Intrafamilial oocyte donation in classic galactosemia: ethical and societal aspects

Classic galactosemia is a rare inherited disorder of galactose metabolism. Primary ovarian insufficiency (POI) with subfertility affects > 80% of female patients and is an important concern for patients and their parents. Healthcare providers are often consulted for subfertility treatment possibilities. An option brought up by the families is intrafamilial oocyte donation (mother-to-daughter or sister-to-sister). In addition to POI, galactosemia patients can also present varying cognitive and neurological impairments, which may not be fully clear at the time when mother-to-daughter oocyte donation is considered. Ethical and societal aspects arise when exploring this option. This study aimed to provide guidance in aspects to consider based on the views of different groups involved in the oocyte donation process. A qualitative study using in-depth semi-structured interviews with > 50 participants (patients, family members, and healthcare providers) was conducted. From these interviews, themes of concern emerged, which are illustrated and reviewed: (1) family relations, (2) medical impact, (3) patients’ cognitive level, (4) agreements to be made in advance and organization of counseling, (5) disclosure to the child, and (6) need for follow-up. We conclude that discussing and carrying out intrafamilial oocyte donation in galactosemia patients requires carefully addressing these themes. This study adds value to the already existing recommendations on intrafamilial oocyte donation in general, since it highlights important additional aspects from the perspectives of patients and their families

Cumulative live birth rates in low-prognosis women

STUDY QUESTION: Do cumulative live birth rates (CLBRs) over multiple IVF/ICSI cycles confirm the low prognosis in women stratified according to the POSEIDON criteria? SUMMARY ANSWER: The CLBR of low-prognosis women is ~56% over 18 months of IVF/ICSI treatment and varies between the POSEIDON groups, which is primarily attributable to the impact of female age. WHAT IS KNOWN ALREADY: The POSEIDON group recently proposed a new stratification for low-prognosis women in IVF/ICSI treatment, with the aim to define more homogenous populations for clinical trials and stimulate a patient-tailored therapeutic approach. These new criteria combine qualitative and quantitative parameters to create four groups of low-prognosis women with supposedly similar biologic characteristics. STUDY DESIGN, SIZE, DURATION: This study analyzed the data of a Dutch multicenter observational cohort study including 551 low-prognosis women, aged <44 years, who initiated IVF/ICSI treatment between 2011 and 2014 and were treated with a fixed FSH dose of 150 IU/day in the first treatment cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: Low-prognosis women were categorized into one of the POSEIDON groups based on their age (younger or older than 35 years), anti-Müllerian hormone (AMH) level (above or below 0.96 ng/ml), and the ovarian response (poor or suboptimal) in their first cycle of standard stimulation. The primary outcome was the CLBR over multiple complete IVF/ICSI cycles, including all subsequent fresh and frozen-thawed embryo transfers, within 18 months of treatment. Cumulative incidence curves were obtained using an optimistic and a conservative analytic approach. MAIN RESULTS AND THE ROLE OF CHANCE: The CLBR of the low-prognosis women was on average ~56% over 18 months of IVF/ICSI treatment. Younger unexpected poor (n = 38) and suboptimal (n = 179) responders had a CLBR of ~65% and ~68%, respectively, and younger expected poor responders (n = 65) had a CLBR of ~59%. The CLBR of older unexpected poor (n = 41) and suboptimal responders (n = 102) was ~42% and ~54%, respectively, and of older expected poor responders (n = 126) ~39%. For comparison, the CLBR of younger (n = 164) and older (n = 78) normal responders with an adequate ovarian reserve was ~72% and ~58% over 18 months of treatment, respectively. No large differences were observed in the number of fresh treatment cycles between the POSEIDON groups, with an average of two fresh cycles per woman within 18 months of follow-up. LIMITATIONS, REASONS FOR CAUTION: Small numbers in some (sub)groups reduced the precision of the estimates. However, our findings provide the first relevant indication of the CLBR of low-prognosis women in the POSEIDON groups. Small FSH dose adjustments between cycles were allowed, inducing therapeutic disparity. Yet, this is in accordance with current daily practice and increases the generalizability of our findings. WIDER IMPLICATIONS OF THE FINDINGS: The CLBRs vary between the POSEIDON groups. This heterogeneity is primarily determined by a woman's age, reflecting the importance of oocyte quality. In younger women, current IVF/ICSI treatment reaches relatively high CLBR over multiple complete cycles, despite reduced quantitative parameters. In older women, the CLBR remains relatively low over multiple complete cycles, due to the co-occurring decline in quantitative and qualitative parameters. As no effective interventions exist to counteract this decline, clinical management currently relies on proper counselling. STUDY FUNDING/COMPETING INTEREST(S): No external funds were obtained for this study. J.A.L. is supported by a Research Fellowship grant and received an unrestricted personal grant from Merck BV. S.C.O., T.C.v.T., and H.L.T. received an unrestricted personal grant from Merck BV. C.B.L. received research grants from Merck, Ferring,

