Hazekamp, J., Bergh, C., Wennerholm, U. B., Hovatta, O., Karlström, P. O., & Selbing, A. (2000). Avoiding multiple pregnancies in ART: consideration of new strategies. Human reproduction (Oxford, England), 15(6), 1217-1219. https://doi.org/10.1093/humrep/15.6.1217
Hazekamp J, Bergh C, Wennerholm UB, Hovatta O, Karlström PO, Selbing A. Avoiding multiple pregnancies in ART: consideration of new strategies. Hum Reprod. 2000;15(6):1217-1219. doi:10.1093/humrep/15.6.1217
Hazekamp, Johan, et al. "Avoiding multiple pregnancies in ART: consideration of new strategies." Human reproduction (Oxford, England), vol. 15, no. 6, 2000, pp. 1217-1219.
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To maximize pregnancy rates, physicians who perform IVF, often transfer multiple embryos, which increases the multiple birth risk. Multiple birth infants are at significant risk for a number of adverse outcomes including preterm delivery, low birth weight, congenital malformations, fetal and infant deaths and long term morbidity and disability among survivors. Since the ultimate goal for an IVF treatment is the birth of a healthy infant, an important issue for all kinds of assisted reproductive technologies (ART) must be the reduction or elimination of multiple pregnancies. In this article, different strategies to avoid multiple births in ART are discussed.
Landsverk E et al., 2025·PLoS medicine·Free full text on PubMed Central
A higher risk of placenta previa after assisted reproductive technology (ART) is well established. The underlying mechanisms are poorly understood, but may relate to embryo culture duration, cryopreservation, and cause of infertility. Within-mother analyses, where each woman is her own control (i.e., sibling design), help disentangle treatment contributions from maternal confounders that are stable between pregnancies. We aimed to investigate the risk of placenta previa in pregnancies achieved after ART according to embryo culture duration, cryopreservation, and infertility factors while accounting for stable maternal factors using within-mother analyses. We used linked nationwide registry data from Denmark (1994 to 2014), Finland (1990 to 2014), Norway (1988 to 2015), and Sweden (1988 to 2015). All women who gave their first birth during the study period at age 20 years or older were eligible and contributed up to 4 deliveries (singleton or multifetal) occurring between 22 and 44 weeks of gestation, excluding deliveries where maternal age exceeded 45 years. We used multilevel logistic regression to compare risk of placenta previa after ART (n = 139,694 deliveries) versus natural conception (n = 5,614,512 deliveries), both at the population level and within mothers, adjusting for year of delivery, maternal age, parity, and country. We categorized ART according to culture duration, embryo cryopreservation, and infertility factors. Population level risk of placenta previa was higher for ART versus natural conception (odds ratio [OR], 4.16; 95% confidence interval [CI], 3.96-4.37). Controlling for stable maternal factors, the association attenuated, but risk remained higher for ART versus natural conception (OR within mothers, 2.64; 95% CI, 2.31-3.02). Compared to naturally conceived, a larger difference in risk was seen for pregnancies from fresh embryos than for pregnancies from frozen embryos. Further categorization by culture duration showed the largest risk difference after fresh blastocyst transfer, and the smallest after frozen cleavage stage embryo transfer, which persisted in sensitivity analyses (including restriction to singletons). When stratified according to infertility factors at the population level, women with endometriosis conceiving by ART had the highest risk of placenta previa (OR, 9.35; 95% CI, 8.50-10.29), whereas women with polycystic ovary syndrome (PCOS) conceiving by ART had the lowest risk (OR, 1.52; 95% CI, 1.12-2.09), compared to natural conception. Within mothers, we found a higher risk of placenta previa after ART compared to natural conception for women with endometriosis (OR, 2.08; 95% CI, 1.50-2.90), but not for women with PCOS (OR, 0.88; 95% CI, 0.41-1.89 [unadjusted due to sparse data]). However, within-mother analyses are restricted to multiparous women with deliveries after different conception methods. Therefore, findings from these analyses might not generalize to all women undergoing ART. The risk of placenta previa in pregnancies conceived by ART differed by embryo culture duration, cryopreservation, and underlying infertility. The highest risk was seen after fresh embryo transfer and especially fresh blastocyst transfer. Women with endometriosis had a higher risk than women with other infertility factors, and within mothers, their risk was higher after ART than after natural conception. Identifying the responsible mechanisms might provide opportunities for prevention.
