Perinatal and maternal outcome after vitrification of blastocysts: a Nordic study in singletons from the CoNARTaS group.

STUDY QUESTION: Is transfer of vitrified blastocysts associated with higher perinatal and maternal risks compared with slow-frozen cleavage stage embryos and fresh blastocysts? SUMMARY ANSWER: Transfer of vitrified blastocysts is associated with a higher risk of preterm birth (PTB) when compared with slow-frozen cleavage stage embryos and with a higher risk of a large baby, hypertensive disorders in pregnancy (HDPs) and postpartum hemorrhage (PPH) but a lower risk of placenta previa when compared with fresh blastocysts. WHAT IS KNOWN ALREADY: Transfer of frozen-thawed embryos (FETs) plays a central role in modern fertility treatment, limiting the risk of ovarian hyperstimulation syndrome and multiple pregnancies. Following FET, several studies report a lower risk of PTB, low birth weight (LBW) and small for gestational age (SGA) yet a higher risk of fetal macrosomia and large for gestational age (LGA) compared with fresh embryos. In recent years, the introduction of new freezing techniques has increased treatment success. The slow-freeze technique combined with cleavage stage transfer has been replaced by vitrification and blastocyst transfer. Only few studies have compared perinatal and maternal outcomes after vitrification and slow-freeze and mainly in cleavage stage embryos, with most studies indicating similar outcomes in the two groups. Studies on perinatal and maternal outcomes following vitrified blastocysts are limited. STUDY DESIGN, SIZE, DURATION: This registry-based cohort study includes singletons born after frozen-thawed and fresh transfers following the introduction of vitrification in Sweden and Denmark, in 2002 and 2009, respectively. The study includes 3650 children born after transfer of vitrified blastocysts, 8123 children born after transfer of slow-frozen cleavage stage embryos and 4469 children born after transfer of fresh blastocysts during 2002-2015. Perinatal and maternal outcomes in singletons born after vitrified blastocyst transfer were compared with singletons born after slow-frozen cleavage stage transfer and singletons born after fresh blastocyst transfer. Main outcomes included PTB, LBW, macrosomia, HDP and placenta previa. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were obtained from the CoNARTaS (Committee of Nordic ART and Safety) group. Based on national registries in Sweden, Finland, Denmark and Norway, the CoNARTaS cohort includes all children born after ART treatment in public and private clinics 1984-2015. Outcomes were assessed with logistic multivariable regression analysis, adjusting for the country and year of birth, maternal age, body mass index, parity, smoking, parental educational level, fertilisation method (IVF/ICSI), single embryo transfer, number of gestational sacs and the child's sex. MAIN RESULTS AND THE ROLE OF CHANCE: A higher risk of PTB (<37 weeks) was noted in the vitrified blastocyst group compared with the slow-frozen cleavage stage group (adjusted odds ratio, aOR [95% CI], 1.33 [1.09-1.62]). No significant differences were observed for LBW (<2500 g), SGA, macrosomia (≥4500 g) and LGA when comparing the vitrified blastocyst with the slow-frozen cleavage stage group. For maternal outcomes, no significant difference was seen in the risk of HDP, placenta previa, placental abruption and PPH in the vitrified blastocyst versus the slow frozen cleavage stage group, although the precision was limited.When comparing vitrified and fresh blastocysts, we found higher risks of macrosomia (≥4500 g) aOR 1.77 [1.35-2.31] and LGA aOR 1.48 [1.18-1.84]. Further, the risks of HDP aOR 1.47 [1.19-1.81] and PPH aOR 1.68 [1.39-2.03] were higher in singletons born after vitrified compared with fresh blastocyst transfer while the risks of SGA aOR 0.58 [0.44-0.78] and placenta previa aOR 0.35 [0.25-0.48] were lower. LIMITATIONS, REASONS FOR CAUTION: Since vitrification was introduced simultaneously with blastocyst transfer in Sweden and Denmark, it was not possible to explore the effect of vitrification per se in this study. WIDER IMPLICATIONS OF THE FINDINGS: The results from the change of strategy to vitrification of blastocysts are reassuring, indicating that the freezing technique per se has no major influence on the perinatal and maternal outcomes. The higher risk of PTB may be related to the extended embryo culture rather than vitrification. STUDY FUNDING/COMPETING INTEREST(S): The study is part of the ReproUnion Collaborative study, co-financed by the European Union, Interreg V ÖKS. The study was also financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (LUA/ALF 70940), Hjalmar Svensson Research Foundation and NordForsk (project 71 450). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: ISRCTN11780826.

Determinants of monozygotic twinning in ART: a systematic review and a meta-analysis.

