The cognitive and socio-emotional development of 5-year-old children born after PGD.

STUDY QUESTION: Does PGD increase the risk on adverse cognitive and socio-emotional development? SUMMARY ANSWER: The cognitive and socio-emotional development in children born after PGD seems to be normal when compared to control groups. WHAT IS KNOWN ALREADY: A limited number of studies with small sample sizes indicate that the cognitive and socio-emotional development of (pre)school-aged children born after either PGD or PGS seem to be comparable to those of children born after IVF/ICSI and to naturally conceived (NC) children from the general population. STUDY DESIGN, SIZE, DURATION: For this study we invited 72 5-year-old PGD children, 128 5-year-old IVF/ICSI children and 108 5-year-old NC children from families with a genetic disorder. All children were invited between January 2014 and July 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 51 PGD children, 52 IVF/ICSI children and 35 NC children underwent neuropsychological testing (WPPSI-III-NL and AWMA). The children's parent(s) and teachers filled in questionnaires evaluating children's executive functioning (Behaviour Rating Inventory of Executive Functions; BRIEF) and socio-emotional development (Child Behaviour Checklist; CBCL and Caregiver-Teacher Report Form; C-TRF). MAIN RESULTS AND THE ROLE OF CHANCE: The mean full-scale intelligence quotient scores (P = 0.426) and performance on the AWMA Listening Span task (P = 0.873) and Spatial Span task (P = 0.458) were comparable between the three groups. Regarding socio-emotional development, the teachers' scores revealed more externalizing (P = 0.011) and total problem (P = 0.019) behaviour in PGD children than for IVF/ICSI children; both groups did not differ significantly from the NC children (P = 0.11). More children (13%) with an affected first-degree family member (mostly parent) were included in the PGD group than in the NC group. Scores in all groups fell within the normal population range and should be considered normal. LIMITATIONS, REASONS FOR CAUTION: The number of NC children from families with a genetic disorder was relatively small. Furthermore, the fathers' CBCL results were based on small samples. WIDER IMPLICATIONS OF THE FINDINGS: PGD children show levels of cognitive and socio-emotional development at 5 years that are within the normal range, despite the biopsy involved in PGD and the potential extra psychological burden associated with the presence of a genetic disorder in the family. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMw (70-71300-98-106). None of the authors have any competing interests to declare. TRIAL REGISTRATION NUMBER: NCT02149485.

ESHRE PGD Consortium data collection XIV-XV: cycles from January 2011 to December 2012 with pregnancy follow-up to October 2013.

STUDY QUESTION: How does the data collection XIV-XV of the European Society of Human Reproduction and Embryology (ESHRE) PGD Consortium compare with the cumulative data for data collections I-XIII? SUMMARY ANSWER: The 14th and 15th retrospective collection represents valuable data on PGD/PGS cycles, pregnancies and children: the main trend observed is the increased application of array technology at the cost of FISH testing in PGS cycles and in PGD cycles for chromosomal abnormalities. WHAT IS KNOWN ALREADY: Since 1999, the PGD Consortium has collected, analysed and published 13 previous data sets and an overview of the first 10 years of data collections. STUDY DESIGN, SIZE, DURATION: Data were collected from each participating centre using a FileMaker Pro database (versions 5-12). Separate predesigned FileMaker Pro files were used for the cycles, pregnancies and baby records. The study documented cycles performed during the calendar years 2011 and 2012 and follow-up of the pregnancies and babies born which resulted from these cycles (until October 2013). PARTICIPANTS/MATERIALS, SETTINGS, METHOD: Data were submitted by 71 centres (full PGD Consortium members). Records with incomplete or inconsistent data were excluded from the calculations. Corrections, calculations and tables were made by expert co-authors. MAIN RESULTS AND THE ROLE OF CHANCE: For data collection XIV-XV, 71 centres reported data for 11 637 cycles with oocyte retrieval (OR), along with details of the follow-up on 2147 pregnancies and 1755 babies born. A total of 1953 cycles to OR were reported for chromosomal abnormalities, 144 cycles to OR for sexing for X-linked diseases, 3445 cycles to OR for monogenic diseases, 6095 cycles to OR for PGS and 38 cycles to OR for social sexing. From 2010 until 2012, the use of arrays for genetic testing increased from 4% to 20% in PGS and from 6% to 13% in PGD cycles for chromosomal abnormalities; the uptake of biopsy at the blastocyst stage (from <1% up to 7%) was only observed in cycles for structural chromosomal abnormalities, alongside the application of array comparative genomic hybridization. LIMITATIONS, REASONS FOR CAUTION: The findings apply to the 71 participating centres and may not represent worldwide trends in PGD. WIDER IMPLICATIONS OF THE FINDINGS: The annual data collections provide an important resource for data mining and for following trends in PGD/PGS practice. STUDY FUNDING/COMPETING INTEREST(S): None.

