Sesh Kamal Sunkara

A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept

The management of patients with impaired or poor ovarian response (POR) remains a controversial and complex clinical issue. A systematic review of 47 randomized controlled trials revealed 41 different definitions of POR (1). Notably, the number of oocytes retrieved was adopted as a criterion of POR in 40% of the trials, although the threshold number differed considerably among studies (1). To standardize the definition of POR, Ferraretti et al. (2) proposed new criteria, known as the ‘‘Bologna criteria,’’ based on three conditions: 1) advanced maternal age (R40 years) or any other POR risk factor; 2) a previous incident of POR; and 3) a low ovarian reserve test in terms of antim€ ullerian hormone (AMH) and antral follicle count (AFC). Two of these three criteria are required for a POR diagnosis. In addition, two cycles with POR after maximal stimulation are sufficient to classify a patient as a poor responder even in the absence of the other criteria mentioned. Although the Bologna criteria were found to be useful in predicting the outcome of IVF and for counseling purposes, their use in clinical trials has been questioned because they entail the risk of grouping together women who differ significantly in biologic characteristics (3). For example, according to the Bologna criteria, young women with a low ovarian reserve associated with a previous episode of POR, young women with a normal ovarian reserve and two POR episodes, and older women (R40 years) with a normal ovarian reserve and a previous episode of POR would be included in the same category even though the clinical management of these patients requires different strategies. In clinical terms, apart from the number of oocytes retrieved, various features that may affect treatment outcomes must be considered in the management of patients, namely: 1) the age-related embryo/blastocyst aneuploidy rate, which could dramatically change the prognosis in women that have the same oocyte yield; and 2) ovarian ‘‘sensitivity’’ to exogenous gonadotropins, which could be related to a specific genetic profile. To introduce a more nuanced picture of POR, we here propose clinically relevant criteria that can help to guide the physician in the management of patients. In detail, we suggest a more specific new definition of ‘‘low prognosis’’ patients that:

Pre-term birth and low birth weight following preimplantation genetic diagnosis: analysis of 88 010 singleton live births following PGD and IVF cycles.

STUDY QUESTION Is PGD associated with the risk of adverse perinatal outcomes such as pre-term birth (PTB) and low birth weight (LBW)? SUMMARY ANSWER There was no increase in the risk of adverse perinatal outcomes of PTB, and LBW following PGD compared with autologous IVF. WHAT IS KNOWN ALREADY Pregnancies resulting from ART are associated with a higher risk of pregnancy complications compared with spontaneously conceived pregnancies. The possible reason of adverse obstetric outcomes following ART has been attributed to the underlying infertility itself and embryo specific epigenetic modifications due to the IVF techniques. It is of interest whether interventions such as embryo biopsy as performed in PGD affect perinatal outcomes. STUDY DESIGN, SIZE, DURATION Anonymous data were obtained from the Human Fertilization and Embryology Authority (HFEA), the statutory regulator of ART in the UK. The HFEA has collected data prospectively on all ART performed in the UK since 1991. Data from 1996 to 2011 involving a total of 88 010 singleton live births were analysed including 87 571 following autologous stimulated IVF ± ICSI and 439 following PGD cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS Data on all women undergoing either a stimulated fresh IVF ± ICSI treatment cycle or a PGD cycle during the period from 1996 to 2011 were analysed to compare perinatal outcomes of PTB and LBW among singleton live births. Logistic regression analysis was performed adjusting for female age category, year of treatment, previous IVF cycles, infertility diagnosis, number of oocytes retrieved, whether IVF or ICSI was used and day of embryo transfer. MAIN RESULTS AND THE ROLE OF CHANCE There was no increase in the risk of PTB and LBW following PGD versus autologous stimulated IVF ± ICSI treatment, unadjusted odds of PTB (odds ratio (OR) 0.68, 95% CI: 0.46–0.99) and LBW (OR 0.56, 95% CI: 0.37–0.85). After adjusting for the potential confounders, there was again no increase in the risk of the adverse perinatal outcomes following PGD: PTB (adjusted odds ratio (aOR) 0.66, 95% CI: 0.45–0.98) and LBW (aOR 0.58, 95% CI: 0.38–0.88). LIMITATIONS, REASONS FOR CAUTION Although the analysis was adjusted for a number of important confounders, the data set had no information on confounders such as smoking, body mass index and the medical history of women during pregnancy to allow adjustment. There was no information on the stage of embryo at biopsy, whether blastomere or trophectoderm biopsy. WIDER IMPLICATIONS FOR THE FINDINGS The demonstration that PGD is not associated with higher risk of PTB and LBW provides reassurance towards its current expanding application. STUDY FUNDING/COMPETING INTEREST(S) No funding was obtained. There are no competing interests to declare.

