Elias M. Dahdouh

Impact of blastocyst biopsy and comprehensive chromosome screening technology on preimplantation genetic screening: a systematic review of randomized controlled trials

Embryonic aneuploidy is highly prevalent in IVF cycles and contributes to decreased implantation rates, IVF cycle failure and early pregnancy loss. Preimplantation genetic screening (PGS) selects the most competent (euploid) embryos for transfer, and has been proposed to improve IVF outcomes. Use of PGS with fluorescence-in-situ hybridization technology after day 3 embryo biopsy (PGS-v1) significantly lowers live birth rates and is not recommended for use. Comprehensive chromosome screening technology, which assesses the whole chromosome complement, can be achieved using different genetic platforms. Whether PGS using comprehensive chromosome screening after blastocyst biopsy (PGS-v2) improves IVF outcomes remains to be determined. A systematic review of randomized controlled trials was conducted on PGS-v2. Three trials met full inclusion criteria, comparing PGS-v2 and routine IVF care. PGS-v2 is associated with higher clinical implantation rates, and higher ongoing pregnancy rates when the same number of embryos is transferred in both PGS and control groups. Additionally, PGS-v2 improves embryo selection in eSET practice, maintaining the same ongoing pregnancy rates between PGS and control groups, while sharply decreasing multiple pregnancy rates. These results stem from good-prognosis patients undergoing IVF. Whether these findings can be extrapolated to poor-prognosis patients with decreased ovarian reserve remains to be determined.

Technical Update: Preimplantation Genetic Diagnosis and Screening

OBJECTIVE To update and review the techniques and indications of preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS). OPTIONS Discussion about the genetic and technical aspects of preimplantation reproductive techniques, particularly those using new cytogenetic technologies and embryo-stage biopsy. OUTCOMES Clinical outcomes of reproductive techniques following the use of PGD and PGS are included. This update does not discuss in detail the adverse outcomes that have been recorded in association with assisted reproductive technologies. EVIDENCE Published literature was retrieved through searches of The Cochrane Library and Medline in April 2014 using appropriate controlled vocabulary (aneuploidy, blastocyst/physiology, genetic diseases, preimplantation diagnosis/methods, fertilization in vitro) and key words (e.g., preimplantation genetic diagnosis, preimplantation genetic screening, comprehensive chromosome screening, aCGH, SNP microarray, qPCR, and embryo selection). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies published from 1990 to April 2014. There were no language restrictions. Searches were updated on a regular basis and incorporated in the update to January 2015. Additional publications were identified from the bibliographies of retrieved articles. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. (Table 1) BENEFITS, HARMS, AND COSTS: This update will educate readers about new preimplantation genetic concepts, directions, and technologies. The major harms and costs identified are those of assisted reproductive technologies. SUMMARY Preimplantation genetic diagnosis is an alternative to prenatal diagnosis for the detection of genetic disorders in couples at risk of transmitting a genetic condition to their offspring. Preimplantation genetic screening is being proposed to improve the effectiveness of in vitro fertilization by screening for embryonic aneuploidy. Though FISH-based PGS showed adverse effects on IVF success, emerging evidence from new studies using comprehensive chromosome screening technology appears promising. Recommendations 1. Before preimplantation genetic diagnosis is performed, genetic counselling must be provided by a certified genetic counsellor to ensure that patients fully understand the risk of having an affected child, the impact of the disease on an affected child, and the benefits and limitations of all available options for preimplantation and prenatal diagnosis. (III-A) 2. Couples should be informed that preimplantation genetic diagnosis can reduce the risk of conceiving a child with a genetic abnormality carried by one or both parents if that abnormality can be identified with tests performed on a single cell or on multiple trophectoderm cells. (II-2B) 3. Invasive prenatal or postnatal testing to confirm the results of preimplantation genetic diagnosis is encouraged because the methods used for preimplantation genetic diagnosis have technical limitations that include the possibility of a false result. (II-2B) 4. Trophectoderm biopsy has no measurable impact on embryo development, as opposed to blastomere biopsy. Therefore, whenever possible, trophectoderm biopsy should be the method of choice in embryo biopsy and should be performed by experienced hands. (I-B) 5. Preimplantation genetic diagnosis of single-gene disorders should ideally be performed with multiplex polymerase chain reaction coupled with trophectoderm biopsy whenever available. (II-2B) 6. The use of comprehensive chromosome screening technology coupled with trophectoderm biopsy in preimplantation genetic diagnosis in couples carrying chromosomal translocations is recommended because it is associated with favourable clinical outcomes. (II-2B) 7. Before preimplantation genetic screening is performed, thorough education and counselling must be provided by a certified genetic counsellor to ensure that patients fully understand the limitations of the technique, the risk of error, and the ongoing debate on whether preimplantation genetic screening is necessary to improve live birth rates with in vitro fertilization. (III-A) 8. Preimplantation genetic screening using fluorescence in situ hybridization technology on day-3 embryo biopsy is associated with decreased live birth rates and therefore should not be performed with in vitro fertilization. (I-E) 9. Preimplantation genetic screening using comprehensive chromosome screening technology on blastocyst biopsy, increases implantation rates and improves embryo selection in IVF cycles in patients with a good prognosis. (I-B).