BRCA1 mutation carriers have a lower number of mature oocytes after ovarian stimulation for IVF/PGD.

PURPOSE: The aim of this study was to determine whether BRCA1/2 mutation carriers produce fewer mature oocytes after ovarian stimulation for in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD), in comparison to a PGD control group. METHODS: A retrospective, international, multicenter cohort study was performed on data of first PGD cycles performed between January 2006 and September 2015. Data were extracted from medical files. The study was performed in one PGD center and three affiliated IVF centers in the Netherlands and one PGD center in Belgium. Exposed couples underwent PGD because of a pathogenic BRCA1/2 mutation, controls for other monogenic conditions. Only couples treated in a long gonadotropin-releasing hormone (GnRH) agonist-suppressive protocol, stimulated with at least 150 IU follicle stimulating hormone (FSH), were included. Women suspected to have a diminished ovarian reserve status due to chemotherapy, auto-immune disorders, or genetic conditions (other than BRCA1/2 mutations) were excluded. A total of 106 BRCA1/2 mutation carriers underwent PGD in this period, of which 43 (20 BRCA1 and 23 BRCA2 mutation carriers) met the inclusion criteria. They were compared to 174 controls selected by frequency matching. RESULTS: Thirty-eight BRCA1/2 mutation carriers (18 BRCA1 and 20 BRCA2 mutation carriers) and 154 controls proceeded to oocyte pickup. The median number of mature oocytes was 7.0 (interquartile range (IQR) 4.0-9.0) in the BRCA group as a whole, 6.5 (IQR 4.0-8.0) in BRCA1 mutation carriers, 7.5 (IQR 5.5-9.0) in BRCA2 mutation carriers, and 8.0 (IQR 6.0-11.0) in controls. Multiple linear regression analysis with the number of mature oocytes as a dependent variable and adjustment for treatment center, female age, female body mass index (BMI), type of gonadotropin used, and the total dose of gonadotropins administered revealed a significantly lower yield of mature oocytes in the BRCA group as compared to controls (p = 0.04). This finding could be fully accounted for by the BRCA1 subgroup (BRCA1 mutation carriers versus controls p = 0.02, BRCA2 mutation carriers versus controls p = 0.50). CONCLUSIONS: Ovarian response to stimulation, expressed as the number of mature oocytes, was reduced in BRCA1 but not in BRCA2 mutation carriers. Although oocyte yield was in correspondence to a normal response in all subgroups, this finding points to a possible negative influence of the BRCA1 gene on ovarian reserve.

Recurrent miscarriage in translocation carriers: no differences in clinical characteristics between couples who accept and couples who decline PGD.

STUDY QUESTION: Do clinical characteristics of recurrent miscarriage couples with a chromosomal abnormality and who opt for PGD differ from couples that decline PGD after extensive genetic counselling? SUMMARY ANSWER: No differences in clinical characteristics are identified between recurrent miscarriage couples carrying a structural chromosomal abnormality who opt for PGD compared with those that decline PGD after extensive genetic counselling. WHAT IS KNOWN ALREADY: Couples who have experienced two or more miscarriages (recurrent miscarriage) are at increased recurrence risk if one of the partners carries a structural chromosomal abnormality. PGD can be offered to avoid (another) miscarriage or pregnancy termination when (invasive) prenatal diagnosis shows an abnormal result. To date, no reports are available that describe reproductive decision-making after genetic counselling on PGD in these specific couples. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of 294 couples carrying a structural chromosomal abnormality seeking genetic counselling on PGD between 1996 and 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were recurrent miscarriage couples carrying a structural chromosomal abnormality. They had been referred for genetic counselling to the only national licensed PGD centre. Clinical characteristics analysed included couple associated characteristics, characteristics concerning reproductive history and external characteristics such as type of physician that referred the couple for genetic counselling and the clinical geneticist performing the counselling on PGD. MAIN RESULTS AND THE ROLE OF CHANCE: Of 294 couples referred for counselling on PGD, 26 were not accepted because they did not meet the criteria for IVF-PGD. The remaining cohort of 268 couples consisted of two-thirds female and one-third male carriers. Main PGD indications were reciprocal translocations (83.9%) and Robertsonian translocations (16.7%). Following genetic counselling, 76.9% of included couples chose PGD as their reproductive option, the others declined PGD. Reproductive choice is not influenced by sex of the translocation carrier (P = 0.499), type of chromosomal abnormality (P = 0.346), number of previous miscarriages (P = 0.882), history of termination of pregnancy (TOP) because of an unbalanced fetal karyotype (P = 0.800), referring physician (P = 0.208) or geneticist who performed the counselling (P = 0.410). LIMITATIONS, REASONS FOR CAUTION: This study only included recurrent miscarriage couples carrying a structural chromosomal abnormality, who were actually referred to a PGD clinic for genetic counselling. We lack information on couples who were not referred for PGD. Some of these patients may not have been informed on PGD at all, while others were not referred for counselling because they did not opt for PGD to start with. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that reproductive choices in couples with recurrent miscarriage on the basis of a structural chromosomal abnormality are not influenced by characteristics of the couple itself, nor by their obstetric history or external characteristics. These findings suggest that a couples' intrinsic attitude towards PGD treatment is a major factor influencing their reproductive choice. Future research will focus on these personal motives that seem to push reproductive decision-making following genetic counselling in a given direction.

