Expanding the phenotypic spectrum of ARCN1-related syndrome.

PURPOSE: This study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome. METHODS: Patients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. RESULTS: In total, we identified 14 cases of ARCN1-related syndrome, (9 pediatrics, and 5 fetal cases from 3 families). The clinical features these newly identified cases were compared to 6 previously reported cases for a total of 20 cases. Intrauterine growth restriction, micrognathia, and short stature were present in all patients. Other common features included prematurity (11/15, 73.3%), developmental delay (10/14, 71.4%), genitourinary malformations in males (6/8, 75%), and microcephaly (12/15, 80%). Novel features of ARCN1-related syndrome included transient liver dysfunction and specific glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, cataracts, and lethal skeletal manifestations. Developmental delay was seen in 73% of patients, but only 3 patients had intellectual disability, which is less common than previously reported. CONCLUSION: ARCN1-related syndrome presents with a wide clinical spectrum ranging from a severe embryonic lethal syndrome to a mild syndrome with intrauterine growth restriction, micrognathia, and short stature without intellectual disability. Patients with ARCN1-related syndrome should be monitored for liver dysfunction during illness, cataracts, and hepatoblastoma. Additional research to further define the phenotypic spectrum and possible genotype-phenotype correlations are required.

Customized Frozen Embryo Transfer after Identification of the Receptivity Window with a Transcriptomic Approach Improves the Implantation and Live Birth Rates in Patients with Repeated Implantation Failure.

The aim of this prospective study was to evaluate outcome benefits expected in repeated implantation failure (RIF) patients (n = 217) after customized embryo transfer based upon identification of the receptivity window by transcriptomic approach using the Win-Test. In this test, the expression of 11 endometrial genes known to be predictive of endometrial receptivity is assessed by RT-PCR in biopsies collected during the implantation window (6-9 days after the spontaneous luteinizing hormone surge during natural cycles, 5-9 days after progesterone administration during hormone replacement therapy cycles). Then, patients underwent either customized embryo transfer (cET, n = 157 patients) according to the Win-Test results or embryo transfer according to the classical procedure (control group, n = 60). Pregnancy and live birth rates were compared in the two groups. The Win-Test showed that in 78.5% of women, the receptivity window lasted less than 48 h, although it could be shorter (< 24 h, 9.5%) or longer (> 48 h, 12%). This highlighted that only in 20% of patients with RIF the endometrium would have been receptive if the classical embryo transfer protocol was followed. In the other 80% of patients, the receptivity window was delayed by 1-3 days relative to the classical timing. This suggests that implantation failure could be linked to inadequate timing of embryo transfer. In agreement, both implantation (22.7% vs. 7.2%) and live birth rates per patient (31.8% vs. 8.3%) were significantly higher in the cET group than in the control group. cET on the basis of the Win-Test results could be proposed to improve pregnancy and live birth rates.ClinicalTrials.gov ID: NCT04192396; December 5, 2019, retrospectively registered.

Luteal phase progesterone supplementation following induced natural cycle frozen embryo transfer: A retrospective cohort study.

INTRODUCTION: The objective of this study was to assess the impact on the clinical pregnancy rate of luteal phase progesterone treatment in patients being prepared for natural cycle frozen embryo transfer (FET) with induced ovulation. MATERIAL AND METHODS: This retrospective cohort study collect all the FET protocols over a 6-month period at Strasbourg University Hospital fertility unit between December 2016 and May 2017. In total 293 consecutive patients with regular menstrual cycles were prepared for natural cycle FET during this period. All patients had an embryo cryopreservation secondary to in vitro fertilisation (IVF) or by intracytoplasmic sperm injection (ICSI). There were 2 protocols during this period and patients either received or did not received progesterone. Ovulation was routinely triggered in all patients by injection of choriogonadotrophin alfa. Patients in the treated group received vaginal natural micronized progesterone treatment of 400mg daily, starting on the day of ovulation. The principal assessment criterion was the occurrence of pregnancy. RESULTS: In total, 231 patients were analysed: 108 in the group not receiving progesterone and 123 in the group receiving progesterone. Patient characteristics were comparable between groups. A higher clinical pregnancy rate (39% vs. 24.1%, p=0.02; 95CI [1.10; 3.74]) was recorded in the treated group. CONCLUSIONS: Our results suggest that luteal phase support with vaginal progesterone statistically increases the clinical pregnancy rate following hCG-triggered natural cycle FET and that it should be used more widely.

