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.

Survey shows that Swedish healthcare professionals have a positive attitude towards surrogacy but the health of the child is a concern.

AIM: In February 2016, Sweden upheld its ban on surrogacy following a Government enquiry. This survey investigated attitudes towards surrogacy among primary health professionals working with children and their experiences of working with families following surrogacy abroad. METHODS: From April to November 2016, nurses, physicians and psychologist working in primary child health care in four counties in Sweden were invited to participate in a cross-sectional online survey about surrogacy. RESULTS: The mean age of the 208 participants was 49.2 years (range 27-68) and nearly 91% were women. Approximately 60% supported legalised surrogacy. Wanting a conscience clause to be introduced in Sweden was associated with not supporting surrogacy for any groups, while personal experiences of infertility and clinical experiences with families following surrogacy were associated with positive attitudes towards surrogacy for heterosexual couples. The majority (64%) disagreed that surrogate children were as healthy as other children, and many believed that they risked worse mental health (21%) and social stigmatisation (21%). CONCLUSION: We found that 60% supported legalised surrogacy, but many expressed concerns about the children's health and greater knowledge about the medical and psychosocial consequences of surrogacy is needed.

Anxiety and depression symptoms among sub-fertile women, women pregnant after infertility treatment, and naturally pregnant women.

BACKGROUND: Infertility has been associated with psychological distress, but whether these symptoms persist after achieving pregnancy via assisted reproductive technology (ART) remains unclear. We compared the prevalence of anxiety and depressive symptoms between women seeking for infertility treatment and women who conceived after ART or naturally. METHODS: Four hundred and sixty-eight sub-fertile non-pregnant women, 2972 naturally pregnant women and 143 women pregnant after ART completed a questionnaire in this cross-sectional study. The Anxiety subscale of the Hospital Anxiety and Depression Scale (HADS-A≥8) and Edinburgh Postnatal Depression Scale (EPDS≥12) were used for assessing anxiety and depressive symptoms, respectively. Multivariate Poisson regression models with robust variance were applied to explore associations with anxiety and depressive symptoms. RESULTS: The prevalence of anxiety and depressive symptoms among sub-fertile, non-pregnant women (57.6% and 15.7%, respectively) were significantly higher compared to women pregnant after ART (21.1% and 8.5%, respectively) and naturally pregnant women (18.8% and 10.3%, respectively). History of psychiatric diagnosis was identified as an independent risk factor for both anxiety and depressive symptoms. The presence of at least one unhealthy lifestyle behavior (daily tobacco smoking, weekly alcohol consumption, BMI≥25, and regular physical exercise<2h/week) was also associated with anxiety (Prevalence Ratio, PR: 1.24; 95%CI: 1.09-1.40) and depressive symptoms (PR: 1.25; 95%CI: 1.04-1.49). CONCLUSIONS: Women pregnant after ART showed no difference in anxiety and depressive symptoms compared to naturally pregnant women. However, early psychological counseling and management of unhealthy lifestyle behaviors for sub-fertile women may be advisable, particularly for women with a previous history of psychiatric diagnosis.

Folic acid supplementation and IVF pregnancy outcome in women with unexplained infertility.

Folic acid supplements are commonly used by infertile women which leads to a positive folate status. However, the effect of folic acid supplements on pregnancy outcome in women with unexplained infertility has not been well investigated. This study evaluated folic acid supplement use and folate status in women with unexplained infertility in relation to IVF pregnancy outcome. In addition, use of folic acid supplements and folate status were compared between women with unexplained infertility and fertile, nonpregnant control women. Women with unexplained infertility used significantly more folic acid supplements and had higher median total folic acid intake from supplements compared with fertile control women (both P < 0.001). Women with unexplained infertility also had significantly higher median plasma folate and lower median plasma homocysteine concentrations than fertile women (both P < 0.001), but folic acid supplementation or folate status were not related to pregnancy outcome in women with unexplained infertility. In conclusion, folic acid supplementation or good folate status did not have a positive effect on pregnancy outcome following infertility treatment in women with unexplained infertility. Folate is one of the B vitamins which has been suggested to be related to infertility. Folic acid is an artificial form of folate which is commonly used in dietary supplements. Folic acid supplementation has been shown to increase folate concentrations and decrease concentrations of the amino acid homocysteine in the blood. Folic acid supplementation is commonly used by infertile women, but the effect on pregnancy outcome in women with a diagnosis of unexplained infertility has not been thoroughly investigated. In the present study, folic acid supplement use and folate status (concentrations of folate and homocysteine) in women with unexplained infertility were evaluated in relation to pregnancy outcome. In addition, the use of folic acid supplements and folate status were compared between women with unexplained infertility and fertile control women. Our results showed that women with unexplained infertility used considerably more folic acid supplements and had higher total folic acid intake from supplements compared with fertile control women. Women with unexplained infertility had better blood folate and homocysteine concentrations than fertile women, but folic acid supplementation or folate status were not related to pregnancy outcome following the infertility treatment. In conclusion, high folic acid intake or good folate status did not increase the possibility of a birth of a healthy baby after infertility treatment in women with unexplained infertility.