Decision-making on preimplantation genetic diagnosis and prenatal diagnosis: a challenge for couples with hereditary breast and ovarian cancer.

STUDY QUESTION: How do couples with a BRCA1/2 mutation decide on preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND) for hereditary breast and ovarian cancer syndrome (HBOC)? SUMMARY ANSWER: BRCA couples primarily classify PGD and/or PND as reproductive options based on the perceived severity of HBOC and moral considerations, and consequently weigh the few important advantages of PGD against numerous smaller disadvantages. WHAT IS KNOWN ALREADY: Awareness of PGD is generally low among persons at high risk for hereditary cancers. Most persons with HBOC are in favour of offering PGD for BRCA1/2 mutations, although only a minority would consider this option for themselves. Studies exploring the motivations for using or refraining from PGD among well-informed BRCA carriers of reproductive age are lacking. We studied the reproductive decision-making process by interviewing a group of well-informed, reproductive aged couples carrying a BRCA1/2 mutation, regarding their decisional motives and considerations. STUDY DESIGN, SIZE, DURATION: This exploratory, qualitative study investigated the motives and considerations taken into account by couples with a BRCA1/2 mutation and who have received extensive counselling on PGD and PND and have made a well-informed decision regarding this option. Eighteen couples took part in focus group and dyadic interviews between January and September 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Semi-structured focus groups were conducted containing two to four couples, assembled based on the reproductive method the couple had chosen: PGD (n = 6 couples) or conception without testing (n = 8 couples). Couples who had chosen PND for BRCA (n = 4) were interviewed dyadically. Two of the women, of whom one had chosen PND and the other had chosen no testing, had a history of breast cancer. MAIN RESULTS AND THE ROLE OF CHANCE: None of the couples who opted for PGD or conception without testing found the use of PND, with possible pregnancy termination, acceptable. PND users chose this method because of decisive, mainly practical reasons (natural conception, high chance of favourable outcome). Motives and considerations regarding PGD largely overlapped between PGD users, PND users and non-users, all mentioning some significant advantages (e.g. protecting the child and family from the mutation) and many smaller disadvantages (e.g. the necessity of in vitro fertilization (IVF), low chance of pregnancy by IVF/PGD). For female carriers, the safety of hormonal stimulation and the time required for PGD before undergoing preventive surgeries were important factors in the decision. Non-users expressed doubts about the moral justness of their decision afterwards and emphasized the impact the decision still had on their lives. LIMITATIONS, REASON FOR CAUTION: The interviewed couples were at different stages in their chosen trajectory, up to 3 years after completion. This may have led to recall bias of original motives and considerations. Couples who did not actively seek information about PGD were excluded. Therefore the results may not be readily generalizable to all BRCA couples. WIDER IMPLICATIONS OF THE FINDINGS: The perceived severity of HBOC and, for female carriers, the safety of hormonal stimulation and the time frames for PGD planning before preventive surgeries are essential items BRCA couples consider in reproductive decision-making. The emotional impact of this decision should not be underestimated; especially non-users may experience feelings of doubt or guilt up to several years afterwards. PGD counselling with tailored information addressing these items and decisional support in order to guarantee well-informed decision-making is needed. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Dutch breast cancer foundation Stichting Pink Ribbon, grant number 2010.PS11.C74. None of the authors have competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Transvaginal ultrasound measurement of cervical length in the supine and upright positions versus Bishop score in predicting successful induction of labor at term.