BACKGROUND: The incidence of monozygotic twins (MZT) after ART appears to be higher than the incidence after spontaneous conceptions contradicting the aim of ART to avoid multiple pregnancies because of the associated risks. OBJECTIVE AND RATIONALE: The aim was to study the frequency of MZT after IVF and ICSI and how it is influenced by the day of embryo transfer, maternal age, zona pellucida manipulation, controlled ovarian stimulation, stimulation protocol, culture media and embryo quality. SEARCH METHODS: Original studies and reviews were identified by searching the PubMed, Embase and Cochrane databases up to March 2017. The inclusion criterion was publications focusing on the five study questions related to MZT in our study. The exclusion criteria were articles that did not include blastocyst transfer, were on non-humans, were not published in peer-reviewed journals, and were based only on case studies. All of the articles were categorized according to the Oxford Centre for Evidence-based Medicine's 'Levels of Evidence', and quality and risk of bias assessment was performed with 'The Cochrane Collaboration's Risk of Bias Tools'. A meta-analysis was performed to study the impact of the day of embryo transfer on the MZT rate. OUTCOMES: The literature search resulted in a total of 42 articles, including 38 original studies, for analysis. The included original studies reported a MZT rate with blastocyst transfer from zero to 13.2%. Our meta-analysis found a higher frequency of MZT after blastocyst transfer compared with cleavage-stage embryos transfer: odds ratio = 2.18, 95% CI: 1.93-2.48 (fixed effect meta-analysis). A younger maternal age may increase the MZT rate, and recent studies regarding the use of zona pellucida manipulating techniques have disagreed with the previous suspicion of a higher MZT rate after the use of these methods. The extended culture to-blastocyst stage is a potential risk factor for MZT, but it is uncertain whether this phenomenon is due to the extended time, culture media or greater likelihood of younger oocytes to reach the blastocyst stage. An increased frequency of MZT following the GnRH-agonist suppression protocol has been suggested, as well as a decreased frequency of MZT with high gonadotrophin doses, which could reflect an age-related effect. Only limited literature has focused on the role of embryo morphology in the MZT rate, therefore, this issue remains unresolved. WIDER IMPLICATIONS: We found blastocyst transfer to be a risk factor for MZT. Hence, the results of this meta-analysis may weaken the previously proposed view that greater experience with blastocyst transfer and improved culture media could decrease the high rate of MZT after blastocyst transfer. To minimize the rate of MZT and the associated complications, the mechanisms underlying blastocyst transfer and MZT pregnancy must be elucidated.

Perinatal outcomes in 6,338 singletons born after intrauterine insemination in Denmark, 2007 to 2012: the influence of ovarian stimulation.

OBJECTIVE: To study perinatal outcomes in singletons born after intrauterine insemination (IUI) compared with children born after in vitro fertilization (IVF), intracytoplasmic sperm injection, and spontaneous conception (SC), and to assess predictors of poor outcome in singletons born after IUI, exploring the effect of ovarian stimulation. DESIGN: National cohort study, 2007-2012. SETTING: Danish national registries. PATIENT(S): Four thousand two hundred twenty-eight singletons born after insemination with partner semen (IUI-H) and 1,881 singletons born after insemination with donor semen. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA). RESULT(S): Children born after IUI-H had higher risks of PTB, LBW, and SGA vs. SC singletons (adjusted odds ratios [aOR] 1.3; 95% confidence interval (CI), 1.1-1.5; 1.4; 95% CI, 1.2-1.7; and 1.4; 95% CI, 1.2-1.6), respectively. Compared with IVF, risk of SGA was similar, but risks of PTB and LBW were lower (aOR 0.6; 95% CI, 0.5-0.8; and 0.8; 95% CI, 0.6-0.9). Compared with intracytoplasmic sperm injection, no differences were found. For children born after IUI with donor semen, results were similar to those for IUI-H. Risks of LBW and SGA were higher in IUI singletons born after ovarian stimulation with clomiphene citrate, compared with natural-cycle IUI (aOR 1.5; 95% CI, 1.1-2.1 and 1.6; 95% CI, 1.1-2.4). Treatment with follicle-stimulating hormone vs. natural-cycle IUI did not seem to affect perinatal outcomes. CONCLUSION(S): Singletons born after IUI had higher risk of adverse perinatal outcomes compared with SC children, similar to ICSI, but favorable outcomes compared with IVF. Stimulation with clomiphene citrate was associated with higher risk of SGA compared with natural-cycle IUI, but follicle-stimulating hormone treatment did not seem to be associated with adverse outcomes.

[The prognosis for children born after assisted reproduction]. / Prognosen for børn født efter assisteret reproduktion.

Children who are born after assisted reproduction (ART) have a slightly increased risk of being born preterm, of having low birthweight and a higher perinatal mortality than spontaneously conceived children. The higher rate of multiple births among women having had ART can to some extent explain this. However, adverse outcomes persist even in ART singletons. The characteristics of the infertile parents have negative effects on the outcome, but also the hormone stimulation and the in vitro techniques are thought to play a role. A milder hormone stimulation and elective single embryo transfer, which reduces the number of multiples after ART, have improved the overall health of children born as a result of ART.

Clear cell sarcoma of soft tissues.

Clear cell sarcoma (CCS) is a rare but highly malignant tumor of soft tissues often appearing as a small tender mass in the deep tissues of the distal extremities. We have studied 17 patients with such lesions treated since 1986 and have a high incidence of local recurrence and metastasis with a survival rate of only 47% despite surgery and for many of the patients, adjuvant therapy. The purpose of this article is to warn the readers of the dangers related to treating this seemingly benign lesion and urge them to perform wide surgery and utilize adjuvant therapy.