Pregnancy outcome in Turner syndrome: A French multi-center study after the 2009 guidelines.

OBJECTIVE: This study aimed to assess the application of the French guidelines for pregnancies in Turner syndrome (TS) and their impact on perinatal prognosis. STUDY DESIGN: We performed a French multi-center retrospective study (14 centers), including TS pregnant patients (spontaneously or by Assisted Reproductive Technology (ART)) between January 2006 and July 2017. Only clinical pregnancies were analyzed. The adjustment of medical follow-up modalities to French guidelines was evaluated for all pregnancies after 2009. Pregnancies from oocyte donation (OD) after 2009 were compared to those of a cohort of TS pregnancies obtained by OD before 2009, which were reported by the French Study Group for Oocyte Donation. RESULTS: One hundred seventy pregnancies in 103 patients were included: 35 spontaneous, 5 by means of intra-conjugal ART, and 130 with OD. No serious maternal complications were observed. We reported two stillbirths and one intra uterine fetal death. The French guidelines were partially respected. The preconceptional assessment was carried out in 74% of cases. Cardiology follow-up during pregnancy was performed in accordance with guidelines in 74% of patients. Postpartum cardiac ultrasonography was performed in 45% of pregnancies but only in 11% within 8 days post-partum. When compared to the 2009 historical cohort, the rates of high blood pressure (19% vs. 38%; p < 0.005) pre-eclampsia (8% vs. 21%; p < 0.005) and prematurity <35 weeks (15% vs 38%; p < 0.0001) were lower. CONCLUSIONS: The implementation of guidelines has allowed the standardization of TS pregnancy care and improved perinatal indicators for both mothers and children. However, an effort must be done, in a postpartum survey.

Hypertensive pathologies and egg donation pregnancies: Results of a large comparative cohort study.

OBJECTIVE: To determine whether egg donation (ED) pregnancies are at higher risk of pregnancy-induced hypertension (PIH) than those achieved by autologous assisted reproductive technology (ART; controls). DESIGN: Anonymous comparative observational matched cohort study. SETTING: Assisted reproductive technology centers. PATIENT(S): Two hundred seventeen ED and 363 control singleton pregnancies matched at 7-8 weeks (pregnancy date, parity, cycle type [fresh/frozen] and women's age). According to French practice, all women were under 45. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Percentage of PIH for ED versus controls. RESULT(S): The groups were comparable (mean age, 34.5). PIH was more frequent during ED pregnancies (17.8% vs. 5.3%), as was preeclampsia (11.2% vs. 2.8%) and eclampsia (1.8% vs. 0.0%). In multivariate analyses, PIH risk increased with ED (odds ratio [OR], 3.92; 95% confidence interval [CI], 1.93-7.97) and women's age (OR, 1.08; 95% CI, 1.00-1.16). No significant effect of previous pregnancies or cycle rank/type was observed. CONCLUSION(S): This study had sufficient power to detect doubling of the PIH rate. It was demonstrated that the risk of PIH was tripled for ED versus controls. Even in young women, ED is a risk factor for PIH. An immunological explanation seems most likely, that is, the fetus is fully allogeneic to its mother. This risk must be acknowledged to inform couples and provide careful pregnancy monitoring.

Materno-fetal cardiovascular complications in Turner syndrome after oocyte donation: insufficient prepregnancy screening and pregnancy follow-up are associated with poor outcome.

