High-order Multiple Pregnancies Research Articles

A year of inaction on high-order multiple pregnancies due to ovulation induction

In the January 2001 issue of Fertility & Sterility, Howard Jones Jr. and John Schnorr reprimanded a U.S. fertility organization for not developing and enforcing guidelines to reduce the incidence of high-order multiple pregnancies (birth of three or more babies) (1). They cited a U.S. Department of Health and Human Services report stating that infertility treatment accounted for more than 225,000 excess multiple births between 1980 and 1997 (2). Ovulation induction exclusive of IVF was responsible for 38% of high-order multiple pregnancies.

Inevitable risk of high-order multiple pregnancies following IUI, the need for strict criteria for its prevention: two case reports

Intrauterine insemination with controlled super-ovulation (IUI/SO) is appropriate management of subfertility where the Fallopian tubes are healthy and patent and the sperm quality is satisfactory. The treatment is monitored by intermittent transvaginal ultrasound scans to assess follicular development. There is an unavoidable increased risk of multiple pregnancy including higher order pregnancy. These two case reports suggest the need for national standards regarding the abandonment of the treatment cycle to further reduce the risk of high order multiple implantations.

Multiple pregnancy

The incidence of multiple pregnancies has increased considerably over the past 20 years in the western world. The number of twin pregnancies has increased by approximately 25% and the rate of triplet and higher order multiple pregnancies has more than doubled. This is due to the use of ovarian hyperstimulation and assisted reproduction techniques, and to the increasing maternal age. Multiple pregnancy can be considered as the most important adverse outcome of infertility treatment. The main determinant for outcome and management of multiple pregnancies is the chorionicity. This can be determined by ultrasound until 14 weeks of gestation. Twenty percent of all twin pregnancies are monochorionic, and 15% of these develop severe twin to twin transfusion syndrome, which is best treated by LASER separation of the communicating blood vessels. Obstetric complications associated with multiple gestation also occur more frequently in monochorionic twins. They include increased incidence of preterm labor, intrauterine growth restriction and assisted or surgical delivery. Neonatal problems include low birthweight and increased prevalence of congenital malformations. Overall, there has been a decrease in neonatal mortality of twins and triplets over the past 10 years, which is mainly due to the enormous advances in neonatal intensive care.

Monozygotic twinning is not associated with zona pellucida micromanipulation but increases with high order multiple pregnancies

Objective: Monozygotic twinning results from the division of a single fertilized ovum into two genetically identical embryos. The factors that affect the frequency of monozygotic twinning have been poorly characterized. IVF treatment has been associated with increase in monozygotic twins possibly due to the presence of more embryos in the uterine cavity. Studies using animal models have called attention to the zona pellucida as an important factor in the twinning equation. The aim of our study was to examine whether zona pellucida micromanipulation procedure (intra-cytoplasmic sperm injection-ICSI, or assisted hatching-AHA) is associated with monozygotic twinning in IVF treatment.

Fine adjustments for a fixed dose of rec-hFSH, avoid ovarian hyperstimulation and high order multiple pregnancy without compromising pregnancy rates in anovulatory patients

Objective: Hyperestimulation and multiple pregnancies continue to be the most frequent and severe complications in gonadotropin treatments for anovulatory patients. The objective of this study was to evaluate ovulation induction in anovulatory women with a standardized protocol using low dose rec-hFSH with fine dose adjustments and minimal monitoring

The use of outcomes-based data in reducing high order multiple pregnancies: The role of age, embryo score and ovum donation

