Jesper Friis Petersen

Vaginal bleeding in the first trimester indicates threatened pregnancy loss and may be due to progesterone insufficiency. Vaginal micronised progesterone (400 mg vaginal tablets twice a day) can increase live birth rates and is recommended for women with threatened pregnancy loss and a history of three or more losses (number needed to treat = 8). It should be considered for women with one (number needed to treat = 20) or two losses. Insufficient data exist to recommend other treatments such as tranexamic acid and bed rest.

BACKGROUND: The ovarian response to gonadotropin stimulation varies widely among women, and could impact the probability of live birth as well as treatment risks. Many studies have evaluated the impact of different gonadotropin starting doses, mainly based on predictive variables like ovarian reserve tests (ORT) including anti-Müllerian hormone (AMH), antral follicle count (AFC), and basal follicle-stimulating hormone (bFSH). A Cochrane systematic review revealed that individualizing the gonadotropin starting dose does not affect efficacy in terms of ongoing pregnancy/live birth rates, but may reduce treatment risks such as the development of ovarian hyperstimulation syndrome (OHSS). An individual patient data meta-analysis (IPD-MA) offers a unique opportunity to develop and validate a universal prediction model to help choose the optimal gonadotropin starting dose to minimize treatment risks without affecting efficacy. OBJECTIVE AND RATIONALE: The objective of this IPD-MA is to develop and validate a gonadotropin dose-selection model to guide the choice of a gonadotropin starting dose in IVF/ICSI, with the purpose of minimizing treatment risks without compromising live birth rates. SEARCH METHODS: Electronic databases including MEDLINE, EMBASE, and CRSO were searched to identify eligible studies. The last search was performed on 13 July 2022. Randomized controlled trials (RCTs) were included if they compared different doses of gonadotropins in women undergoing IVF/ICSI, presented at least one type of ORT, and reported on live birth or ongoing pregnancy. Authors of eligible studies were contacted to share their individual participant data (IPD). IPD and information within publications were used to determine the risk of bias. Generalized linear mixed multilevel models were applied for predictor selection and model development. OUTCOMES: A total of 14 RCTs with data of 3455 participants were included. After extensive modeling, women aged 39 years and over were excluded, which resulted in the definitive inclusion of 2907 women. The optimal prediction model for live birth included six predictors: age, gonadotropin starting dose, body mass index, AFC, IVF/ICSI, and AMH. This model had an area under the curve (AUC) of 0.557 (95% confidence interval (CI) from 0.536 to 0.577). The clinically feasible live birth model included age, starting dose, and AMH and had an AUC of 0.554 (95% CI from 0.530 to 0.578). Two models were selected as the optimal model for combined treatment risk, as their performance was equal. One included age, starting dose, AMH, and bFSH; the other also included gonadotropin-releasing hormone (GnRH) analog. The AUCs for both models were 0.769 (95% CI from 0.729 to 0.809). The clinically feasible model for combined treatment risk included age, starting dose, AMH, and GnRH analog, and had an AUC of 0.748 (95% CI from 0.709 to 0.787). WIDER IMPLICATIONS: The aim of this study was to create a model including patient characteristics whereby gonadotropin starting dose was predictive of both live birth and treatment risks. The model performed poorly on predicting live birth by modifying the FSH starting dose. On the contrary, predicting treatment risks in terms of OHSS occurrence and management by modifying the gonadotropin starting dose was adequate. This dose-selection model, consisting of easily obtainable patient characteristics, aids in the choice of the optimal gonadotropin starting dose for each individual patient to lower treatment risks and potentially reduce treatment costs.

This study aimed to develop a dynamic model for predicting outcome during the first trimester of pregnancy using baseline demographic data and serially collected blood samples and transvaginal sonographies. A prospective cohort of 203 unselected women with an assumed healthy pregnancy of < 8 weeks’ gestation was followed fortnightly from 4–14 weeks’ gestation until either miscarriage or confirmed first trimester viability. The main outcome was development of a model to predict outcome from gestational age-dependent hazard ratios using both baseline and updated serial data from each visit. Secondary outcomes were descriptions of risk factors for miscarriage. The results showed that 18% of the women experienced miscarriages. A fetal heart rate detected before 8 weeks’ gestation indicated a 90% (95% CI 85–95%) chance of subsequent delivery. Maternal age (≥ 35 years), insufficient crown-rump-length (CRL) and mean gestational sac diameter (MSD) development, and presence of bleeding increased the risk of miscarriage. Serum biomarkers, including hCG, progesterone, and estradiol, were found to impact the risk of miscarriage with estradiol as the most important. The best model to predict miscarriage was a combination of maternal age, vaginal bleeding, CRL, and hCG. The second-best model was the sonography-absent model of maternal age, bleeding, hCG, and estradiol. This study suggests that combining maternal age, and evolving data from hCG, estradiol, CRL, and bleeding could be used to predict fetal outcome during the first trimester of pregnancy.Trial registration ClinicalTrials.gov identifier: NCT02761772.