Attitudes towards embryo donation among infertile couples with frozen embryos.

STUDY QUESTION: What are the attitudes towards different aspects of embryo donation among Swedish infertile couples who have surplus cryopreserved embryos? SUMMARY ANSWER: Nearly three-quarters of infertile couples with surplus embryos were in favour of embryo donation. A majority of respondents were also in favour of embryos being donated for research. WHAT IS KNOWN ALREADY: Currently, embryo donation to other infertile couples is prohibited by law in Sweden. Encouraging results have been published from countries allowing embryo donation, although it is a complex procedure associated with many emotional, ethical, legal and psychosocial aspects. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included 471 infertile couples (942 patients) treated during the period March 2006 to March 2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile couples who had been treated at a Swedish university-based hospital and private IVF clinic and who had cryopreserved embryos were sent questionnaires with questions regarding socio-demographic data and their attitudes towards embryo donation. MAIN RESULTS AND THE ROLE OF CHANCE: The response rate to the questionnaire was 58%. Of the respondents, 76% supported the donation of surplus embryos to other infertile couples, but there were divided opinions regarding the disclosure of the genetic parents' identities. Close to 60% of the participants indicated that donations of embryos should be allowed for research and about 45% of the participants approved donations of embryos to single women. LIMITATIONS, REASONS FOR CAUTION: The relatively low response rate and the hypothetical nature of the questions may limit the validity of the results. WIDER IMPLICATIONS OF THE FINDINGS: The results from the study indicate that cryopreserved embryos may be available for donation to other infertile couples, particularly where restrictions can be set on recipient characteristics.

Regulation of muscular contractions in the human Fallopian tube through prostaglandins and progestagens.

BACKGROUND: Transport of gametes and embryos is an important function of the Fallopian tube. Both muscular contractions and cilia activity are involved in the transportation. Prostaglandins (PGs) are known mediators of muscular contractility. PG receptors have previously been demonstrated in the human Fallopian tube. The aim was to study the effect of PGs and progestagens, antiprogestin, hCG and oxytocin on muscular contractions in the human Fallopian tube, and the hormonal regulation of PG receptors. METHODS: Twenty-two healthy women operated for benign causes were included in the study. The ampullary-isthmic junction of the Fallopian tubes was excised and used for in vitro contractility studies. The effect of PGE(1), PGE(2), PGF(2alpha), progesterone, mifepristone, levonorgestrel, oxytocin and hCG on contractility was studied. Explants of Fallopian tubes were cultured for 24 h to study the effect of progestagens and hCG on the expression of PG receptors using immunohistochemistry and real-time PCR. RESULTS: Muscular contractions increased after treatment with PGF(2alpha) and PGE(2) (P < 0.05). The contractions decreased after PGE(1), progesterone, levonorgestrel, mifepristone, oxytocin and hCG (P < 0.05). In tubal explant studies, relative mRNA expression of EP1, EP2, EP3 and FP increased after levonorgestrel treatment (P < 0.05). Mifepristone and levonorgestrel treatment increased immunostaining intensity of EP1 and EP2 protein, in lumen, muscle and vessels. Progesterone and mifepristone increased immunostaining of FP in vessels. CONCLUSIONS: These data suggest that the transport of gametes and embryos involves the action of PGs, progesterone, oxytocin and hCG on muscular contractility.

Leukaemia inhibitory factor receptor and gp130 in the human Fallopian tube and endometrium before and after mifepristone treatment and in the human preimplantation embryo.

Leukaemia inhibitory factor (LIF) is a cytokine, which is associated with reproductive processes such as embryo development and implantation. The objectives of this study were to detect the presence of LIF receptor (LIFR) and glycoprotein 130 (gp 130) in the human Fallopian tube, endometrium and preimplantation embryo and to study the effect of mifepristone on the expression of LIFR and gp130 in the Fallopian tube. Twenty-two healthy fertile women received a single dose of 200 mg mifepristone or placebo immediately after ovulation (LH + 2). Biopsies were obtained from the Fallopian tubes during laparoscopic sterilization once between days LH + 4 and LH + 6 and from endometrium once between days LH + 6 and LH + 8. Preimplantation embryos were received from couples undergoing in vitro fertilization treatment. Immunohistochemistry was used to detect the presence of LIFR and gp130 in the Fallopian tube, endometrium and preimplantation embryo. Real-time PCR was used to study LIFR and gp130 expression in the Fallopian tube and endometrium. LIFR and gp130 were localized in the Fallopian tube, preimplantation embryo and endometrium. LIFR was more abundant in the Fallopian tube than in the endometrium. In the blastocyst, the staining of gp130 was mainly localized in the inner cell mass, whereas LIFR was expressed in all cells. The presence of LIFR and gp130 in the Fallopian tube and preimplantation embryo indicates a role for LIF in communication between the embryo and the Fallopian tube. Mifepristone did not affect the expression of LIFR and gp130 in the Fallopian tube, nor in the endometrium suggesting that progesterone might not be directly involved in the regulation of LIFR or gp130.