CONTEXT: Recombinant human GH treatment and oocyte donation (OD) have improved the quality of life in women with Turner syndrome (TS). However, life expectancy is reduced, mainly due to cardiovascular complications. Pregnancy may itself increase that risk and be associated with hazardous materno-fetal outcome. OBJECTIVE: The objective of this study was to evaluate the materno-fetal outcome of ongoing pregnancies beyond 20 wk of gestation obtained by OD in TS. DESIGN: This was a multicenter retrospective study including all assisted reproductive technology centers affiliated with the French Study Group for Oocyte Donation. RESULTS: Among 93 patients, only 37.6% were prescreened with echocardiography or thoracic magnetic resonance imaging. Maternal outcome was dominated by 37.8% of pregnancy-associated hypertensive disorders including preeclampsia in 54.8% and severe eclampsia in four patients. Prematurity occurred in 38.3% and was correlated with pregnancy-associated hypertensive disorder (P = 0.01). The frequency of in utero growth retardation was 27.5%. One fetal demise was linked to eclampsia. Two patients died from aortic rupture after cesarean section in a context of aortic root dilatation. Only 40% of pregnancies were associated with an absolutely normal materno-fetal outcome. CONCLUSIONS: OD pregnancies in TS who have not been managed following recent specific recommendations were at high risk for maternal death by aortic dissection and for preeclampsia and its complications (fetal distress and in utero growth retardation). These recommendations include previous echocardiography, thoracic magnetic resonance imaging, and overnight blood pressure monitoring associated with a tight follow-up during pregnancy. Until future assessment of these recent recommendations, pregnancies obtained in TS after OD must be still considered as very high-risk pregnancies.

Turner syndrome and pregnancy: clinical practice. Recommendations for the management of patients with Turner syndrome before and during pregnancy.

Following the death in France by acute aortic dissection of two women with Turner syndrome who were pregnant following oocyte donation, the Director of the French Biomedicine Agency (Agence de la biomédecine) sent a letter to the President of the French College of Obstetricians and Gynaecologists (FCOG). He requested the College's expertise in reviewing point-by-point the cases and risk factors and in determining whether there are grounds to propose additional measures complementary to the recommendations made by the Haute autorité de santé or French National Authority for Health (HAS) in 2008 in terms of indication and monitoring of patients. A joint practice committee of the FCOG, the French Cardiologic Society, the French Chest and Cardiovascular Surgery Society, the French Society of Anaesthesia and Intensive Care, the French Endocrine Society, the French study group for oocyte donation, and the Biomedicine Agency defined the exact questions to be put to the experts, chose these experts, followed them up and drafted the synthesis of recommendations resulting from their work. The questions concerned the check-up before pregnancy of Turner patients, contraindication and acceptance of pregnancy, information for the patients, and recommendations for antenatal care, delivery and postnatal follow-up.

Safety and efficacy of sperm washing in HIV-1-serodiscordant couples where the male is infected: results from the European CREAThE network.

OBJECTIVE: To examine the safety and effectiveness of assisted reproduction using sperm washing for HIV-1-serodiscordant couples wishing to procreate where the male partner is infected. DESIGN AND METHODS: A retrospective multicentre study at eight centres adhering on the European network CREAThE and involving 1036 serodiscordant couples wishing to procreate. Sperm washing was used to obtain motile spermatozoa for 3390 assisted reproduction cycles (2840 intrauterine inseminations, 107 in-vitro fertilizations, 394 intra-cytoplasmic sperm injections and 49 frozen embryo transfers). An HIV test was performed in female partners at least 6 months after assisted reproduction attempt. The outcome measures recorded were number of assisted reproduction cycles, pregnancy outcome and HIV test on women post-treatment. RESULTS: A total of 580 pregnancies were obtained from 3315 cycles. Pregnancy outcome was unknown in 47 cases. The 533 pregnancies resulted in 410 deliveries and 463 live births. The result of female HIV testing after assisted reproduction was known in 967 out of 1036 woman (7.1% lost to follow-up). All tests recorded were negative. The calculated probability of contamination was equal to zero (95% confidence interval, 0-0.09%). CONCLUSION: This first multicentre retrospective study of assisted reproduction following sperm washing demonstrates the method to be effective and to significantly reduce HIV-1 transmission risk to the uninfected female partner. These results support the view that assisted reproduction with sperm washing could not be denied to serodiscordant couples in developed countries and, where possible, could perhaps be integrated into a global public health initiative against HIV in developing countries.

