Progesterone supplementation in natural cycles improves live birth rates after embryo transfer of frozen-thawed embryos-a randomized controlled trial.

STUDY QUESTION: Does supplementation with vaginal tablets of progesterone after frozen-thawed embryo transfer in natural cycles improve the live birth rate? SUMMARY ANSWER: Supplementation with vaginal tablets of progesterone after frozen-thawed embryo transfer in natural cycles significantly improves the number of live births. WHAT IS KNOWN ALREADY: Progesterone supplementation during luteal phase and early pregnancy may improve the number of live births after frozen-thawed embryo transfer. However, due to the limited number of previous studies, being mainly retrospective, evidence is still limited. STUDY DESIGN, SIZE, DURATION: This is a prospective randomized controlled trial, performed at two university clinics. In total, 500 subjects were randomized with a 1:1 allocation into two groups, during the period February 2013 to March 2018. Randomization was performed after a frozen embryo transfer in a natural cycle by use of opaque sealed envelopes. The primary outcome was live birth rate; secondary outcomes were pregnancy, biochemical pregnancy, clinical pregnancy and miscarriage rate, and if there was a possible association between the serum progesterone concentration on the day of embryo transfer and live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women, receiving embryo transfer in natural cycles participated in the study. The embryos were frozen on Day 2, 3, 5 or 6. In total, 672 women having regular menstrual cycles were invited to participate in the study; of those, 500 agreed to participate and 488 were finally included in the study. Half of the study subjects received progesterone supplementation with progesterone vaginal tablets, 100 mg twice daily, starting from the day of embryo transfer. The other half of the subjects were not given any treatment. Blood samples for serum progesterone measurements were collected from all subjects on the day of embryo transfer. MAIN RESULTS AND THE ROLE OF CHANCE: There were no differences in background characteristics between the study groups. In the progesterone supplemented group, 83 of 243 patients (34.2%) had a live birth, compared to 59 of 245 patients (24.1%) in the control group (odds ratio 1.635, 95% CI 1.102-2.428, P = 0.017*). The number of pregnancies was 104 of 243 (42.8%) and 83 of 245 (33.9%), respectively (odds ratio 1.465, 95% CI 1.012-2.108, P = 0.049*) and the number of clinical pregnancies was 91 of 243 (37.4%) and 70 of 245 (28.6%), respectively (odds ratio 1.497, 95% CI 1.024-2.188, P = 0.043*). There were no significant differences in biochemical pregnancy rate or miscarriage rate. There was no correlation between outcome and serum progesterone concentration. LIMITATIONS, REASONS FOR CAUTION: The study was not blinded because placebo tablets were not available. Supplementation started on embryo transfer day, regardless of the age of the embryos, which resulted in a shorter supplementation time for Day 5/6 embryos compared to Day 2/3 embryos. WIDER IMPLICATIONS OF THE FINDINGS: Supplementation with progesterone in natural cycles improved the number of live births after frozen-thawed embryo transfer and should therefore be considered for introduction in clinical routine. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Uppsala University, the Uppsala-Family Planning Foundation, and Ferring Pharmaceuticals AB, Malmö, Sweden. The authors have no personal conflicting interests to declare. TRIAL REGISTRATION NUMBER: NL4152. TRIAL REGISTRATION DATE: 5 December 2013. DATE OF FIRST PATIENT'S ENROLMENT: 18 February 2013.

Mode of conception in relation to nausea and vomiting of pregnancy: a nested matched cohort study in Sweden.

Nausea and vomiting of pregnancy (NVP) is a common condition reported however inconclusively among pregnancies after assisted conception. The study objective was thus to explore whether NVP is associated to mode of conception or other in vitro fertilization (IVF)-related variables. This nested matched cohort study, originating from the BASIC-project, was conducted at the Uppsala University Hospital in Sweden between 2010 and 2016. IVF pregnancies (n = 210) and age and parity-matched women with spontaneous pregnancies (n = 420) comprised the study sample. The study outcome was self-reported NVP at gestational week 17. IVF treatment and pregnancy data were obtained after scrutinization of the medical records. NVP with or without medications was not associated with mode of conception (chi-square test, p = 0.889), even after adjusting for potential confounders. In a subgroup analysis among IVF pregnancies, NVP without medication was more frequently seen in the group who received cleavage stage embryos vs blastocysts (chi-square test, p = 0.019), exhibiting a marginally significant but strongly increased effect even after adjustment [crude RRR 3.82 (95% CI 1.23-11.92) and adjusted RRR 3.42 (95% CI 0.96-12.11)]. No difference in the rate of NVP with or without medication between women that underwent fresh and frozen/thawed embryo transfers as well as IVF or ICSI was observed. Conception through IVF is not associated with NVP. Transfer of a blastocyst may decrease the risk of developing NVP and further, large-scale prospective studies are required to validate this finding.

Severe obstetric lacerations associated with postpartum depression among women with low resilience - a Swedish birth cohort study.

