Multiple gestation associated with infertility therapy: a committee opinion.

This Committee Opinion provides practitioners with suggestions to reduce the likelihood of iatrogenic multiple gestation resulting from infertility treatment. This document replaces the document of the same name previously published in 2012 (Fertil Steril 2012;97:825-34 by the American Society for Reproductive Medicine).

Live birth after in vitro maturation in women with gonadotropin resistance ovary syndrome: report of two cases.

PURPOSE: Gonadotropin-resistant ovary syndrome (GROS) is a rare endocrine disorder that causes hypergonadotropic hypogonadism, amenorrhea, and infertility. This study reports live birth in two women with GROS who underwent fertility treatment with in vitro maturation (IVM). METHODS: Both patients had primary infertility, amenorrhea (primary and secondary), typical secondary sexual characters, elevated gonadotropin levels, normal ovarian reserve, normal chromosomal characteristics, and previous nonresponsiveness gonadotropin stimulations. One patient had polymorphism of the follicle-stimulating hormone receptor, which is a predictor of poor ovarian response. Given unresponsiveness to exogenous gonadotropin stimulations, IVM with human chorionic gonadotropin priming (hCG-IVM) was performed in both patients. All transferrable embryos were vitrified. RESULTS: Both patients achieved pregnancy after their first frozen embryos transfer, and each delivered a healthy baby boy. CONCLUSIONS: These results suggest that IVM should be a first-line therapeutic option for patients with GROS.

Reduction in multiple pregnancy rate in donor oocyte-recipient gestational carrier (GC) in vitro fertilization (IVF) cycles in the USA with single-embryo transfer and preimplantation genetic testing.

PURPOSE: To evaluate the utilization of single-embryo transfer (SET) and preimplantation genetic testing (PGT) in gestational carrier IVF cycles in the USA with donor oocyte and examine the impact on live birth and multiple gestation. METHODS: Retrospective cohort study using the Society of Assisted Reproductive Technology (SART) clinic database of 4776 donor oocyte-recipient IVF cycles in which a GC was used. The cycles were separated into 4 groups by use of PGT and number of embryos transferred as follows: (1) PGT and single-embryo transfer (PGT-SET); (2) PGT and multiple embryo transfer (PGT-MET); (3) no PGT and SET (NoPGT-SET); (4) no PGT and MET (NoPGT-MET). Primary outcomes were live birth rate (LBR) and multiple pregnancy rate (MPR). RESULTS: More than one blastocyst was transferred in 48.7% (2323/4774) of the cycles. When ≥1 blastocyst was transferred, with or without the use of PGT, the MPR was 45.5% and 42.0%, respectively. In comparison, in the PGT-SET and NoPGT-SET groups, the MPR was 1.4% (8/579) and 3.3% (29/883), respectively. Live birth rates increased with the use of PGT-A and with MET. CONCLUSION: This study shows that SET, with or without PGT, is associated with a significantly reduced MPR in donor oocyte-recipient GC IVF cycles while maintaining high LBR. It also demonstrates that many infertility centers in the USA are not adhering to ASRM embryo transfer guidelines. Our findings highlight an opportunity to increase GC safety, which ultimately may lead to widened access to this increasingly restricted service outside the USA.

Adding new ingredients to the recipe for successful embryo transfers.

The success of a pregnancy and the birth of a heathy baby following embryo transfer are conditioned by many factors, including embryo quality and the uterine environment. While we keep looking for more indicators of embryo quality, it also is critical to understand what constitutes a favorable uterine environment leading to a successful pregnancy and birth. This issue of JARG offers new insights on both components-so called by some "the seed and the soil"-and also highlights the critical interactions between the two. Collectively, these publications are contributing to a better understanding of basic embryology and reproductive biology. They could lead to multiple applications to mitigate infertility issues; however, our knowledge base remains rudimentary when it comes to sorting out the 'soil or seed' dilemma. The call from all authors for more research in their respective areas resonates within the ART community. Recognizing the practical and ethical limitations of studies in human patients also reemphasizes the need for solid research in multiple animal models to better understand what constitutes the best recipe for successful embryo transfer outcomes.

Risks of nonchromosomal birth defects, small-for-gestational age birthweight, and prematurity with in vitro fertilization: effect of number of embryos transferred and plurality at conception versus at birth.