Sargisian N et al., 2024·European heart journal·Free full text on PubMed Central
Children born after assisted reproductive technology (ART) have worse perinatal outcomes compared with spontaneously conceived children. This study investigates whether children conceived after ART have a higher risk of congenital heart defects (CHDs) compared with children born after spontaneous conception (SC). All 7 747 637 liveborn children in Denmark (1994-2014), Finland (1990-2014), Norway (1984-2015), and Sweden (1987-2015), where 171 735 children were conceived after ART, were included. National ART and medical birth registry data were cross-linked with data from other health and population registries. Outcomes were major CHDs, severe CHDs, 6 hierarchical CHD lesion groups, and 10 selected major CHDs, diagnosed prenatally or up to 1 year of age (Denmark, Finland, and Sweden) and prenatally or at birth (Norway). The association between ART and CHDs was assessed with multivariable logistic regression analysis, with adjustment for available confounders. Major CHDs were detected in 3159 children born after ART (1.84%) and in 86 824 children born after SC [1.15%; adjusted odds ratio (AOR) 1.36; 95% confidence interval (CI) 1.31-1.41]. Risk was highest in multiples, regardless of conception method. Severe CHDs were detected in 594 children born after ART (0.35%) and in 19 375 children born after SC (0.26%; AOR 1.30; 95% CI 1.20-1.42). Risk was similar between ICSI and IVF and between frozen and fresh embryo transfer. Assisted reproductive technology-conceived children have a higher prevalence of major CHDs, being rare, but severe conditions. The absolute risks are, however, modest and partly associated with multiple pregnancies, more prevalent in ART.
Smeenk J et al., 2023·Human Reproduction·Free full text on PubMed Central
**STUDY ** What are the data and trends on ART and IUI cycle numbers and their outcomes, and on fertility preservation (FP) interventions, reported in 2019 as compared to previous years? **SUMMARY ** The 23rd ESHRE report highlights the rising ART treatment cycles and children born, alongside a decline in twin deliveries owing to decreasing multiple embryo transfers; fresh IVF or ICSI cycles exhibited higher delivery rates, whereas frozen embryo transfers (FET) showed higher pregnancy rates (PRs), and reported IUI cycles decreased while maintaining stable outcomes. **WHAT ** ART aggregated data generated by national registries, clinics, or professional societies have been gathered and analyzed by the European IVF-Monitoring (EIM) Consortium since 1997 and reported in a total of 22 manuscripts published in *Human Reproduction* and *Human Reproduction Open*. **STUDY DESIGN, SIZE, ** Data on medically assisted reproduction (MAR) from European countries are collected by EIM for ESHRE each year. The data on treatment cycles performed between 1 January and 31 December 2019 were provided by either national registries or registries based on initiatives of medical associations and scientific organizations or committed persons in one of the 44 countries that are members of the EIM Consortium. **PARTICIPANTS/MATERIALS, SETTING, ** Overall, 1487 clinics offering ART services in 40 countries reported, for the second time, a total of more than 1 million (1 077 813) treatment cycles, including 160 782 with IVF, 427 980 with ICSI, 335 744 with FET, 64 089 with preimplantation genetic testing (PGT), 82 373 with egg donation (ED), 546 with IVM of oocytes, and 6299 cycles with frozen oocyte replacement (FOR). A total of 1169 institutions reported data on IUI cycles using either husband/partner's semen (IUI-H; n = 147 711) or donor semen (IUI-D; n = 51 651) in 33 and 24 countries, respectively. Eighteen countries reported 24 139 interventions in pre- and post-pubertal patients for FP, including oocyte, ovarian tissue, semen, and testicular tissue banking. **MAIN ** In 21 countries (21 in 2018) in which all ART clinics reported to the registry 476 760 treatment cycles were registered for a total population of approximately 300 million inhabitants, allowing the best estimate of a mean of 1581 cycles performed per million inhabitants (range: 437–3621). Among the reporting countries, for IVF the clinical PRs per aspiration slightly decreased while they remained similar per transfer compared to 2018 (21.8% and 34.6% versus 25.5% and 34.1%, respectively). In ICSI, the corresponding PRs showed similar trends compared to 2018 (20.2% and 33.5%, versus 22.5% and 32.1%) When freeze-all cycles were not considered for the calculations, the clinical PRs per aspiration were 28.5% (28.8% in 2018) and 26.2% (27.3% in 2018) for IVF and ICSI, respectively. After FET with embryos originating from own eggs, the PR per thawing was at 35.1% (versus 33.4% in 2018), and with embryos originating from donated eggs at 43.0% (41.8% in 2018). After ED, the PR per fresh embryo transfer was 50.5% (49.6% in 2018) and per FOR 44.8% (44.9% in 2018). In IVF and ICSI together, the trend toward the transfer of fewer embryos continues with the transfer of 1, 2, 3, and ≥4 embryos in 55.4%, 39.9%, 2.6%, and 0.2% of all treatments, respectively (corresponding to 50.7%, 45.1%, 3.9%, and 0.3% in 2018). This resulted in a reduced proportion of twin delivery rates (DRs) of 11.9% (12.4% in 2018) and a similar triplet DR of 0.3%. Treatments with FET in 2019 resulted in twin and triplet DR of 8.9% and 0.1%, respectively (versus 9.4% and 0.1% in 2018). After IUI, the DRs remained similar at 8.7% after IUI-H (8.8% in 2018) and at 12.1% after IUI-D (12.6% in 2018). Twin and triplet DRs after IUI-H were 8.7% and 0.4% (in 2018: 8.4% and 0.3%) and 6.2% and 0.2% after IUI-D (in 2018: 6.4% and 0.2%), respectively. Eighteen countries (16 in 2018) provided data on FP in a total number of 24 139 interventions (20 994 in 2018). Cryopreservation of ejaculated sperm (n = 11 592 versus n = 10 503 in 2018) and cryopreservation of oocytes (n = 10 784 versus n = 9123 in 2018) were most frequently reported. **LIMITATIONS, ** Caution with the interpretation of results should remain as data collection systems and completeness of reporting vary among European countries.
