EudraCT #: 2008-005452-24. ClinicalTrial.gov: NCT00756028. Trial registration date: 18 September 2008. Date of first patient's enrolment: 14 January 2009.

ObjectiveTo compare the ongoing pregnancy rate between a freeze-all strategy and a fresh transfer strategy in assisted reproductive technology treatment.DesignMulticentre, randomised controlled superiority trial.SettingOutpatient fertility clinics at eight public hospitals in Denmark, Sweden, and Spain.Participants460 women aged 18-39 years with regular menstrual cycles starting their first, second, or third treatment cycle of in vitro fertilisation or intracytoplasmic sperm injection.InterventionsWomen were randomised at baseline on cycle day 2 or 3 to one of two treatment groups: the freeze-all group (elective freezing of all embryos) who received gonadotropin releasing hormone agonist triggering and single frozen-thawed blastocyst transfer in a subsequent modified natural cycle; or the fresh transfer group who received human chorionic gonadotropin triggering and single blastocyst transfer in the fresh cycle. Women in the fresh transfer group with more than 18 follicles larger than 11 mm on the day of triggering had elective freezing of all embryos and postponement of transfer as a safety measure.Main outcome measuresThe primary outcome was the ongoing pregnancy rate defined as a detectable fetal heart beat after eight weeks of gestation. Secondary outcomes were live birth rate, positive human chorionic gonadotropin rate, time to pregnancy, and pregnancy related, obstetric, and neonatal complications. The primary analysis was performed according to the intention-to-treat principle.ResultsOngoing pregnancy rate did not differ significantly between the freeze-all and fresh transfer groups (27.8% (62/223) v 29.6% (68/230); risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.76). Additionally, no significant difference was found in the live birth rate (27.4% (61/223) for the freeze-all group and 28.7% (66/230) for the fresh transfer group; risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.83). No significant differences between groups were observed for positive human chorionic gonadotropin rate or pregnancy loss, and none of the women had severe ovarian hyperstimulation syndrome; only one hospital admission related to this condition occurred in the fresh transfer group. The risks of pregnancy related, obstetric, and neonatal complications did not differ between the two groups except for a higher mean birth weight after frozen blastocyst transfer and an increased risk of prematurity after fresh blastocyst transfer. Time to pregnancy was longer in the freeze-all group.ConclusionsIn women with regular menstrual cycles, a freeze-all strategy with gonadotropin releasing hormone agonist triggering for final oocyte maturation did not result in higher ongoing pregnancy and live birth rates than a fresh transfer strategy. The findings warrant caution in the indiscriminate application of a freeze-all strategy when no apparent risk of ovarian hyperstimulation syndrome is present.Trial registrationClinicaltrials.gov NCT02746562.

14 January 2009.

Study question Does maternal infection with SARS-CoV-2 in first trimester pregnancy have an impact on the fetal development as measured by nuchal translucency thickness and pregnancy loss? Summary answer Nuchal translucency thickness at the first trimester scan was not significantly different in pregnant women with versus without SARS-CoV-2 infection in early pregnancy and there was no significant increased risk of pregnancy loss in women with SARS-CoV-2 infection in the first trimester. What is known already Pregnant women are more vulnerable to viral infections. Previous coronavirus epidemics have been associated with increased maternal morbidity, mortality and adverse obstetric outcomes. Currently, no evidence exists regarding possible effects of SARS-CoV-2 in first trimester pregnancies. Study design, size, duration Cohort study of 1,019 women with a double test taken between Feb. 17 and Apr. 23, 2020, as a part of the combined first trimester risk assessment, and 36 women with a first trimester pregnancy loss between Apr. 14 and May 21, 2020, prior to the double test. The study period was during the first SARS-CoV-2 epidemic wave in Denmark. Participants/materials, setting, methods Cohort 1 included pregnant women with a double test taken within the study period. The excess serum from each double test was analyzed for SARS-CoV-2 antibodies. Results were correlated to the nuchal translucency thickness and the number of pregnancy losses before or at the time of the first trimester scan. Cohort 2 included women with a pregnancy loss before the gestational age for double test sample. Serum from a blood test taken the day the pregnancy loss was identified was analyzed for SARS-CoV-2 antibodies. The study was conducted at a public university hospital serving approximately 12% of pregnant women and births in Denmark. All participants in the study provided written informed consent. Main results and the role of chance Eighteen (1.8%) women had SARS-CoV-2 antibodies in the serum from the double test suggestive of SARS-CoV-2 infection in early pregnancy. There was no significant difference in nuchal translucency thickness for women testing positive for previous SARS-CoV-2 infection (n = 18) versus negative (n = 994) (p = 0.62). There was no significant increased risk of pregnancy loss for women with positive antibodies (n = 1) (OR 3.4, 0.08-24.3 95% CI, p = 0.27). None of the women had been hospitalized due to SARS-CoV-2 infection. None of the women with pregnancy loss prior to the double test (Cohort 2) had SARS-CoV-2 antibodies. Limitations, reasons for caution These results may only apply to similar populations and to patients who do not require hospitalization due to SARS-CoV-2 infection. A limitation of the study is that only 1.8% of the study population had SARS-CoV-2 antibodies suggestive of previous infection. Wider implication of the findings Maternal SARS-CoV-2 infection had no effect on the nuchal translucency thickness and there was no significant increased risk of pregnancy loss for women with SARS-CoV-2 infection in first trimester pregnancy. Evidence concerning Covid-19 in pregnancy is still limited. These data indicate that infection with SARS-CoV-2 in not hospitalized women does not pose a significant threat in first trimester pregnancies. Follow up studies are needed to establish any risk to a fetus exposed to maternal SARS-CoV-2 infection. Study funding/competing interest(s) Prof. Henriette Svarre Nielsen (HSN) and colleagues received a grant from the Danish Government for research of Covid-19 among pregnant women. The Danish government was not involved in the study design, data collection, analysis, interpretation of data, writing of the report or decision to submit the paper for publication. AI, JOL, JBR, DMS, JEF, and ERH received funding from a Novo Nordisk Foundation (NNF) Young Investigator Grant (NNF15OC0016662) and a Danish National Science Foundation Center Grant (6110-00344B). AI received a Novo Scholarship. JOL is funded by an NNF Pregraduate Fellowship (NNF19OC0058982). DW is funded by the NNF (NNF18SA0034956, NNF14CC0001, NNF17OC0027594). AMK is funded by a grant from the Rigshospitalet’s research fund. Henriette Svarre Nielsen has received speakeŕs fees from Ferring Pharmaceuticals, Merck Denmark A/S and Ibsa Nordic (outside the submitted work). Nina la Cour Freiesleben has received a grant from Gedeon Richter (outside the submitted work). Astrid Marie Kolte has received speakeŕs from Merck (outside the submitted work). The other authors did not report any potential conflicts of interest.