PURPOSE: Excess embryos transferred (ET) (> plurality at birth) and fetal heartbeats (FHB) at 6 weeks' gestation are associated with reductions in birthweight and gestation, but prior studies have been limited by small sample sizes and limited IVF data. This analysis evaluated associations between excess ET, excess FHB, and adverse perinatal outcomes, including the risk of nonchromosomal birth defects. METHODS: Live births conceived via IVF from Massachusetts, New York, North Carolina, and Texas included 138,435 children born 2004-2013 (Texas), 2004-2016 (Massachusetts and North Carolina), and 2004-2017 (New York) were classified by ET and FHB. Major birth defects were reported by statewide registries within the first year of life. Logistic regression was used to estimate adjusted odds ratios (AORs) and 95% CIs of the risks of a major nonchromosomal birth defect, small-for-gestational age birthweight (SGA), low birthweight (LBW), and preterm birth (≤36 weeks), by excess ET, and excess ET + excess FHB, by plurality at birth (singletons and twins). RESULTS: In singletons with [2 ET, FHB =1] and [≥3 ET, FHB=1], risks [AOR (95% CI)] were increased, respectively, for major nonchromosomal birth defects [1.13 (1.00-1.27) and 1.18 (1.00-1.38)], SGA [1.10 (1.03-1.17) and 1.15 (1.05-1.26)], LBW [1.09 (1.02-1.13) and 1.17 (1.07-1.27)], and preterm birth [1.06 (1.00-1.12) and 1.14 (1.06-1.23)]. With excess ET + excess FHB, risks of all adverse outcomes except major nonchromosomal birth defects increased further for both singletons and twins. CONCLUSION: Excess embryos transferred are associated with increased risks for nonchromosomal birth defects, reduced birthweight, and prematurity in IVF-conceived births.

[Delayed delivery in multiple pregnancy: about a case and literature review]. / Accouchement différé d´une grossesse multiple: à propos d´un cas et revue de la littérature.

Delayed delivery is designed to allow the remaining fetus(es) to develop after premature expulsion of the first twin in the second trimester of pregnancy. This decision is aimed to allow the remaining fetus(es) to reach full fetal growth. We here report a clinical case of delayed delivery in a patient with triple pregnancy in whom the time between the expulsion of the first twin and the birth of the third twin was 10 weeks. The purpose of this study was to highlight the benefit and indications for delayed delivery.

Avoiding multiple pregnancies in assisted reproductive technologies: transferring one embryo at a time should be the norm.

Multiple pregnancies following fertility treatments typically occur in 30% of women in whom more than one embryo is transferred. Worldwide, fewer than 20 countries have fully funded public fertility treatments, and many women utilizing assisted reproduction technologies are transferring more than one embryo for financial reasons because they consider it will be cheaper to have two embryos transferred in the one procedure. Yet, there is a large body of evidence for the poorer health, economic, and social outcomes for mother and baby from multiple pregnancies. Some countries have reduced the multiple pregnancy rate to less than 5% by linking the funding of ART to policies where the large majority of transfers are single embryos.

Current evidence supporting a goal of singletons: a review of maternal and perinatal outcomes associated with twin versus singleton pregnancies after in vitro fertilization and intracytoplasmic sperm injection.

With increasing use of in vitro fertilization and intracytoplasmic sperm injection (IVF-ICSI) almost 2% of all babies born in the United States each year are now conceived with these technologies, making outcomes of IVF-ICSI extremely important not only to patients and families but to public health. Twin pregnancy rates after IVF-ICSI in the United States have declined since their peak in 2013 but remain at approximately 1 in 10 to 1 in 20 pregnancies. A review of the current international literature on twin versus singleton pregnancy outcomes after IVF-ICSI treatment confirms statistically significantly higher risks to maternal and perinatal health and statistically significantly higher health care costs. The field of infertility care should continue to work to develop practices that lower twin pregnancy rates to an absolute minimum to maximize the safety of these medical treatments.

Funding and public reporting strategies for reducing multiple pregnancy from fertility treatments.

