Higher-order Multiple Gestations Research Articles

First reported case of sextuplets conceived via letrozole for ovulation induction

To report the first case of sextuplets conceived via letrozole during ovulation induction. Case report. Private fertility clinic. A 32-year-old female with a history of secondary infertility and polycystic ovary syndrome. Letrozole, 7.5 mg, on cycle days 3-7 after a progesterone-induced menses. Clinical pregnancy. Sexchorionic-sexamniotic pregnancy. High-order multiple gestations are possible with letrozole ovulation induction, so patients should be counseled appropriately and follicle monitoring considered.

Selective reduction in complex monochorionic gestations.

The early determination of chorionicity in twin gestations is a critical factor in the management of twin gestations. While twins and higher order multiple gestations have increased risks of almost any complication of pregnancy, those pregnancies involving a monochorionic (MC) twin pair are at an especially high risk. The presence of vascular anastomoses within a MC placenta creates risk for discordant malformations, twin reversed arterial perfusion sequence, twin-to-twin transfusion syndrome, or severe selective intrauterine growth restriction. While selective reduction of higher order multiple pregnancies is performed to reduce pregnancy-related risks and improve overall outcomes, selective reduction is also an important management strategy in situations where MC pregnancies develop complex complications. This procedure can be lifesaving for the cotwin by preventing intrauterine demise or extreme prematurity. There are several techniques that can be considered, each with its own advantages and disadvantages.

What makes them split? Identifying risk factors that lead to monozygotic twins after in vitro fertilization

To identify the incidence, risk factors, and obstetric/perinatal outcomes associated with monozygotic twins (MZTs) after IVF. Nested case-control. University-based center. The IVF cycles eventuating in pregnancy from 2000-2009. None. The MZT incidence, chorionicity/zygosity, pregnancy/neonatal outcome. Of 6,223 gestations, 131 MZTs were diagnosed (2.1% incidence; 2.0% in autologous and 2.7% in donor IVF cycles), 10 were dichorionic, and 121 were monochorionic. Controlling for all risk factors, young oocyte age, extended culture (noncleavage embryos transferred on/after day 4), and year of IVF treatment cycle were significantly associated with MZT. When assessing factors associated with specific MZT placentation, day 3 assisted hatching correlated more with dichorionic MZT, whereas extended culture and advanced day 5 embryonic stage correlated with monochorionic MZT. Comparing monozygotic to dizygotic multigestation outcomes, MZT fared worse; however, once controlling for triplet gestation, only gestational age at delivery remained significantly compromised in the monozygotic group. After IVF the incidence of MZT is high, with young oocyte age, year of treatment, and extended culture (or embryo stage at transfer) conferring greatest risk. Regarding MZT type, assisted reproductive technology (ART) procedures may influence the timing of embryonic splitting (i.e., division in early embryonic development may be influenced by zona pellucida [ZP] manipulation whereas later splitting may occur during delayed implantation). Poor obstetric/perinatal outcome is significantly impacted by the presence of an "extra" fetus, as high-order multiple gestation concurrent with an MZT conveyed the worst prognosis.

Selective reduction in multiple gestations

The frequency of multiple gestations has increased dramatically. Twins and higher order multiple gestations have pregnancies with increased risks for almost every complication of pregnancy, especially preterm labour, preterm delivery, and congenital anomalies. Monochorionic twins, by virtue of the unique placental angioarchitecture, are at risk for additional complications, such as severe discordant malformations, twin reversed arterial perfusion sequence, twin-to-twin transfusion syndrome or severe selective intrauterine growth restriction. These complications create unique challenges to those who manage multiple pregnancies. Reduction of higher order multiple pregnancies is on option to reduce pregnancy related risks and improve overall outcomes. Selective termination in complex monochorionic pregnancies can be lifesaving for the co-twin by preventing intrauterine demise or extreme prematurity. It is critical, however, to determine chorionicity before considering any approach to selective reduction. Techniques applied to dichorionic twins cannot be directly translated to cases involving monochorionic twins.

Does multi‐fetal pregnancy reduction adversely influence intra‐uterine growth?

Multi-fetal pregnancy reduction (MFPR) is offered in the management of higher-order multiple gestations to reduce the risks associated with such pregnancies. Pregnancy outcomes, including birthweight, following MFPR have been examined with variable findings. However, little attention has been paid to in utero growth in such pregnancies. This study examines whether the intra-uterine growth performance of a twin pregnancy resulting from MFPR differs from that of an unreduced twin pregnancy. This was a retrospective analysis comparing the intrauterine growth of 20 higher order multiple pregnancies that underwent MFPR with resulting di-chorionic twin gestations with 293 unreduced di-chorionic twin gestations. Biometric nomograms were derived for the unreduced twin population and the biometric parameters for the reduced pregnancies were compared with these. There was a difference with respect to femur length in the period 20-28weeks (p=0.003) but no other significant differences were observed. MFPR does not itself adversely influence intra-uterine fetal growth.