Objective: This report demonstrates the efficacy of clinic-specific guidelines in reducing the incidence of high order multiple pregnancy(ies) (HMP) from in vitro fertilization (IVF). Design: IRB approved retrospective analysis of IVF outcomes from two united IVF programs (1995–9), with followup analysis (2000–01) based on the information gained from 1995–9. Materials/Methods: During 1995–9, 777 clinical pregnancies resulted from 1740 IVF embryo transfers (ET)s in two united IVF programs. Good outcomes for an IVF cycle were defined as singleton or twin deliveries and bad outcomes as no delivery, miscarriages, need for multifetal reduction, triplet, or quadruplet pregnancies. The IVF cases under study were retrospectively analyzed by logistic regression using multiple variables. The utility of the historical information generated from 1995–9 for determining the optimal number of embryos to transfer in order to reduce the incidence of HMP was evaluated in 2000–2001. Results: The best outcome for donor egg (DE) <35 yrs old, DE >35 yrs old and non-DE cycles <35 yrs old were achieved with the transfer of two (57.7%), three (43.2%) and three (43.2%) embryos, respectively. The highest risk for HMP was associated with the transfer of three or more embryos in DE cycles <35 yrs old which accounted for 23.9% of all HMP. Logistic regression revealed that age <35 (p <0.0001), embryo score (ES) (p <0.0001), and donor egg (p = 0.0262) significantly affected the good/bad rate. The ES correlated with the percentage of good outcomes/cycle (GR) in a linear fashion as defined by the equation (GR = 3.3 + 2.0 ES) within the range 4 <ES <26 (r = 0.91). Follow up analysis revealed the near complete elimination of HMP with DE IVF- one triplet for 2000–1. Furthermore, a 52% reduction (p = 0.001) in HMP from 9.1 (71/777) to 4.4% (25/569), in the absence of change in the overall pregnancy rate (PR) for DE (58.4 (153/262) vs 59.3% (99/167)) and non-DE cycles (41.5 (608/1452) vs 44.5% (470/1056)), was noted in 1995–9 compared to 2000–1, respectively. This reduction was accomplished primarily, but not exclusively, in DE cycles. Finally, among physicians experiencing the greatest reduction in HMP (7.6 in 1995–9 to 2.7% in 2000–1, p = 0.02), no significant reduction was noted in clinical PRs (39.9 to 37.9%) over the two study periods, respectively. Conclusions: Heightened awareness of clinic-specific high risk categories (age, ES, and DE) during patient informed consent for IVF-ET resulted in a significant reduction (52–64%) in HMP without significantly reducing the clinical PR. A standardized national embryo scoring system incorporated into the SART data collection system may provide useful information to IVF patients and potentially help reduce the incidence of HMP without compromising the PR. Supported by: IVF Research Fund, Division of Reproductive Endocrinology and Infertility, University of Utah Health Sciences Center.

Embryo developmental analysis can be used to decrease high order multiple pregnancies through reduction in the number of embryos selected for transfer

Embryo developmental analysis can be used to decrease high order multiple pregnancies through reduction in the number of embryos selected for transfer

Conversion to in-vitro fertilization (IVF) offers a viable alternative in intrauterine insemination (IUI) candidates who are at risk for high order multiple pregnancies

Objective: Patients undergoing ovarian stimulation who exhibit a high number of developing follicles are at increased risk of having a high order multiple gestation. Typically these cycles are either canceled, or converted to IVF where the number of transferred embryos can be limited. This study was undertaken to compare IVF cycle outcome of patients converted from IUI with age-matched IVF patients.

Factors affecting the outcome of pregnancy following multifetal pregnancy reduction

Objective: With the wide application of ART, multiple pregnancy rate has been increased. Multifetal pregnancy reduction (MFPR) is considered to be useful in improving the outcome of high-order multiple pregnancy. However, factors influencing the outcome are not established well. The Specific aim of this study was to identify the factors affecting the pregnancy outcome following MFPR.

Monochorionic high-order multiple pregnancies and multifetal pregnancy reduction

OBJECTIVE: To study the frequency and obstetric outcome of monochorionic multiple pregnancies in a population referred for fetal reduction. METHODS: Data charts of all patients with multifetal (≥3) pregnancies referred for fetal reduction over the last 10 years were reviewed for the presence of monochorionic twin pairs or triplets. RESULTS: Twenty-nine of 239 high-order multiple pregnancies contained a monochorionic component (12.1%), eight of which were monochorionic triplets. Half of all naturally conceived pregnancies contained a monochorionic component. High-order multiple pregnancies with a monochorionic component resulted significantly more frequently from natural conceptions (7 of 29) than multichorionic pregnancies (7 of 210) ( P = .001). Fetal reduction of the monochorionic twin pair in 21 pregnancies resulted in eight twin and 13 singleton pregnancies; mean gestational age at delivery was, respectively, 34.3 ± 2.9 and 39.2 ± 1.4 weeks. Pregnancy loss rate was one of 21 (4.8%). In the remaining eight multiple pregnancies with a monochorionic triplet present, three were complicated by a twin reversed arterial perfusion sequence, and two couples requested a first trimester termination of pregnancy. Fetal reduction of the monochorionic triplet in a dichorionic quadruplet pregnancy resulted in a normal pregnancy outcome. In two monochorionic triplet pregnancies, fetal reduction to monochorionic twin pregnancies with bipolar coagulation of the umbilical cord resulted in a favorable pregnancy outcome. CONCLUSION: Monochorionic twins or triplets are frequently part of naturally conceived high-order multiple pregnancies. Reduction of the monochorionic twin pairs improves pregnancy outcome. Monochorionic triplet pregnancies show a high complication rate, but may benefit from fetal reduction by cord coagulation.