The health of children born through assisted reproductive technologies (ART) is particularly vulnerable to policy decisions and market forces that play out before they are even conceived. ART treatment is costly, and public and third-party funding varies significantly between and within countries, leading to considerable variation in consumer affordability globally. These relative cost differences affect not only who can afford to access ART treatment, but also how ART is practiced in terms of embryo transfer practices, with less affordable treatment creating a financial incentive to transfer more than one embryo to maximize the pregnancy rates in fewer cycles. One mechanism for reducing the burden of excessive multiple pregnancies is to link insurance coverage to the number of embryos that can be transferred; another is to combine supportive funding with patient and clinician education and public reporting that emphasizes a "complete" ART cycle (all embryo transfers associated with an egg retrieval) and penalizes multiple embryo transfers. Improving funding for fertility services in a way that respects clinician and patient autonomy and allows patients to undertake a sufficient number of cycles to minimize moral hazard improves outcomes for mothers and babies while reducing the long-term economic burden associated with fertility treatments.

Why are multiple pregnancy rates and single embryo transfer rates so different globally, and what do we do about it?

In the early years of in vitro fertilization, overall pregnancy rates were low, and it was considered necessary to transfer more than one embryo to increase the chances of pregnancy. It was not until advances in assisted reproductive technologies resulting in increased pregnancy rates that the concept of transferring just one embryo was considered possible. A consequence of improvements in implantation rates was also an increase in multiple pregnancies when more than one embryo was transferred. Although some countries have reduced the number of embryos transferred, international data show that in many parts of the world high twin and higher order multiple pregnancy rates still exist. Even in developed countries these problems persist depending on clinical practice, funding of health services, and patient demands. Perinatal and other outcomes are significantly worse with twins compared with singleton pregnancies and there is an urgent need to reduce multiple pregnancy rates to at least 10%. This has been achieved in several countries and clinics by introducing single embryo transfer but there are many barriers to the introduction of this technique in most clinics worldwide. We discuss the background to the high multiple rate in assisted reproduction and the factors that contribute to its persistence even in excellent clinics and in high-quality health services. Practices that may promote single embryo transfer are discussed.

Does the transfer of a poor quality embryo with a good quality embryo benefit poor prognosis patients?

BACKGROUND: While single embryo transfer (SET) is widely advocated, double embryo transfer (DET) remains preferable in clinical practice to improve IVF success rate, especially in poor prognosis patients with only poor quality embryos (PQEs) available in addition to one or no good quality embryos (GQEs). Furthermore, previous studies suggest PQE might adversely affect the implantation of a GQE when transferred together. This study aims to evaluate the effect of transferring an additional PQE with a GQE on the outcomes in poor prognosis patients. METHODS: A total of 5037 frozen-thawed blastocyst transfer (FBT) cycles between January 2012 and May 2019 were included. Propensity score matching was applied to control for potential confounders, and we used generalized estimating equations (GEE) models to identify the association between the effect of an additional PQE and the outcomes. RESULTS: Overall, transferring a PQE with GQE (Group GP) achieved significantly higher pregnancy rate (PR), live birth rate (LBR) and multiple pregnancy rate (MPR) than GQE only (group G). The addition of a PQE increased LBR in patients aged 35 and over and in patients who received over 3 cycles of embryo transfer (ET) (48.1% vs 27.2%, OR:2.56, 95% CI: 1.3-5.03 and 46.6% vs 35.4%, OR:1.6, 95% CI: 1.09-2.35), but not in women under 35 and in women who received less than 3 cycles of ET (48.7% vs 43.9%, OR:1.22, 95% CI: 0.93-1.59 and 48.3% vs 41.4%, OR:1.33, 95% CI: 0.96-1.85). Group GP resulted in significantly higher MPR than group G irrespective of age and the number of previous IVF cycles. CONCLUSIONS: An additional PQE does not negatively affect the implantation potential of the co-transferred GQE. Nevertheless, the addition of a PQE contributes to both live birth and multiple birth in poor prognosis patients. Physicians should still balance the benefits and risks of DET.

High-quality Cleavage Embryo versus Low-quality Blastocyst in Frozen-thawed Cycles: Comparison of Clinical Outcomes.