H Petersen S et al., 2023·Hypertension (Dallas, Tex. : 1979)
Frozen embryo transfer (frozen-ET) is increasingly common because of improved cryopreservation methods and elective freezing of all embryos. Frozen-ET is associated with higher risk of hypertensive disorders in pregnancy than both natural conception and fresh embryo transfer (fresh-ET), but whether this is attributable to parental factors or treatment is unknown. Using the Medical Birth Registries of Denmark (1994-2014), Norway, and Sweden (1988-2015), linked to data from national quality registries and databases on assisted reproduction, we designed a population-based cohort study with within-sibship comparison. We included 4 426 691 naturally conceived, 78 300 fresh-ET, and 18 037 frozen-ET singleton pregnancies, of which 33 209 sibships were conceived using different conception methods. Adjusted odds ratios (aOR) of hypertensive disorders in pregnancy for fresh-ET and frozen-ET versus natural conception with 95% CI were estimated using multilevel logistic regression, where random effects provided conventional population-level estimates and fixed effects gave within-sibship estimates. Main models included adjustment for birth year, maternal age, parity, and country. Risk of hypertensive disorders in pregnancy was higher after frozen-ET compared to natural conception, both at population-level (7.4% versus 4.3%, aOR, 1.74 [95% CI, 1.61-1.89]) and within sibships (aOR, 2.02 [95% CI, 1.72-2.39]). For fresh-ET, risk was similar to natural conception, both at population-level (aOR, 1.02 [95% CI, 0.98-1.07]) and within sibships (aOR, 0.99 [95% CI, 0.89-1.09]). Frozen-ET was associated with substantially higher risk of hypertensive disorders in pregnancy, even after accounting for shared parental factors within sibships.
To limit the high number of multiple pregnancies in an IVF program. In Vitro Fertilization Laboratory, Fertility Department, Public Hospital. The number of embryos transferred was limited to two instead of three. Limiting the number of embryos transferred to only two did not influence the take home baby rate but eliminated triplet and quadruplet gestations. Moreover, the number of patients with good quality supernumerary embryos available for cryopreservation increased. To reduce the high frequency of multiple gestations in an IVF program, the number of embryos replaced should be limited to a maximum of two.
The use of assisted reproductive technology (ART) for treating the infertile couple is increasing in the United States. The purpose of this paper is to review the short-term outcomes after ART. Pregnancy rates after ART have shown nearly continuous improvement in the years since its inception. A number of factors affect the pregnancy rate, with the most important being a woman's age. Certain clinical diagnoses are associated with a poorer outcome from ART, including the presence of hydrosalpinges, uterine leiomyomata that distort the endometrial cavity, and decreased ovarian reserve. Multiple gestations are the major complication after ART. New laboratory techniques, including extended embryo culture, may allow the transfer of fewer embryos to maintain pregnancy rates while reducing the risk of multiple gestations. Although much of the morbidity in children born after ART is the result of multiples, recent analysis suggests that even singletons are at higher risk for perinatal morbidity, including preterm delivery and small for gestational age infants. In vitro fertilization may be associated with a slight increased risk for birth defects. The major short-term complication of ART in women is the development of ovarian hyperstimulation syndrome. This syndrome is difficult to predict, but new treatments are being developed that may limit its frequency. Because of its high pregnancy rate, couples are moving to ART more quickly in the management of their infertility. All outcomes of ART, including pregnancy rates and adverse complications, need to be compared with standard non-ART therapy when deciding the appropriate course of treatment for a given couple.