Obstetrical and neonatal outcomes following unsuccessful external cephalic version: a stratified analysis amongst failures, successes, and controls.

Abstract Objective: Though on average one out of every two external cephalic versions (ECV) fails to rotate the breech fetus, little is known about the outcomes of pregnancies in which ECV is unsuccessful. The objective of the present study is to compare obstetrical and neonatal outcomes following failure of ECV, relative to cases of breech controls without an attempt at ECV. Study design: We conducted a retrospective, population-based, cohort study using the CDCs Birth Data files from the US for the year 2006. We stratified the cohort according to fetal presentation and ECV status: success, failure, and no ECV (controls). The effect of failure of ECV on the risk of several neonatal and obstetrical outcomes was estimated using logistic regression analysis, adjusting for relevant confounders. Results: We analyzed a total of 4 273 225 births, out of which 183 323 (4.3%) met inclusion criteria. Relative to breech controls, failed ECV occurred more frequently amongst Caucasian, college-educated, married women bearing a female fetus. Compared to no ECV, failure of ECV was associated with increased odds of PROM (aOR, 1.75; 95% CI, 1.60–1.90), elective cesarean delivery (aOR, 1.53; 95% CI, 1.36–1.72), cesarean delivery in labor (aOR, 1.38; 95% CI, 1.21–1.57), abnormal fetal heart tracing (aOR, 1.78; 95% CI, 1.50–2.11), assisted ventilation at birth (aOR, 1.50; 95% CI, 1.27–1.78), 5-min APGAR scores <7 (aOR, 1.35; 95% CI, 1.20–1.51), and NICU admission (aOR, 1.48; 95% CI, 1.20–1.82). The delayed spontaneous fetal restitution rate was 13%. When stratifying controls with regards to trial of labor status, the increased risk of failed ECV persisted for cesarean delivery, NICU admission, assisted ventilation and abnormal fetal tracing, independently of whether a trial of labor took place. Conclusion: Relative to breech controls without attempt at ECV, failure of ECV to restitute cephalic presentation appears to be associated with an increased risk of adverse perinatal and obstetrical outcomes.

Maternal and obstetrical predictors of sudden infant death syndrome (SIDS)