This study compared the clinical outcomes of the frozen-thawed cycles of high-quality cleavage embryos with low-quality blastocysts to provide a reference for the choice of frozen-thawed embryo transfer schemes and to improve clinical pregnancy rates. A retrospective analysis was performed on the clinical data of patients undergoing frozen-thawed embryo transfer at the Reproductive Medicine Center of Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology from 2016 to 2017. In total, 845 cases were divided into a high-quality cleavage embryo group (group A) and a low-quality blastocyst group (group B). Each group was further divided into subgroups based on the number of transplants. Group A was categorized into two subgroups comprising of 94 cases in subgroup A1 (1 high-quality 8-cell group) and 201 cases in subgroup A2 (2 high-quality 8-cell group). Group B was divided into four subgroups consisting of 73 cases in subgroup B1 (D53BC group), 65 cases in subgroup B2 (D54BC group), 110 cases in subgroup B3 (D63BC group), and 282 cases in subgroup B4 (D64BC group). The pregnancy outcomes and neonatal outcomes between the groups were compared. The clinical pregnancy rates (56.72% and 60.00%) and live birth rates (47.76% and 46.15%) in subgroups A2 and B2 showed no significant differences, but these rates were significantly higher in subgroups A2 and B2 than in the rest subgroups (P<0.05). The multiple birth rate (26.32%) in the subgroup A2 was significantly higher than that in the rest subgroups (P<0.05). There were no statistically significant differences in the abortion rates among all groups (P>0.05). In terms of neonatal outcomes, there were no statistically significant differences in the proportion of premature births, sex ratios, and birth defects among the low-weight and gigantic infants (P>0.05). Transplanting two high-quality cleavage embryos during the frozen-thawed embryo transfer cycles could significantly increase clinical pregnancy rates and live birth rates, but at the same time, it also increased the risks of multiple births and complications to mothers and infants. The D54BC subgroup had the most significant advantages among all groups (P<0.05). The rest low-quality blastocysts had clinical outcomes similar to the single high-quality cleavage embryo group.

Strategies to reduce multiple pregnancies during medically assisted reproduction.

Multiple birth rates after fertility treatment are still high in many countries. Multiple births are associated with increased rates of preterm birth and low birth weight babies, in turn increasing the risk of severe morbidity for the children. The multiple birth rates vary in different countries between 2% and 3% and up to 30% in some settings. Elective single-embryo transfer, particularly in combination with frozen-embryo transfer and milder stimulation in ovulation induction/intrauterine insemination, to avoid multifollicular development is an effective strategy to decrease the multiple birth rates while still achieving acceptable live-birth rates. Although this procedure is used successfully in many countries, it ought to be implemented broadly to improve the health of the children. One at a time should be the normal routine.

Establishment of day 7 blastocyst freezing criteria using blastocyst diameter for single vitrified-warmed blastocyst transfer from live birth outcomes: a single-center, large cohort, retrospectively matched study.

PURPOSE: To establish blastocyst freezing criteria for day 7 blastocyst (day 7 BL) for single vitrified-warmed blastocyst transfer (SVBT) by examining the diameter of blastocysts. METHODS: Patients who underwent day 7 BL transfer cycles (1143 cycles, mean age: 38.5 ± 3.5) and randomly selected patients after 1:1 matching who underwent day 6 BL transfer cycles and day 2-single-embryo transfer (SET) cycles were used for analysis. Comparison of the miscarriage (per clinical pregnancy) and live birth rates were made among day 2-SET, day 7 BL, and day 6 BL. These blastocyst groups were stratified into six groups based on blastocyst diameter, namely, 180 µm, 190 µm, 200 µm, 210 µm, over 220 µm, and hatched, for making the freezing criteria. RESULTS: For each diameter, 180 µm, 190 µm, 200 µm, 210 µm, over 220 µm, and hatched, the live birth rates of day 7 BL after SVBT were 9.0%, 11.9%, 11.5%, 15.6%, 20.0%, and 19.9%, respectively. Compared with the 14.6% live birth rate of the day 2-SET group, the live birth rate of 220 µm day 7 BL was significantly higher (P < 0.05) and was around the same in other diameter groups. CONCLUSION: Our study demonstrates that sufficient live birth rates can be obtained after SVBT even from blastocysts on day 7 when blastocysts were vitrified at expanded blastocyst stage of over 180 µm of diameter or at hatched blastocyst stage and were transferred at the optimal time. This is the first study to establish a day 7 blastocyst freezing criteria using blastocyst diameter, which is an objective assessment way.