Worldwide, more than 7 million children have now been born after these delivery rates are steadily rising and now comprise 2-6% of births in the European countries. To achieve higher pregnancy rates, the transfer of two or more embryos was previously the gold standard in ART. However, recently the practise has moved towards a single embryo transfer policy to avoid multiple births. The positive consequences of the declining multiple birth rates after ART are decreasing perinatal risks and overall improved health for the ART progeny. In this review we summarize the risks for short- and long-term health in ART singletons and discuss if the increased health risks are associated with intrinsic maternal or paternal factors related to subfertility or to the ART treatments per se. Although the risks are modest, singletons born after ART are more likely to have adverse perinatal outcomes compared to spontaneously conceived (SC) singletons dependent on the ART method. Fresh embryo transfer is associated with a higher risk of small for gestational age babies (SGA), low birthweight and preterm birth (PTB), while frozen embryo transfer is associated with large-for-gestational age babies and pre-eclampsia. ICSI may be associated with a higher risk of birth defects and transferral of the poor semen quality to male progeny, while oocyte donation is associated with increased risk of SGA and pre-eclampsia. Concerning long-term health risks, the current evidence is limited but suggests an increased risk of altered blood pressure and cardiovascular function in ART children. The data that are available for malignancies seem reassuring, while results on neurodevelopmental health are more equivocal with a possible association between ART and cerebral palsy. The laboratory techniques used in ART may also play a role, as different embryo culture media give rise to different birthweights and growth patterns in children, while culture to blastocyst stage is associated with PTB. In addition, children born after ART have altered epigenetic profiles, and these alterations may be one of the key areas to explore to improve our understanding of adverse child outcomes after ART. A major challenge for research into adverse perinatal outcomes is the difficulty in separating the contribution of infertility per se from the ART treatment (i.e. 'the chicken or the egg'?). Choosing and having access to the appropriate control groups for the ART children in order to eliminate the influence of subfertility per se (thereby exploring the pure association between ART and child outcomes) is in itself challenging. However, studies including children of subfertile couples or of couples treated with milder fertility treatments, such as IUI, as controls show that perinatal risks in these cohorts are lower than for ART children but still higher than for SC indicating that both subfertility and ART influence the future outcome. Sibling studies, where a mother gave birth to both an ART and a SC child, support this theory as ART singletons had slightly poorer outcomes. The conclusion we can reach from the well designed studies aimed at disentangling the influence on child health of parental and ART factors is that both the chicken and the egg matter.
Delaying conception has increased the demand on assisted reproduction. Currently, more than 1% of children are conceived through assisted reproductive technologies (ART) worldwide and this number is likely to continue increasing. Like any other medical intervention ART is associated with both short-term and long-term complications. The major short-term complications include ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies. OHSS is difficult to predict, but meticulous preventive strategies and protocols are being developed that may limit it. Most of the morbidities in children born after ART are related to multiple pregnancies. New laboratory methodologies may allow the transfer of fewer embryos to maintain satisfactory live birth rates while reducing the risk of multiple pregnancies. In vitro fertilization may be associated with a slight increased risk for birth defects. Analysis of possible risks from these techniques is confounded by factors of underlying parental subfertility, fertility treatments and multiple births. The long-term sequelae remain largely undetermined. All outcomes of ART, including pregnancy rates and adverse complications, need to be compared with standard non-ART when deciding the appropriate course of treatment. The importance of counselling should never be ignored in any treatment decision.
Assisted Reproduction › Safety and Risks › Multiple Gestation
PMID 10831543 10831543 DOI 10.1093/humrep/15.6.1217 10.1093/humrep/15.6.1217 Hazekamp et al. 2000, Hazekamp 2000
Cite this article
Hazekamp, J., Bergh, C., Wennerholm, U. B., Hovatta, O., Karlström, P. O., & Selbing, A. (2000). Avoiding multiple pregnancies in ART: consideration of new strategies. Human reproduction (Oxford, England), 15(6), 1217-1219. https://doi.org/10.1093/humrep/15.6.1217
Hazekamp J, Bergh C, Wennerholm UB, Hovatta O, Karlström PO, Selbing A. Avoiding multiple pregnancies in ART: consideration of new strategies. Hum Reprod. 2000;15(6):1217-1219. doi:10.1093/humrep/15.6.1217
Hazekamp, Johan, et al. "Avoiding multiple pregnancies in ART: consideration of new strategies." Human reproduction (Oxford, England), vol. 15, no. 6, 2000, pp. 1217-1219.