Perinatal outcomes after stimulated versus natural cycle IVF: a systematic review and meta-analysis

Pregnancies resulting from assisted reproductive techniques are at higher risk of adverse perinatal outcomes compared with spontaneous conceptions. Underlying infertility and IVF procedures have been linked to adverse perinatal outcomes. It is important to know if ovarian stimulation influences perinatal outcomes after IVF. A systematic search for relevant studies was conducted up to November 2016 on the following databases: PubMed, EMBASE, DARE and Cochrane Central Register of Controlled Trials. Perinatal outcomes included preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA), large for gestational age (LGA) and congenital anomalies. Data from four studies, which included a total of 96,996 and 704 singleton live births after stimulated IVF and natural or modified natural cycle IVF, were included in the meta-analysis. The risk of PTB (RR 1.27, 95% CI 1.03 to 1.58) and LBW (RR 1.95, 95% CI 1.03 to 3.67) were significantly higher after stimulated compared with natural or modified natural cycle IVF. Data from one study were available for SGA, LGA, congenital anomalies and no significant differences were reported between the groups. This study suggests a higher risk of PTB and LBW after stimulated IVF compared with natural or modified natural IVF, although the absolute increase in risk may be low.

Higher risk of preterm birth and low birth weight following oocyte donation: A systematic review and meta-analysis

OBJECTIVES To perform a systematic review and meta-analysis of the known literature to assess whether the perinatal outcomes are different after oocyte donation (OD) compared to autologous oocyte (AO) in vitro fertilization (IVF) pregnancies. STUDY DESIGN A systematic literature search was done for studies published in English from 1980 to 2016. Studies comparing perinatal outcomes of pregnancies following fresh or frozen OD and AO IVF were included. Meta-analysis was performed using the Rev Man 5.3 software (Cochrane Collaboration) for the perinatal outcomes of PTB (<37 weeks), early PTB (<32 weeks), LBW (<2500g), very LBW (<1500g), and SGA (<10th centile). Six studies provided data on PTB, three studies on early PTB, five studies on LBW, four studies on very LBW and three studies on SGA after fresh embryo transfer. Two studies provided data on PTB, early PTB, LBW and very LBW after frozen embryo transfer. RESULTS There is an increased risk of PTB following fresh embryo transfer in OD pregnancies than in AO IVF pregnancies (OR 1.45, 95% CI 1.20-1.77). If the PTB risk is assumed to be to 9% for pregnancies following AO IVF, then OD pregnancies will have a PTB risk between 10.8% and 15.9%. Similarly, the risk of LBW is higher after fresh embryo transfer in OD pregnancies than AO IVF pregnancies (OR 1.34, 95% CI 1.12-1.60). If the assumed LBW risk is 9% for AO IVF pregnancies, then OD pregnancies have a LBW risk between 10.1% and 14.4%. There is an increased risk of early PTB (OR 2.14, 95% CI 1.40-3.25) and very LBW (OR 1.51, 95% CI 1.17-1.95) in a fresh embryo transfer after OD as compared to AO IVF pregnancies. CONCLUSIONS There appears to be a higher risk of adverse perinatal outcomes following fresh OD compared to AO IVF pregnancies.

Perinatal outcomes after gestational surrogacy versus autologous IVF: analysis of national data