Maternal physical activity and sedentary behaviour before and during in vitro fertilization treatment: a longitudinal study exploring the associations with controlled ovarian stimulation and pregnancy outcomes.

PURPOSE: To evaluate the association of objectively measured physical activity (PA) and sedentary behaviour before and during in vitro fertilization (IVF) with controlled ovarian stimulation (COS) and pregnancy outcomes. METHODS: This longitudinal study involved 107 infertile women undergoing IVF treatment. PA and sedentary behaviour were measured for 14 consecutive days using accelerometry as follows: (1) before IVF treatment, (2) during IVF at the implantation time, immediately after embryo transfer, and (3) after positive pregnancy test. Total screen time was assessed by questionnaires. COS results were measured as the number of oocytes and embryos obtained, and the study outcomes included positive hCG, clinical pregnancy, and live birth. RESULTS: Compared with baseline activity levels, women significantly reduced their PA and increased sedentary behaviour during IVF (p ≤ 0.001). Higher average PA, light PA, and ratio between breaks in every ≥ 30-min blocks of sedentary time showed positive associations, while sedentary time, number, and time accumulated in blocks of ≥ 30 min of sedentary time associated negatively with oocyte and embryo counts (all p < 0.05). Women with high total screen time during non-work days (≥ 7 h) obtained 4.7 oocytes (p = 0.005) and 2.8 embryos (p = 0.008) less in COS. PA and sedentary behaviour before and during IVF did not affect the positive hCG, clinical pregnancy, and live birth outcomes. CONCLUSION: Our study results suggest that higher time spent in PA and lower time spent in sedentary behaviour before entering assisted reproduction is associated with better COS outcomes, while activity levels before and during IVF do not affect the implantation, pregnancy, and live birth outcomes.

Hemodynamics of the umbilical artery and conceptus-related measurements in singleton and twin pregnancies in ewes.

In sheep, adequate physiological maternal adaptations to twin fetuses are key for their prenatal development. We hypothesized that there is a relationship between maternal circulating steroid hormone concentration, hematocrit, and patterns of conceptus growth and umbilical artery hemodynamics in twin vs singleton pregnancies. Ewes carrying singletons (n = 6) or twins (n = 7) were selected. Hematocrit, progesterone (P4) and estradiol-17ß (E2) concentrations were analyzed. Blood flow of the umbilical artery (UBF) was assessed through Doppler ultrasonography. Ewes carrying twins had a decreased (p = 0.03) hematocrit. There was a tendency (p = 0.08) for ewes carrying twins to have increased P4 from day 20 to 40. From day 50 to 70, P4 tended to be increased (p = 0.07) and E2 was increased (p = 0.01) in ewes carrying twins. From day 90 to 120, ewes carrying twins had greater (p ≤ 0.04) P4. Ewes carrying twins had increased (p < 0.01) P4 and tended to have (p = 0.06) increased E2. From day 60 until 110, placentomes from twins were larger (p ≤ 0.05). On day 50, UBF was greater (p = 0.04; 27.38 vs. 20.95 ± 1.99 ml/min) in twins. It has been suggested that physiological adaptations during early pregnancy can significantly impact fetal development in multiple offspring carrying ewes. Our findings suggest that increased umbilical artery blood flow early in gestation, associated with increased maternal concentrations of P4 and E2, and decreased hematocrit (related to plasma volume) could contribute to those adaptations.

Health Pregnancy, Healthy Baby: testing the added benefits of pregnancy ultrasound scan for child development in a randomised control trial.