Abstract Objective: Public Health initiatives, such as the “Safe to Sleep” campaign, have traditionally targeted infants’ risk factors for the prevention of Sudden Infant Death Syndrome (SIDS). However, controversy remains regarding maternal and obstetrical risk factors for SIDS. In our study, we sought out to determine both modifiable and non-modifiable obstetrical and maternal risk factors associated with SIDS. Methods: We conducted a population-based cohort study using the CDC’s Linked Birth–Infant Death data from the United States for the year 2010. The impact of several obstetrical and maternal risk factors on the risk of overall infant mortality and SIDS was estimated using unconditional regression analysis, adjusting for relevant confounders. Results: Our cohort consisted of 4,007,105 deliveries and 24,174 infant deaths during the first year of life, of which 1991 (8.2%) were due to SIDS. Prominent risk factors for SIDS included (OR [95% CI]): black race, 1.89 [1.68–2.13]; maternal smoking, 3.56 [3.18–3.99]; maternal chronic hypertension, 1.73 [1.21–2.48]; gestational hypertension, 1.51 [1.23–1.87]; premature birth <37 weeks, 2.16 [1.82–2.55]; IUGR, 2.46 [2.14–2.82]; and being a twin, 1.81 [1.43–2.29], p < 0.0001. Relative to a cohort of infants who died of other causes, risk factors with a predilection for SIDS were maternal smoking, 2.48 [2.16–2.83] and being a twin, 1.52 [1.21–1.91], p < 0.0001. Conclusions for practice: While certain socio-demographic and gestational characteristics are important risk factors, maternal smoking remains the strongest prenatal modifiable risk factor for SIDS. We recommend the continuation of Public Health initiatives that promote safe infant sleeping practices and smoking cessation during and after pregnancy.

Preimplantation genetic screening using comprehensive chromosome screening: evidence and remaining challenges

Sir, We read with great interest a recent systematic review by Lee et al. published inyour journal evaluating the clinical effectiveness ofpreimplantation genetic diagnosis for aneuploidy in all 24 chromosomes (PGD-A) (Lee et al., 2015). The authors conclude that, for the time being, the role for PGD-A remains uncertain regarding its clinicaland costeffectiveness. In our opinion, a number of observations need to be addressed with regards to the implication of their findings. First, in order to ensure standard nomenclature in preimplantation genetics, it must be made clear that what the authors refer to as PGD-A is otherwise known as preimplantation genetic screening (PGS). The term ‘PGD’ should be reserved for patientscarrying specificgenetic disorders in whicha preimplantationdiagnosis for the abnormality in question is desired. Secondly, the authors reach their conclusion through a systematic review of studies with varied levels of evidence including both randomized control trials (RCTs) and observational studies. In the presence of level I evidence from RCTs, the inclusion of lower level evidence in a systematic review may induce erroneous conclusions and adversely impact clinical practice. A recent systematic review by our team (Dahdouh et al., 2015) restricted only to RCTs dealing with PGS using comprehensive chromosome screening (CCS) technology (Yang et al., 2012; Forman et al., 2013; Scott et al., 2013a) concluded that the use of PGS-CCS for the purpose of embryo selection in good-prognosis patients with normal ovarian reserve was favourable. Implantation rates (IR) were improved in the three RCTs with PGS-CCS following blastocyst biopsy. Using this approach, elective single embryo transfer (eSET) is optimized by improving the chance of delivering a healthy term singleton. With the high IR reported using PGS-CCS, eSET practice should be the standard of care. According to our review, the minimal standard for the success of this technology in today’s practice should be having enough experience with embryo biopsy and extended embryo culture, and validating the genetic platforms for CCS in order not to discard normal euploid embryos. We agree that the use of PGS with fluorescence in situ hybridization (FISH) following cleavage-stage biopsy did not confer any advantageous results in IVF practice. However, in our opinion, the reason was not primarily related to the FISH technology, where up to 80% of embryonic aneuploidy can be diagnosed using 12 probes, but rather to the combination of FISH and day-3 embryo biopsy. Cleavage-stage biopsy might have been deleterious on embryo development under certain circumstances (e.g. retrieving two blastomeres, biopsy on poor quality embryos). In level I evidence data comparing day-3 to day-5 embryo biopsies (Scott et al., 2013b), cleavage-stage biopsy was associated with a 39% decrease in implantation potential, whereas no impact on embryo development was observed following blastocyst biopsy. A valid criticism regarding this paper was that IR in both day-3 and day-5 embryos were surprisingly equivalent. However, some investigators reported positive clinical outcomes from RCTs on PGS applied on day-3 embryo biopsy, both with FISH (Rubio et al., 2013) and with array comparative genomic hybridization (aCGH) (preliminary results, ClinicalTrials.gov NCT01571076). Therefore, embryo culture conditions and biopsy media and technique, are key laboratory aspects to consider for the ideal PGS practice. In addition, the authors claim that there are no reports on subsequent embryo transfer cycles following PGS-CCS. However, some authors recently reported increased IR with subsequent euploid frozen blastocyst transfers (Yang et al., 2013). With regards to cost-effectiveness, weagree with the authors that studies performed on the cost of PGS-CCS following at least two embryo transfer cycles compared with control groups will be needed to resolve this matter. Future RCTs on PGS-CCS should be conducted on a multicentre basis, including different geographic locations, different patient populations (e.g. decreased ovarian reserve, advanced maternal age) and different embryo stage biopsy (e.g. day-3 versus day-5). We are witnessing the early days of the development of this new form of PGS; robust evidence is still needed from ongoing RCTs before it is applied on a regular basis.