Trends in the occurrence, determinants, and consequences of multiple births

After a substantial decrease in the middle of the 20th century, multiple pregnancy rates have increased in many Western countries. Between the mid-1970s and 1998, the rate of twin pregnancies increased by 50% to 60% in England and Wales, France, and the United States. The rates of triplet or higher-order multiple pregnancies increased by 310% in France, 430% in England and Wales, and 696% in the United States. One fourth to one third of the increase in twin or triplet pregnancies are attributable to a contemporaneous increase in maternal age. Furthermore, in countries with high occurrence of multiple births, 30% to 50% of twin pregnancies and at least 75% of triplet pregnancies occur after infertility treatment. The impact of the increase in multiple births on preterm delivery rates in the overall population is mainly attributable to twin pregnancies. In Canada, France, and the United States, an increase in preterm births among multiples contributed almost as much as the increase in occurrence of multiple births to the increase or stabilization of the overall rates of preterm delivery observed in these countries.

We didn't deserve this: bereavement associated with multifetal reduction.

With the dramatic increase in the incidence of higher-order multiple pregnancies, more and more women are advised to consider undergoing multifetal reduction. However, little is known about the woman's experience of making the decision to undergo or forgo reduction. This study explored the experiences of seven women in making this decision and to identify any effects of it. Vivid descriptions emerged of multiple levels of bereavement. Several participants lamented that nothing occurred naturally in their pregnancies, from conception right through delivery and life with multiples.

We Didn't Deserve This: Bereavement Associated with Multifetal Reduction

With the dramatic increase in the incidence of higher-order multiple pregnancies, more and more women are advised to consider undergoing multifetal reduction. However, little is known about the woman's experience of making the decision to undergo or forgo reduction. This study explored the experiences of seven women in making this decision and to identify any effects of it. Vivid descriptions emerged of multiple levels of bereavement. Several participants lamented that nothing occurred naturally in their pregnancies, from conception right through delivery and life with multiples.

Prevention of high order multiple pregnancy

Prevention of high order multiple pregnancy

Conversion of high-response gonadotropin intrauterine insemination cycles to in vitro fertilization results in excellent ongoing pregnancy rates

Objective: To determine whether conversion of gonadotropin/IUI cycles at high risk of high-order multiple pregnancies to IVF yields a pregnancy rate high enough to warrant the added intervention. Design: Case-control study. Setting: Brigham and Women’s Hospital assisted reproductive technology program. Patient(s): Seventy-seven patients converted from gonadotropin/IUI to IVF, 77 consecutive age and attempt number–matched controls (sequential controls [SCs]), and 77 consecutive age-, attempt-, and E 2-matched controls (E 2 controls [ECs]). Interventions(s): Gonadotropin/IUI cycles with exuberant responses were converted to IVF (cases) to avoid cycle cancellation and high-order multiple pregnancies. Main Outcome Measure(s): Pregnancy rates, delivery rates, E 2 levels, follicle and oocyte number, and fertilization and implantation rates. Result(s): Compared with SCs and ECs, cases had more follicles (16.3 ± 0.6 vs. 13.3 ± 0.9 and 14.4 ± 0.9) and higher E 2 at hCG administration (1,951 ± 93 vs. 1,568 ± 96 and 1,939 ± 89 pg/mL). Delivery rates among the three groups (45.5% vs. 32.5% and 39.0%) did not differ significantly. Despite the transfer of fewer embryos in cases than in controls (2.5 ± 0.1 vs. 3.1 ± 0.1 and 2.9 ± 0.1), three triplet pregnancies occurred in cases and three in controls. Conclusion(s): Conversion of high responder gonadotropin/IUI patients to IVF is an effective alternative to cycle cancellation and offers a delivery rate as high or higher per cycle than that of planned IVF. Sample size limited the statistical power of the study.

Integration of blastocyst transfer for all patients

Objective: To evaluate the efficacy of using day-5 embryo transfer (ET) for all patients. Design: Retrospective, non-randomized comparison of day-3 ET versus day-5 ET. Setting: Private practice. Patient(s): Women having in vitro fertilization and receiving either day-3 ET or day-5 ET. Intervention(s): Extended embryo culture through embryonic genome activation to select those embryos with higher implantation potential. Main Outcome Measure(s): The following parameters were compared for day-3 ET and day-5 ET: clinical and ongoing pregnancy rates, implantation rates, patients having cryopreservation, and liveborn rates. Result(s): Blastocyst embryo transfer (day-5 ET) increased the clinical and ongoing pregnancy rate for patients <35 years of age and for the total program. The risk of high order multiple pregnancy was reduced by a decrease in the number of embryos transferred (2.0 vs. 2.7; day-5 ET vs. day-3 ET, respectively). However, the multiple pregnancy rate was not different due to an increase in the implantation rate (day-5 ET 43% vs. day-3 ET 27%). There was no difference in the percent of patients not having an ET (day-5 ET 2.8%; day-3 ET 1.3%). Conclusion(s): Blastocyst ET increased the clinical and ongoing pregnancy rate for patients <35 years of age and for the total program, with a concomitant decrease in the number of embryos transferred. However, the decrease in the number of embryos transferred did not decrease the multiple rate, but did reduce the incidence of high order multiples. Most patients (97%) had an embryo transfer. Therefore, culturing embryos an additional 48 hours through embryonic genome activation allows for selection of the most viable embryos without compromising the patient’s opportunity to become pregnant.