BACKGROUND: The 2016 World Health Organization Antenatal Guidelines and the 2015 South African Maternal and Child Health Guidelines recommend one early antenatal ultrasound scan to establish gestational age and to detect multiple pregnancies and fetal abnormalities. Prior research indicates that ultrasound scan can also increase parental-fetal attachment. We aim to establish whether, compared to routine care, messages to promote parental attachment and healthy child development, conducted during one or two pregnancy ultrasound scans, improve early child development and growth, exclusive breastfeeding, parental-child interactions and prenatal and postnatal clinic attendance. METHODS: The effect of messages to sensitise mothers and fathers to fetal development will be tested in a three-armed randomised trial with 100 mothers and their partners from Soweto, Johannesburg in each arm. The primary outcome is child development at 6 months postnatally. Secondary outcomes include infant feeding, parental attachment and interaction, parental mental health and infant growth, assessed at 6 weeks and 6 months. Parents in Arm 1 receive a fetal ultrasound scan < 25 weeks during routine antenatal care at tertiary hospitals, and a second standard ultrasound scan at the research site within 2 weeks. Arm 2 participants receive the routine antenatal ultrasound scan and an additional ultrasound scan < 25 weeks at the research site, together with messages to promote parental attachment and healthy child development. Arm 3 participants receive the routine ultrasound scan and two additional ultrasound scans at the research site, < 25 weeks and < 36 weeks, together with messages to promote parental attachment and healthy child development. DISCUSSION: Evidence from high-income countries suggests that first-time prospective mothers and fathers enjoy seeing their fetus during ultrasound scan and that it is an emotional experience. A number of studies have found that ultrasound scan increases maternal attachment during pregnancy, a predictor of positive parent-infant interactions which, in turn, promotes healthy infant development. It is generally agreed that studies are needed which follow up parental-child behaviour and healthy child development postnatally, include fathers and examine the construct in a wider diversity of settings, especially in low and middle-income countries. Testing the added benefits of pregnancy ultrasound scan for child development is a gap that the proposed trial in South Africa seeks to address. TRIAL REGISTRATION: Pan African Clinical Trials Registry, PACTR201808107241133. Registered on 15 August 2018.

Incidence of surrogacy in the USA and Israel and implications on women's health: a quantitative comparison.

PURPOSE: Gestational surrogacy (GS) has been researched in multiple qualitative studies. In contrast, quantitative aspects of the practice are conspicuously understudied. The present article assesses and compares the incidence of GS in the USA and Israel, two industrialized countries that have maintained active commercial surrogacy practice, for over two decades. METHOD: The article is a secondary analysis of GS figures published by the Israeli Parliament's Centre for Research and Information (2018) and by the USA's Centers for Disease Control (2016) and related professional publications. Each dataset is analyzed in reference to the respective country, so as to devise local incidence scores that are then juxtaposed in inter-country comparison. RESULTS: The incidence of GS rises steeply in both countries. Though US surrogates are contracted by local and international, heterosexual and gay, and partnered and single intended parents, the relative incidence of GS is lower in the USA than in Israel, where only local heterosexual couples could contract a gestational surrogate. An exceptionally high rate of multiple births was observed in both settings, suggesting some overlooking of professional recommendations for elective single-embryo transfer. CONCLUSION: GS incidence appears to resemble the ratio between the countries' respective fertility rates. The paper underscores two main risks facing gestational surrogates: the risk of not conceiving and not being paid and the risk of carrying a multiple pregnancy, which is extremely prevalent in GS pregnancies, and sustaining the short- and long-term health complications that are more prevalent in such pregnancies.

Application of Japanese guidelines for gestational weight gain to multiple pregnancy outcomes and its optimal range in 101,336 Japanese women.

This study was performed to investigate whether the Japanese guidelines for gestational weight gain (GWG) can be used to determine the risks of multiple pregnancy outcomes and estimate optimal GWG in 101,336 women with singleton pregnancies in 2013. Multivariable logistic regression analyses indicated that the risks associated with low birth weight, small for gestational age, and preterm birth increased significantly with weight gain below the Japanese guidelines, and the risks of macrosomia and large for gestational age increased with weight gain above the guidelines regardless of Asian-specific pre-pregnancy body mass index (BMI). The GWG cutoff points estimated from the adjusted area under the receiver operating characteristics curve >0.6 corresponded to 10-13.8 kg in underweight women with pre-pregnancy BMI < 18.5 kg/m2; 10-13.7 kg in normal weight women with pre-pregnancy BMI 18.5-22.9 kg/m2; 8.5-11.4 kg in overweight women with pre-pregnancy BMI 23-24.9 kg/m2, 5-13.3 kg in obese women with pre-pregnancy BMI 25-29.9 kg/m2; and 4.7 kg in obese women with pre-pregnancy BMI ≥ 30 kg/m2. The optimal GWG ranges proposed by the present study are slightly higher than those recommended by the current Japanese guidelines.