm, and signing up for parental education offered routinely (n = 1327). Data were obtained from 1101 subjects, typically in pregnancy week 30. A complete AUDIT form was filled out referring to alcohol use during the year prior to pregnancy. A separate form with the consumption items from AUDIT was filled out to report behaviour during pregnancy. FINDINGS: For the year preceding pregnancy, 17% of subjects reported AUDIT scores of 6 or higher, indicating hazardous or harmful alcohol use in women. Few individuals reported scores of 13 or higher (indicating abuse or dependence), but almost half the subjects (46%) reported binge drinking (six standard drinks on a single occasion) once/month or more often, and 6% reported binge drinking on every occasion of alcohol consumption. One-third of the subjects (30%) continued regular alcohol use during pregnancy, and 6% reported consumption two to four times/month. In a logistic regression model, AUDIT scores for the year prior to pregnancy and subject age, but not education level were significant predictors of continued alcohol use during pregnancy. CONCLUSIONS: Alcohol use during pregnancy is more extensive than has been presumed in Sweden. Simple, clinically useful screening methodology detects hazardous consumption during pregnancy in a manner which regular antenatal care does not. If this methodology can be shown to have similar sensitivity when administered under non-anonymous conditions, it should be made part of routine antenatal care.