The Effect of Adequate Gestational Weight Gain among Adolescents Relative to Adults of Equivalent Body Mass Index and the Risk of Preterm Birth, Cesarean Delivery, and Low Birth Weight.

OBJECTIVE To determine whether similar odds of cesarean delivery (C/S), preterm birth (PTB), and low birth weight (LBW) are observed among adolescents compared with body mass index (BMI)-equivalent adults in cases of adequate gestational weight gain. STUDY DESIGN We conducted a retrospective, population-based, cohort study using the Center for Disease Control and Preventions birth data files from the United States for 2012. We selected from the cohort all singleton, cephalic pregnancies and stratified them according to maternal age, prepregnancy BMI, and gestational weight gain following the 2009 Institute of Medicine (IOM) recommendations. The effect of adequate gestational weight gain among adolescents relative to adults of equivalent BMI on the risk of C/S, PTB, and LBW was estimated using logistic regression analysis, adjusting for relevant confounders. RESULTS We analyzed a total of 3,960,796 births, of which 1,036,646 (26.1%) met the inclusion criteria. In adolescents and adults, likelihood of achieving ideal gestational weight gain decreased with greater prepregnancy BMI. Relative to adults, the overall odds of C/S in all adolescents were (adjusted odds ratio [95% confidence interval]) 0.61 (0.58 to 0.63). When comparing equivalent BMI categories, these odds were unchanged (P < .0001). The overall adjusted odds ratio of LBW was 1.15 (1.13 to 1.16). These odds were significantly higher when BMI stratification took place, decreasing with advancing BMI categories, from 1.23 (1.14 to 1.33) among the underweight, to nonsignificant differences in the obese classes (P < .05). Finally, when including only those achieving ideal weight gain, the overall odds of premature delivery (1.17 [1.14 to 1.20]) were higher among nonobese adolescents, while they were not found among the obese. CONCLUSION When ideal gestational weight gain is attained, only nonobese adolescents exhibit a greater risk of LBW and preterm birth relative to adults of similar BMI, whereas the risk of C/S remains lower for all adolescents, independent of BMI. This information may be useful in the counseling of adolescent pregnancies.

Uterine transplantation is not a good use of limited resources: FOR: Uterine transplantation is not a good use of limited resources—a case of distributive justice and burden of disease

JACQUES BALAYLA, PHYSICIAN, CANADA, ELIAS M DAHDOUH, MEDICAL DIRECTOR, CANADA ....................................................................................................................................................................... The debate surrounding uterine transplantation (UTx) is complex and multifaceted. Although its scientific merit has recently been put in the spotlight, the social, economic and ethical considerations implicated have been largely left out of the mainstream conversation.

Angiographic Embolization of a Postpartum Vulvovaginal Hematoma in a Patient with Situs Inversus Totalis: An Effective Second-Line Treatment

Situs inversus totalis is a rare congenital anomaly where asymmetrical positioning of internal organs may affect the surgical and radiological management of certain conditions. Vulvovaginal hematoma is a life-threatening complication of vaginal delivery whose primary treatment usually consists of incision and drainage of the hematoma and ligation of the responsible vessels, followed by wound packing. Failure of these measures to control the bleeding was previously considered as an indication for laparotomy to perform bilateral hypogastric artery ligation and, if needed, a hysterectomy. Relative to major abdominal surgery, selective percutaneous angiographic embolization offers considerable advantages and significant less morbidity. Indeed, angiographic embolization is routinely used as a measure to control refractory pelvic bleeding, though the literature and experience in women with situs inversus totalis are scarce. In this paper, we report a case of postpartum vulvovaginal hematoma in a patient with situs inversus, refractory to conventional treatment, where arteriographic embolization was successfully used to control the bleeding. The management of this obstetrical complication and the use of this minimally invasive technique are also reviewed. To the best of our knowledge, this is the first report in the literature describing the feasibility of this technique in a patient with situs inversus totalis.