Establishment and application of criteria for the elective transfer of two good-quality embryos to reduce high-order multiple pregnancies.

Aim : This study was carried out to establish criteria for the elective transfer of two good-quality embryos to reduce high-order multiple pregnancy rates. The pregnancy and multiple pregnancy rates per transfer were retrospectively analyzed in 128 in vitro fertilization and embryo transfer (IVF-ET) cycles. Results : The analysis revealed that the pregnancy and multiple pregnancy rates were 26.6% (34 of 128) and 23.5% (eight of 34), respectively. Five twin and three triplet pregnancies were included. The pregnancy rates in women 29years old and younger, 30-34years, 35-39years, and 40years and older were 21.2 (seven of 33), 37.0 (17 of 46), 25.8 (eight of 31), and 11.1% (two of 18), respectively. There was a significant difference of the pregnancy rates between 30 and 34-year-old and 40-year-old and older women (P<0.05). The multiple-pregnancy rate in women 40years and older was 0%. Three triplet pregnancies were established only in the first attempt of IVF-ET. The pregnancy rates in women, to whom good-quality embryos (0-4) were transferred, were 0% (none of 12) for 0, 17.2% (five of 29) for one, 41.2% (seven of 17) for two, 30.8% (12 of 39) for three, and 32.3% (10 of 31) for four and more embryos, respectively. The multiple pregnancy rates in women who had good-quality embryos of one, two, three, and four and more transferred were 0% (none of five), 23.5% (four of seven), 16.7% (two of 12), and 20.0% (two of 10), respectively. Conclusion : The criteria for the elective transfer of two good-quality embryos were established as follows: age<40years, a first treatment cycle, and more than three good-quality embryos available for transfer. After the application of the established criteria, the overall pregnancy and multiple pregnancy rates were 30.4% (14 of 46) and 14.3% (two of 14), respectively, which was satisfactory as compared with those in the 128 IVF-ET cycles before application of the criteria. An elective transfer of two good-quality embryos can be highly recommended to avoid high-order multiple pregnancies in subjects with the established criteria. (Reprod Med Biol 2002; 1: 23-29).

Fetal reduction in multifetal pregnancy--ethical dilemmas.

As a result of the increased use of drugs that enhance fertility, and the advent of in vitro fertilization and embryo transfer over the last 2 decades, the incidence of multifetal pregnancies has increased exponentially. In parallel with this increase methods of care for women carrying multiple fetuses have become more complex and well developed. Importantly, it has become obvious that in the case of such pregnancies the rates of mortality and morbidity of both fetuses and mothers, particularly in cases where four or more fetuses are involved, are extremely high. Improvements in the techniques of assisted fertilization should result in fewer iatrogenic multifetal pregnancies and a commensurate decrease in related risks. Fetal reduction seems to be an acceptable method of improving maternal and fetal outcome in high order multiple pregnancies despite the many unresolved medical and ethical dilemmas.

Blastocyst culture in human IVF: the final destination or a stop along the way?

In the field of human IVF, culturing embryos to the blastocyst stage has gained popularity within the past few years. The impetus to transfer blastocysts has been spurred by several factors: 1) the desire to improve implantation rates in infertility patients, 2) a desire to reduce the multiple pregnancy rate by transferring fewer embryos, 3) the desire to perform pre-implantation genetic diagnosis, and 4) the advent of sequential media. Although culturing human embryos to the blastocyst stage has improved implantation rates and reduced the incidence of multiple pregnancies in some patient populations, it has not worked for all populations of infertility patients. Factors that may affect the ability of a human embryo to reach the blastocyst stage include the patient's age, cohort of ova retrieved, the use of intracytoplasmic sperm injection of blastomere biopsy, culture conditions, or intrinsic factors within the embryo itself. Culture of human embryos to the blastocyst stage can be an effective method for improving implantation rates and reducing the high order multiple pregnancy rates seen in human IVF clinics when more than three embryos are transferred.

Increase in the monozygotic twinning rate after intracytoplasmic sperm injection and blastocyst stage embryo transfer

Increase in the monozygotic twinning rate after intracytoplasmic sperm injection and blastocyst stage embryo transfer