This study aimed to develop a dynamic model for predicting outcome during the first trimester of pregnancy using baseline demographic data and serially collected blood samples and transvaginal sonographies. A prospective cohort of 203 unselected women with an assumed healthy pregnancy of <8 weeks’ gestation was followed fortnightly from 4–14 weeks’ gestation until either miscarriage or confirmed first trimester viability. The main outcome was development of a model to predict viability from gestational age-dependent fetal viability hazard ratios using both baseline and updated serial data from each visit. Secondary outcomes were risk factors for miscarriage. The results showed that 18% of the women experienced miscarriages. A fetal heart rate detected before 8 weeks’ gestation indicated a 90% (95%CI 85–95%) chance of subsequent delivery. Maternal age (≥35 years), insufficient crown-rump-length (CRL) and mean gestational sac diameter (MSD) development, and presence of bleeding increased the risk of miscarriage. Serum biomarkers, including hCG, progesterone, and estradiol, were found to impact the risk of miscarriage with estradiol as the most important. The best model to predict miscarriage was a combination of maternal age, vaginal bleeding, CRL, and hCG. The second-best model was the sonography-absent model of maternal age, bleeding, hCG, and estradiol. This study suggests that combining maternal age, and evolving data from hCG, estradiol, CRL, and bleeding could be used to predict fetal viability during the first trimester of pregnancy. Trial registration: ClinicalTrials.gov identifier: NCT02761772

Background: Pregnancy introduces major physiological changes that also alter biochemical analytes. Maternal and perinatal health can be optimized by early intervention and therefore, pregnancy-specific reference intervals (RIs) for the local population are warranted. While the second and third trimester-specific changes are well described, the first trimester is less well characterized. We therefore wanted to facilitate early detection of abnormalities by generating first trimester reference values for 29 common analytes. Methods: In a prospective early pregnancy (PEP) cohort (2016–2017), 203 pregnant women were recruited from 4 to 8 weeks’ gestation. Consecutive blood samples were drawn every 2 weeks until an ongoing second trimester pregnancy (n = 164) or a miscarriage (n = 39) occurred. After exclusion of women with complicated pregnancies or deliveries (n = 42), 122 women were included. The serum samples collected at 12 weeks’ gestation were analyzed for 29 common analytes. Subsequently the RIs were calculated according to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) recommendations (2.5–97.5th percentiles) and compared with the conventional RIs for non-pregnant women. Results: Human chorionic gonadotropin (hCG), progesterone (P4), estradiol (E2), pregnancy-associated plasma protein A (PAPP-A), cancer antigen 125 (CA125), thyroid stimulating hormone (TSH), creatinine (CREA) and albumin (ALB) showed an early pregnancy-dependent change compared with conventional limits. For ALB the change was seen at 5.5 weeks’ gestation. Conclusions: We report gestational age-specific RIs available from the early part of the first trimester applicable to everyday clinical care of pregnant women. Well-known alterations of RIs seen in later trimesters are also observed in the first.

The concept of sensory delivery rooms was introduced in 2013. These rooms offer programmable calming lights, restful blurred pictures displayed on a wall-sized big screen, and sound effects. The primary aim of this observational study was to analyse the risk of obstetrical interventions among women giving birth for the first-time in a sensory delivery room vs. a standard delivery room. We included nulliparous, term pregnant women having a single baby with a cephalic presentation who were in spontaneous labour and gave birth between March 1^st 2014 and July 1^st 2015 in North Zealand Hospital, Hillerød. A total of 789 women were included in the study, 313 gave birth in a sensory room and 476 in a standard delivery room. The risk of a caesarean delivery was significantly decreased when giving birth in a sensory room compared with a standard delivery room (OR, multiple adjusted: 0.44; 95% CI 0.22–0.87); furthermore, the use of oxytocin infusion was also reduced (OR, multiple adjusted: 0.71; 95% CI 0.50–1.03). This observational cohort study suggests that giving birth in a sensory delivery room could lower the risk of caesarean delivery, potentially reducing the number of such deliveries by one for every 23 patients.