Apgar score and risk of cause-specific infant mortality

1 The Lancet. Ebola: protection of health-care workers. Lancet 2014; 384: 2174. 2 Coordination Nationale Ebola in Guinée, OMS. Rapport de la Situation Epidémiologique, Maladie à Virus Ebola en Guinée du 30 Decembre 2014. Sit_Rep_no 259. Conakry, Guinea: Coordination Nationale Ebola Guinée and Organisation mondiale de la Santé, 2014. 3 Kieny M, Evans D, Schmets G, Kadandale S. Health-system resilience: refl ections on the Ebola crisis in western Africa. Bull World Health Organ 2014; 92: 850. 4 Piot P, Muyembe J-J, Edmunds WJ. Ebola in west Africa: from disease outbreak to humanitarian crisis. Lancet Infect Dis 2014; 14: 1034–35. 5 Delamou A, Hammonds R, Caluwaerts S, Utz B, Delvaux T. Ebola in Africa: beyond epidemics, reproductive health in crisis. Lancet 2014; 384: 2105. 6 Shuchman M. Sierra Leone doctors call for better Ebola care for colleagues. Lancet 2014; 384: e67. in a context where systematic hand washing and use of gloves in health facilities are not standard practice. Contamination has been reported within communities (eg, from unsafe burial ceremonies) in addition to those in the workplace, from relatives who are ill, neighbours, or suspected cases that escape the disease surveillance system. We agree that prevention of Ebola in health-care workers is crucial to improve the health response to all causes of morbidity and mortality in countries affected by Ebola. More efforts are needed in Guinea to reinforce health-care workers’ capabilities to protect themselves, to identify and refer suspected cases of disease, and to rebuild trust with communities and medical staff. Additionally, health-care workers located in the sites of clinical trials need special protective measures because these studies entail invasive procedures. Local personnel should get the same care as expatriate health-care workers receive from their countries.

Is the Flexible GnRH Antagonist Protocol Better Suited for Fresh eSET Cycles

OBJECTIVE This study was performed to evaluate the efficacy of the flexible GnRH antagonist protocol in comparison with the long GnRH agonist protocol in elective single embryo transfer (eSET) practice. It was conducted in a publicly funded in vitro fertilization program. METHODS We performed a prospective cohort analysis of data from a private infertility clinic from August 2010 to August 2011. Three hundred fourteen women with normal ovarian reserve and undergoing fresh eSET cycles were included. Sixty-four women underwent follicular stimulation using a flexible GnRH antagonist protocol, and 250 underwent stimulation with a standard long mid-luteal GnRH agonist protocol. RESULTS Implantation rates (35.9% in the GnRH antagonist group and 29.6% in the GnRH agonist group, P = 0.5) and ongoing pregnancy rates (32.8% in the GnRH antagonist group and 28.8% in the GnRH agonist group, P = 0.5) were equivalent in both groups. The duration of stimulation (9.8 ± 2 days vs. 10.7 ± 1.8 days, P < 0.001) and total FSH dose required (2044 vs. 2775 IU, P < 0.001) were lower in the GnRH antagonist group than in the GnRH agonist group. The number of mature oocytes (6.0 vs. 10.0, P < 0. 001) and number of embryos (5.0 vs. 7.0, P < 0.001) were also lower in GnRH antagonist group. However, the number of embryos cryopreserved was similar in both groups (median 2.0, P = 0.3). CONCLUSION In women undergoing in vitro fertilization, the flexible GnRH antagonist protocol yields implantation and ongoing pregnancy rates that are similar to the long GnRH agonist protocol, and requires lower doses of gonadotropins and a shorter duration of treatment. The flexible GnRH antagonist protocol appears to be the protocol of choice for an eSET IVF program.