Ovarian stimulation for IVF and risk of primary breast cancer in BRCA1/2 mutation carriers

Background: The effect of in vitro fertilisation (IVF) on breast cancer risk for BRCA1/2 mutation carriers is rarely examined. As carriers may increasingly undergo IVF as part of preimplantation genetic diagnosis (PGD), we examined the impact of ovarian stimulation for IVF on breast cancer risk in BRCA1/2 mutation carriers. Methods: The study population consisted of 1550 BRCA1 and 964 BRCA2 mutation carriers, derived from the nationwide HEBON study and the nationwide PGD registry. Questionnaires, clinical records and linkages with the Netherlands Cancer Registry were used to collect data on IVF exposure, risk-reducing surgeries and cancer diagnosis, respectively. Time-dependent Cox regression analyses were conducted, stratified for birth cohort and adjusted for subfertility. Results: Of the 2514 BRCA1/2 mutation carriers, 3% (n = 76) were exposed to ovarian stimulation for IVF. In total, 938 BRCA1/2 mutation carriers (37.3%) were diagnosed with breast cancer. IVF exposure was not associated with risk of breast cancer (HR: 0.79, 95% CI: 0.46–1.36). Similar results were found for the subgroups of subfertile women (n = 232; HR: 0.73, 95% CI: 0.39–1.37) and BRCA1 mutation carriers (HR: 1.12, 95% CI: 0.60–2.09). In addition, age at and recency of first IVF treatment were not associated with breast cancer risk. Conclusion: No evidence was found for an association between ovarian stimulation for IVF and breast cancer risk in BRCA1/2 mutation carriers

Preimplantation genetic diagnosis in mitochondrial DNA disorders: Challenge and success

Background Mitochondrial or oxidative phosphorylation diseases are relatively frequent, multisystem disorders; in about 15% of cases they are caused by maternally inherited mitochondrial DNA (mtDNA) mutations. Because of the possible severity of the phenotype, the lack of effective treatment, and the high recurrence risk for offspring of carrier females, couples wish to prevent the transmission of these mtDNA disorders to their offspring. Prenatal diagnosis is problematic for several reasons, and concern the often poor correlation between mutation percentages and disease severity and the uncertainties about the representativeness of a fetal sample. A new option for preventing transmission of mtDNA disorders is preimplantation genetic diagnosis (PGD), which circumvents these problems by transferring an embryo below the threshold of clinical expression. Methods We present the data on nine PGD cycles in four female carriers of mitochondrial diseases: three mitochondrial encephalopathy, lactic acidosis and strokelike episodes (MELAS) (m.3243A>G), and one Leigh (m.8993T>G). Our threshold for transfer after PGD is 15% for the m.3243A>G mutation and 30% for the m.8993T>G mutation. Results All four female carriers produced embryos eligible for transfer. The m.8993T>G mutation in oocytes/embryos showed more skewing than the m.3243A>G. In about 80% of the embryos the mutation load in the individual blastomeres was fairly constant (interblastomere differences <10%). However, in around 11% (in embryos with the m.3243A>G mutation only), the mutation load differed substantially (>15%) between blastomeres of a single embryo, mostly as a result of one outlier. The m.8993T>G carrier became pregnant and gave birth to a healthy son. Conclusions PGD provides carriers of mtDNA mutations the opportunity to conceive healthy offspring