OBJECTIVE: Women's levels of resilience and attitudes towards perineal lacerations vary greatly. Some women see them as part of the birthing process, while others react with anger, depressed mood or even thoughts of self-harm. A previous study has reported increased risk of postpartum depressive (PPD) symptoms in women with severe perineal lacerations. The aim of this study was to assess the association between severe obstetric perineal lacerations and PPD. A secondary objective was to assess this association among women with low resilience. DESIGN: Nested cohort study. SETTING: Uppsala, Sweden. SAMPLE: Vaginally delivered women with singleton pregnancies (n = 2990). METHODS: The main exposure was obstetric perineal lacerations. Resilience was assessed in gestational week 32 using the Swedish version of the Sense of Coherence Scale. A digital acyclic graph was used to identify possible confounders and mediators. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). A sub-analysis was run after excluding women with normal or high resilience. MAIN OUTCOME MEASURES: Postpartum depression, assessed with the Depression Self-Reporting Scale, completed at 6 weeks postpartum. RESULTS: There was no significant association between severe obstetric perineal lacerations and PPD at 6 weeks postpartum. However, a significant association was found between severe lacerations and PPD in women with low resilience (OR = 4.8, 95% CI 1.2-20), persisting even after adjusting for confounding factors. CONCLUSION: Healthcare professionals might need to identify women with low resilience, as they are at increased risk for PPD after a severe perineal laceration. TWEETABLE ABSTRACT: Severe perineal lacerations associated with postpartum depression in women with low resilience in a Swedish cohort.

Associations between a polymorphism in the hydroxysteroid (11-beta) dehydrogenase 1 gene, neuroticism and postpartum depression.

BACKGROUND: This study examined the association between a single nucleotide polymorphism in the hydroxysteroid (11-beta) dehydrogenase 1 gene and neuroticism, as well as the possible mediatory role of neuroticism in the association between the polymorphism and postpartum depressive symptoms. METHODS: 769 women received questionnaires containing the Edinburgh Postnatal Depression Scale (EPDS) at six weeks postpartum and demographic data at pregnancy week 17 and 32 and at six weeks postpartum, as well as the Swedish universities Scales of Personality at pregnancy week 32. RESULTS: Linear regression models showed an association between the GG genotype and depressive symptoms. When neuroticism was introduced in the model, it was associated with EPDS score, whereas the association between the GG genotype and EPDS became borderline significant. A path analysis showed that neuroticism had a mediatory role in the association between the polymorphism and EPDS score. LIMITATIONS: The use of the EPDS, which is a self-reporting instrument. CONCLUSIONS: Neuroticism was associated with the polymorphism and had a mediatory role in the association between the polymorphism and postpartum depression. This finding elucidates the genetic background of neuroticism and postpartum depression.

Treatment with serotonin reuptake inhibitors during pregnancy is associated with elevated corticotropin-releasing hormone levels.

Treatment with serotonin reuptake inhibitors (SSRI) has been associated with an increased risk of preterm birth, but causality remains unclear. While placental CRH production is correlated with gestational length and preterm birth, it has been difficult to establish if psychological stress or mental health problems are associated with increased CRH levels. This study compared second trimester CRH serum concentrations in pregnant women on SSRI treatment (n=207) with untreated depressed women (n=56) and controls (n=609). A secondary aim was to investigate the combined effect of SSRI treatment and CRH levels on gestational length and risk for preterm birth. Women on SSRI treatment had significantly higher second trimester CRH levels than controls, and untreated depressed women. CRH levels and SSRI treatment were independently associated with shorter gestational length. The combined effect of SSRI treatment and high CRH levels yielded the highest risk estimate for preterm birth. SSRI treatment during pregnancy is associated with increased CRH levels. However, the elevated risk for preterm birth in SSRI users appear not to be mediated by increased placental CRH production, instead CRH appear as an independent risk factor for shorter gestational length and preterm birth.

Personality and risk for postpartum depressive symptoms.

Postpartum depression (PPD) is a common childbirth complication, affecting 10-15 % of newly delivered mothers. This study aims to assess the association between personality factors and PPD. All pregnant women during the period September 2009 to September 2010, undergoing a routine ultrasound at Uppsala University Hospital, were invited to participate in the BASIC study, a prospective study designed to investigate maternal well-being. Depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale (EPDS) while the Depression Self-Rating Scale (DSRS) was used as a diagnostic tool for major depression. Personality traits were evaluated using the Swedish Universities Scale of Personality (SSP). One thousand thirty-seven non-depressed pregnant women were included in the study. Non-depressed women reporting high levels of neuroticism in late pregnancy were at high risk of developing postpartum depressive symptoms (PPDSs) at 6 weeks and 6 months after delivery, even after adjustment for confounders (adjusted odds ratio (aOR) = 3.4, 95 % confidence interval (CI) 1.8-6.5 and adjusted odds ratio (aOR) = 3.9, 95 % CI 1.9-7.9). The same was true for a DSRS-based diagnosis of major depression at 6 months postpartum. Somatic trait anxiety and psychic trait anxiety were associated with increased risk for PPDS at 6 weeks (aOR = 2.1, 95 % CI 1.2-3.5 and aOR = 1.9, 95 % CI 1.1-3.1), while high scores of mistrust were associated with a twofold increased risk for PPDS at 6 months postpartum (aOR 1.9, 95 % CI 1.1-3.4). Non-depressed pregnant women with high neuroticism scores have an almost fourfold increased risk to develop depressive symptoms postpartum, and the association remains robust even after controlling for most known confounders. Clinically, this could be of importance for health care professionals working with pregnant and newly delivered women.