Does an individualized serum anti-Müllerian hormone (AMH) based FSH dosing algorithm used in a GnRH antagonist protocol increase the proportion of patients with an intended number of oocytes (5–14) retrieved compared with a standard regimen? The AMH-based individualized algorithm did not increase the proportion of patients with an intended oocyte retrieval. Individualizing treatment for ovarian stimulation by serum AMH or antral follicle count can theoretically improve the ratio between benefits and risks. Current data suggest that there may be a reduced risk of ovarian hyperstimulation syndrome (OHSS), but without improved pregnancy or live birth rates. Only two randomized controlled trials (RCTs) have examined the potential of AMH-based algorithms to optimize the FSH dosing in ovarian stimulation. A dual-center open-label investigator-driven RCT was conducted between January 2013 and November 2016. Eligibility was assessed in 269 women and 221 were randomized 2:1 between individualized and standard dosing groups. Women with pretreatment serum AMH > 24 pmol/L had 100 IU/day of recombinant FSH (rFSH); AMH 12–24 pmol/L had 150 IU/day of rFSH, and AMH < 12 pmol/L had maximal stimulation with corifollitropin 100 or 150 mg depending on bodyweight ±60 kg. The standard group had 150 IU/day of rFSH irrespective of pretreatment AMH. All patients followed the GnRH-antagonist protocol. The sample size calculation assumed that individualized dosing by AMH would reduce the proportion of unintended oocyte yield (outside the 5–14 range) by 50%, from 35 to 17.5%. In a 2:1 randomization this required 216 patients: 144 in the individualized and 72 patients in the standard group (80% power, 5% significance). All women had a presumed ovulatory normal menstrual cycle, were aged 25–38 years, weighed < 75 kg, had pretreatment AMH 4–40 pmol/L, did their first IVF or ICSI cycle and had two ovaries accessible to oocyte retrieval. Recruitment was conducted from both participating sites. Women were excluded if diagnosed with anovulatory polycystic ovary syndrome, endometriosis grade III/IV, hydrosalpings on ultrasound, recurrent miscarriages (≥3), FSH > 12 IU/L or major medical disorders. After randomization 149 women were allocated to the individualized group and 72 to the standard group. The primary outcome of women with an intended (5–14) number of oocytes retrieved was similar in the individualized (n = 105) versus the standard (n = 55) rFSH treatment group (72% [95% CI 64–79%] versus 78% [95% CI 67–86%], respectively, P = 0.68, between group standardized mean difference (SMD) −6%, 95% CI: −19–8%). In the high AMH stratum of the individualized group, significantly more women (n = 13) had an unintended low number of oocytes (P = 0.029, between group SMD 32%, 95% CI: 9–56%). Conversely, in the low pretreatment AMH stratum, individualized dosing using corifollitropin reduced the proportion of unintended low responders to 24% (95% CI: 12–40%) compared with 47% (95% CI: 26–69%) in the standard group, P = 0.10, between group SMD −23% (95% CI: −54–8%). OHSS was diagnosed in four women (two in each study arm), and all cases were mild. Daily luteal phase questionnaire reporting showed similar wellbeing in terms of abdominal distention, abdominal pain, dyspnea and occurrence of bleeding between groups. The cumulative live birth rate per started cycle was similar (32 and 35%) comparing the individualized with the standard group. This study was powered for showing differences only in the distribution of oocyte retrieval when comparing individualized and standard groups, therefore additional results should be viewed with caution. In addition, there was a change of AMH assay halfway through the study period and the possibility that corifollitropin being introduced to a subgroup of the intervention has introduced confounding cannot be ruled out. In the expected high responder AMH stratum, 100 IU/day is an insufficient rFSH dose in a high proportion of patients. Further research might explore the 125 IU/day dose for the high AMH segment. None for the submitted work. ICMJE declared personal interests for two of the authors. EUDRACT registration number: 2012-004969-40. 27 November 2012. 10 January 2013.