OBJECTIVES: To examine the predictive value of cervical length as measured by transvaginal sonography (TVS) in supine and upright maternal positions for the mode of delivery and induction-to-delivery interval after induction of labor at term, and to compare these measurements with the Bishop score and its predictive value. METHODS: TVS for cervical length measurement in the supine and upright positions and digital examination of the cervix were performed in 68 nulliparous and 34 parous women before induction of labor at term. In assessing the predictive value of the Bishop score and TVS parameters for a vaginal delivery after labor induction only nulliparous women were included in the analysis, since all the parous women delivered vaginally. Both nulliparous and parous women were included in the analysis of the induction-to-delivery interval. The method of labor induction, oxytocin or prostaglandin, was determined on the basis of the pre-induction Bishop score. RESULTS: Logistic regression analysis showed in nulliparous women that only the cervical length measured in the upright position was a significant predictor of the need for Cesarean section (odds ratio 1.14; 95% CI, 1.02-1.27). The areas under the receiver-operating characteristics curve in predicting the need for Cesarean section because of failure to progress were higher for the cervical length, both in supine and upright positions, than for the Bishop score (0.66, 0.68 and 0.46, respectively). Only the Bishop score correlated significantly with the induction-to-delivery interval in both nulliparous and parous women. However, this may have been due to a selection bias, as no significant correlation with Bishop score was found when the oxytocin and prostaglandin induction-to-delivery intervals were analyzed separately. CONCLUSION: Our results suggest that maternal postural change might improve the accuracy of sonographically-measured cervical length for predicting a vaginal delivery after induction of labor at term. However, our results need to be confirmed in a larger and more homogeneous population.

Transperineal versus transvaginal sonographic cervical length measurement in second- and third-trimester pregnancies.

OBJECTIVE: To investigate the reliability of, and patient satisfaction with, transperineal cervical length measurement during the third trimester of pregnancy and to compare these with measurement during the mid-trimester, using transvaginal sonographic imaging of the cervix as a reference. METHODS: Women attending an outpatient clinic for cervical length measurement before 29 weeks or after 35 weeks of gestation were examined by transvaginal and transperineal ultrasound and the results compared. Preference for either method was indicated by both sonographers and patients. RESULTS: Seventy-one patients participated in the study, 23 in the second and 48 in the third trimester of pregnancy. There was failure to obtain a clear image on transperineal ultrasound in 30% of mid-trimester pregnancies, and in 19% of third-trimester cases. Elevation of the patient's hips improved the image in five out of 10 women in whom the scan was repeated following a postural change. Transvaginal cervical length measurements could be obtained in all cases. There was a strong correlation between transvaginal and transperineal measured cervical length (Pearson's correlation coefficient = 0.85). Sonographers preferred transvaginal images of the cervix irrespective of whether they were obtained in the second or third trimester. Transperineal ultrasound was judged as not or mildly painful by most women, but transvaginal ultrasound was preferred. CONCLUSIONS: Transvaginal ultrasound is the least painful, most feasible, and probably most accurate method with which to measure cervical length in the third trimester of pregnancy. Transperineal ultrasound is a feasible alternative, although its application in clinical practice is restricted by the need for an experienced sonographer.

Sonographic longitudinal cervical length measurements in nulliparous women at term: prediction of spontaneous onset of labor.

OBJECTIVE: The aim of this study was to predict spontaneous onset of labor by serial transvaginal ultrasound measurement of cervical length (CL) in a homogeneous population of nulliparous women at term. METHODS: 162 nulliparous women with singleton fetuses in cephalic presentation were examined at weekly intervals from 36 weeks' gestation to delivery. CL was measured by transvaginal ultrasound in the supine and upright positions. RESULTS: There was a significant decrease in CL in the last 12 days prior to delivery. However, this decrease was small with substantial variation between individuals. Women with spontaneous onset of labor could be divided into three different groups: those with unchanged CL before delivery; those with a fall in CL in the last 2 weeks prior to delivery; and those with a gradual change in CL starting before the last 2 weeks prior to delivery. A single CL measurement below 30 mm between 37 and 38 weeks of gestation predicted spontaneous onset of labor before 41 weeks' gestation with a sensitivity of 46%, specificity of 78%, positive predictive value (PPV) of 82%, negative predictive value (NPV) of 40% in the supine position; and sensitivity of 53%, specificity of 72%, PPV of 81%, NPV of 40% in the upright position. CONCLUSION: Between 37 and 38 weeks' gestation, spontaneous onset of labor before 41 weeks can be predicted by a CL measurement, but with low sensitivity and NPV. Inter-individual variations in CL and in CL changes are large, which hampers the value of single and repeated CL measurements for the prediction of spontaneous onset of labor at term.