Encouraging results despite complexity of multidisciplinary care of HIV-infected women using assisted reproduction techniques.

BACKGROUND: Assisted reproduction technologies can treat infertility for human immunodeficiency virus (HIV) seropositive women. We assessed the efficacy of these techniques in the results and difficulties encountered while conducting our assisted reproduction programme for 49 couples in which at least the woman had HIV infection that was currently under control. METHODS: Treatments included intrauterine insemination (IUI), IVF and ICSI, with ovarian stimulation. Embryos were transferred on day 3 after oocyte retrieval. An elective single transfer was performed, except for patients aged > or = 40 years. RESULTS: The median age of the women was 36 years. Ten IUI, nine IVF, 53 ICSI and 10 frozen-thawed embryo transfers have been performed. No pregnancy occurred following the IUI trials but for the couples with IVF and ICSI attempts the clinical pregnancy rate per embryo transfer was 23.9%. Eight babies have been born leading to a 22.2% take home baby rate per treated couple. Contamination was not observed in any newborn. CONCLUSIONS: Assisted reproduction technologies and particularly ICSI can provide HIV seropositive women with a safe means of mothering children. Results are encouraging when considering the age of the patients and a preferential single embryo transfer.

Assisted reproduction techniques for HIV serodiscordant couples: 18 months of experience.

BACKGROUND: Assisted reproduction techniques can minimize the risk of infection and treat possible sterility associated with serodiscordant couples. METHODS: We assessed the efficacy of these techniques in 57 couples in which at least one partner had human immunodeficiency virus (HIV-1) infection that was currently under control (47 men and 10 women). The semen of seropositive men was prepared and tested for viruses. Assisted reproduction techniques included intrauterine insemination (IUI), IVF and especially ICSI, with ovarian stimulation that used a long agonist protocol and recombinant FSH. Embryos were transferred on day 3 after oocyte retrieval. RESULTS: For couples with seropositive men, five IUI and 49 IVF or ICSI attempts were perfomed, whilst for seropositive women these numbers were three IUI and 12 IVF or ICSI. No pregnancy occurred following the eight IUI trials. Seroconversion was not observed in any partners of seropositive men. Efficacy of treatment for these couples with ICSI was good, the clinical pregnancy rate per embryo transfer was 48.8%. The results for seropositive women were disappointing, with a clinical pregnancy rate per embryo transfer of 9.1%. Fourteen babies from 47 treated couples have so far been born and no pregnancies from IUI. CONCLUSIONS: Assisted reproduction techniques and particularly ICSI provide HIV-1-seropositive men with a safe and highly effective means of fathering children. These techniques may be less effective for seropositive women.

Nitric oxide donors for patients undergoing IVF. A prospective, double-blind, randomized, placebo-controlled trial.

BACKGROUND: Nitric oxide (NO) is involved in local control of the uterine cycle and in preparation of the uterus for pregnancy. NO donors, acting as vasodilating agents, may therefore have possible therapeutic uses, for example they may be of benefit to patients with a history of implantation failure. In a prospective, comparative, randomized, placebo-controlled study, we assessed the efficacy of nitroglycerin (NTG) administered to 138 IVF patients with a history of implantation failure. METHODS: Controlled ovarian stimulation was performed with long agonist protocol combined with recombinant FSH. Embryos were transferred on day 2 or 3 after oocyte retrieval. Eligible patients were those who had at least two 'good quality' embryos. The NTG patch was administered the day before embryo transfer and continued until either the results of the pregnancy test were known or until menstruation occurred. RESULTS: Ovarian response, implantation rate and pregnancy rate were comparable between both groups. No difference was observed in uterine Doppler findings, particularly the mean pulsatility index. CONCLUSIONS: NTG treatment the day before embryo transfer was no more effective than placebo in improving the implantation or pregnancy rates in a population of IVF patients with a previous history of implantation failures.