Anonymized data were obtained from the Human Fertilization and Embryology Authority to determine whether gestational surrogacy influences perinatal outcomes compared with pregnancies after autologous IVF. A total of 103,160 singleton live births, including 244 after gestational surrogacy, 87,571 after autologous fresh IVF and intractyoplasmic sperm injection (ICSI) and 15,345 after autologous frozen embryo transfers were analysed. Perinatal outcomes of pretern birth (PTB), low birth weight (LBW) and high birth weight (HBW) were compared. No difference was found in the risk of PTB and LBW after gestational surrogacy compared with autologous fresh IVF-ICSI: PTB (adjusted OR 0.90, 95% CI 0.56 to 1.42), LBW (adjusted OR 0.90, 95% CI 0.57 to 1.43) and gestational surrogacy compared with autologous frozen embryo transfers: PTB (adjusted OR 0.96, 95% CI 0.58 to 1.60), LBW (adjusted OR 1.16, 95% CI 0.69 to 1.96). The incidence of HBW was significantly higher after gestational surrogacy compared with fresh IVF-ICSI (adjusted OR 1.94, 95% CI 1.38 to 2.75); no difference was found in HBW between gestational surrogacy and autologous frozen embryo transfers. The dataset is limited by lack of information on confounders, i.e. ethnicity, body mass index, underlying medical history, which could result in residual confounding.

High-risk of preterm birth and low birth weight after oocyte donation IVF: analysis of 133,785 live births

A higher risk of pregnancy complications occurs after assisted reproductive techniques compared with spontaneously conceived pregnancies. This is attributed to the underlying infertility and assisted reproduction technique procedures involved during treatment. It is a matter of interest whether use of donor oocytes affects perinatal outcomes compared with pregnancies after autologous IVF. Anonymized data were obtained from the Human Fertilization and Embryology Authority. The analysis included 5929 oocyte donation and 127,856 autologous IVF live births. Data from all women who underwent donor oocyte recipient or autologous IVF cycles, both followed with fresh embryo transfer, were analysed to compare perinatal outcomes of preterm birth (PTB) and low birthweight (LBW) after singleton and multiple live births. The risk of adverse perinatal outcomes after oocyte donation was increased: adjusted OR (aOR) 1.56, 99.5% CI 1.34 to 1.80 for PTB and aOR 1.43, 99.5% CI 1.24 to 1.66 for LBW were significantly higher after oocyte donation compared with autologous IVF singletons. The adjusted odds PTB (aOR 1.21, 99.5% CI 1.02 to 1.43) was significantly higher after oocyte donation compared with autologous IVF multiple births. Analysis of this large dataset suggests significantly higher risk of PTB and LBW after ooctye donation compared with autologous IVF pregnancies.

Perinatal outcomes following IVF with use of donor versus partner sperm

It is a matter of interest whether pregnancies with the use of donor sperm are associated with a higher risk of adverse perinatal outcomes compared with partner sperm. Anonymized data were obtained from the Human Fertilization & Embryology Authority. Data from 1991 to 2011 involving a total of 95,787 singleton births (4523 with donor sperm and 91,264 with partner sperm) following fresh IVF/intracytoplasmic sperm injection (ICSI) were analysed to compare perinatal outcomes of preterm birth (PTB), low birthweight (LBW) and high birthweight (HBW). The risk of LBW was significantly lower (adjusted odds ratio [aOR] 0.88, 95% confidence interval [CI]: 0.79-0.99) following donor sperm versus partner sperm IVF/ICSI. There was no significant difference in the risk of PTB (aOR 0.93, 95% CI: 0.83-1.04), early PTB (aOR 0.86, 95% CI: 0.67-1.11), very LBW (aOR 0.95, 95% CI: 0.75-1.20), HBW (aOR 1.09, 95% CI: 0.98-1.21) and very HBW (aOR 1.15, 95% CI: 0.90-1.45) following donor sperm versus partner sperm IVF/ICSI. The current study did not demonstrate an increased risk of adverse perinatal outcomes following donor sperm compared with partner sperm IVF/ICSI treatment.

Perinatal outcomes of singleton live births with and without vanishing twin following transfer of multiple embryos: analysis of 113 784 singleton live births

STUDY QUESTION Does transfer of multiple embryos affect perinatal outcomes of resulting singleton live births following ART? SUMMARY ANSWER There is a higher risk of preterm birth (PTB) and low birthweight (LBW) in singleton live births associated with spontaneous reduction of an initial multiple to singleton gestation following transfer of multiple embryos. WHAT IS KNOWN ALREADY Singleton pregnancies following ART are at a higher risk of adverse perinatal outcomes compared to spontaneous conceptions. Earlier studies have found an increased risk of PTB and LBW in singletons following transfer of multiple embryos versus single embryo transfer (SET). However, these studies did not address the specific role of vanishing twin, i.e. spontaneous reduction of an initial multiple to singleton gestation. STUDY DESIGN, SIZE, DURATION Anonymised data on all ART cycles performed in the UK were obtained from the Human Fertilization and Embryology Authority. Data from 1991 to 2011 involving 508 410 fresh and 131 157 frozen autologous ART cycles resulting in 95 779 and 18 005 singleton live births, respectively, were analyzed. PARTICIPANTS/MATERIALS, SETTING, METHODS Fresh and frozen ART cycles were analyzed separately to compare perinatal outcomes of PTB and LBW of singleton live births resulting from transfer of multiple (≥2) embryos versus SET. Logistic regression analysis was performed adjusting for confounders. Subgroup analyses were carried out for perinatal outcomes of singleton live births with initial multiple or initial single gestational sacs following transfer of multiple embryos versus singleton live births following SET. MAIN RESULTS AND THE ROLE OF CHANCE In fresh cycles, there was a significantly higher risk of PTB (adjusted odds ratio (aOR) 2.70, CI 2.37-3.05) and LBW (aOR 2.76, CI 2.44-3.13) in singleton live births with initial multiple gestational sacs but there was no significant difference in the risk of PTB (aOR 1.08, CI 1.00-1.16) or LBW (aOR 1.08, CI 1.00-1.16) in singleton live births with an initial single gestational sac following transfer of ≥2 embryos compared to those following SET. In frozen cycles, there was a significantly higher risk of PTB (aOR 2.13, CI: 1.55-2.93) and LBW (aOR 2.61, CI: 1.87-3.64) in singleton live births with initial multiple gestational sacs but there was no significant difference in the risk of PTB (aOR 1.02, CI: 0.88-1.18) or LBW (aOR 0.91, CI: 0.77-1.07) in the singleton live births with an initial single gestational sac following transfer of ≥2 embryos compared to those following SET. LIMITATIONS, REASONS FOR CAUTION While the analysis was adjusted for a number of known confounders, the dataset had no information for confounders such as smoking, BMI, previous obstetric history and comorbid medical conditions during pregnancy. The lack of information about the timing of occurrence of the vanishing phenomenon is another limitation because poorer perinatal outcomes of a surviving twin have been reported following second trimester fetal demise compared to the first trimester. WIDER IMPLICATIONS OF THE FINDINGS The study results suggest that the vanishing twin phenomenon is associated with increased risk of PTB and LBW in the resulting singleton live births and there was no increased risk when there was a single gestational sac from the outset following transfer of multiple embryos. STUDY FUNDING/COMPETING INTERESTS Nil.

Personalized ovarian stimulation for assisted reproductive technology: study design considerations to move from hype to added value for patients

Although most medical treatments are designed for the average patient with a one-size-fits-all-approach, they may not benefit all. Better understanding of the function of genes, proteins, and metabolite, and of personal and environmental factors has led to a call for personalized medicine. Personalized reproductive medicine is still in its infancy, without clear guidance on treatment aspects that could be personalized and on trial design to evaluate personalized treatment effect and benefit-harm balance. While the rationale for a personalized approach often relies on retrospective analyses of large observational studies or real-world data, solid evidence of superiority of a personalized approach will come from randomized trials comparing outcomes and safety between a personalized and one-size-fits-all strategy. A more efficient, targeted randomized trial design may recruit only patients or couples for which the personalized approach would differ from the previous, standard approach. Multiple monocenter studies using the same study protocol (allowing future meta-analysis) might reduce the major center effect associated with multicenter studies. In certain cases, single-arm observational studies can generate the necessary evidence for a personalized approach. This review describes each of the main segments of patient care in assisted reproductive technologies treatment, addressing which aspects could be personalized, emphasizing current evidence and relevant study design.

Perinatal outcomes after oocyte donation and in-vitro fertilization

Purpose of review To critically appraise the existing literature on perinatal outcomes following oocyte donation (OD) pregnancies and compare it with autologous in-vitro fertilization (IVF) pregnancies. Recent findings OD pregnancies are at higher risk of developing hypertensive disorders compared with autologous IVF. The risk of preterm birth and low birth weight is higher with singleton and multiple OD compared with autologous IVF pregnancies. There is no increased risk of congenital malformations following OD compared with autologous IVF births. Summary OD pregnancies are at higher risk of developing hypertensive disorders and adverse perinatal outcomes compared with autologous IVF.