The clinical need for a method of identification of embryos destined to become a blastocyst in assisted reproductive technology cycles

To provide a rationale for continuation of efforts to improve the outcome of Assisted Reproductive Technology outcomes, thereby increasing the likelihood of the live birth of healthy neonates. Description of rationale and a framework leading to improvement in Assisted Reproductive Technology outcomes. The opportunity for improvement in the success rate for Assisted Reproductive Technology outcome is predicated on selection of the highest quality embryo(s) for transfer. However, such approaches must be balanced by a limit to the number of embryos transferred so as to reduce the risk for multiple births and particularly higher order multiple gestations. Blastocyst transfer offers one such successful approach, but is confounded by suggestions of an increased risk of both pregnancy complications and epigenetic disorders. There is a need for development of approaches which, individually or in combination, may assist in the early detection of embryos destined to develop into blastocysts.

Potential liability of reproductive endocrinologists for high order multiple gestation.

In light of the recent octuplet birth and the accompanying intensive media coverage, there has been much attention on high order multiple births resulting from assisted reproductive technology. The purpose of this commentary is to review 1) the relative contribution of ART to high order multiple gestation and its impact on infant morbidity, mortality, and health care dollar loss; 2) American Society of Reproductive Medicine's guidelines for the number of embryos transferred in ART; and 3) how reproductive endocrinologists can lessen their exposure to litigation by following the ASRM guidelines for the number of embryos transferred and documenting proper informed consent in the medical records. In situations in which the number of embryos transferred is in excess of the ASRM guidelines, justification for deviating from the ASRM guidelines should be justifiable and documented in the medical records.

Cumulative Pregnancy Rates Offer a More Comprehensive View of Overall In Vitro Fertilization Success for a Given Cycle than Fresh or Frozen Pregnancy Rates Alone

BACKGROUND: IVF pregnancy rates (PR) after a fresh ET or frozen ET highly correlate with the number of embryos transferred and maternal age. To minimize the risk of high-order multiple gestation, many programs limit the number of fresh embryos transferred, especially when excess embryos are available for cryopreservation. An important clinical question is what is the comprehensive chance of achieving a pregnancy after a controlled ovarian hyperstimulation cycle (COH) when the opportunity for both a fresh and frozen ET exist? Unfortunately, PR for fresh ET and frozen ET are usually reported separately.

Prevention of multiple gestation(MG) after assisted reproductive technology (ART)

OBJECTIVE: To develop a decision aid (DA) to help patients decide the optimal number of ET after ART. DESIGN: Prospective cohort. MATERIALS AND METHODS: 1) International Patient Decision Aid Standards for DA: interviews and focus groups of ART providers and patients informed the structure of the DA. Options (#ET) with their benefits (pregnancy) and harms (MG and related risks) are presented. 2) Systematic reviews (SR) give probabilities of maternal and infant risks associated with singleton, twin, and triplet+ MG for 18 outcomes. 3) A novel math model predicts implantation rates for day 3 and day 5 embryos and the probability of singleton, twin or higher based on the # and quality of ET. 4) The DA is tested in 31 patients for: a) change in knowledge about multiple gestation b) patient acceptability. RESULTS: 1) A 2-part DA resulted. Part 1 gives patients age-clinic specific pregnancy/MG rates before ovarian stimulation and helps patients determine values-based risk acceptance. Part 2 gives updated probabilities from the model for singleton,twin and higher order MG based on actual embryo quality on day of ET and #ET. 2) SR showed increased maternal and infant risks specific to ART and MG Eg. Preterm delivery after ART for singletons, twins and triplets+ is 21, 69, and 81% respectively. 3) Model prediction rules had a PPV of 75-85% for day 3 ET. 4) Testing of part 1: Knowledge re: MG was higher post DA (62 vs 77%). All found the DA acceptable, 81% called it “balanced”; 62% found it easy to find the probability of pregnancy but 51% wanted information about embryo quality (part 2) before making the decison. CONCLUSIONS: This DA educates patients about their probability for pregnancy, multiple pregnancy and related risks based on age, clinic and embryo characteristics. Part 1 changes knowledge about MG and is acceptable to patients. Specific information how embryo quality relates to pregnancy and MG is desired by patients before the decision about embryo transfer. Part 2 gives this information. This DA may help prevent MG.

Outcome of pregnancy after in vitro fertilization

In 2004 clinical pregnancy rates per aspiration and per transfer after in vitro fertilization (IVF) in Europe were 26.6% and 30.1%, respectively. The distribution of singleton, twin and triplet deliveries after IVF was 77.2%, 21.7% and 1%, respectively. The reported total multiple delivery rate of 22.7% during 2004 decreased, compared with 23.1% in 2003 and 24.5% in 2002. The proportion of children born after IVF ranged from 0.2% to 6.2% of all infants. Conceptions by IVF are associated with an increased incidence of several obstetrical and perinatal complications. Most of these complications are related to the high incidence of multiple gestations. However, even singleton pregnancies appear to be affected. Neonatal complications are primarly the result of preterm deliveries. Patients should be informed about the fact that pregnancies conceived by IVF are associated with increased risk of multiple gestations, preterm delivery, low birth weight, and complications associated with these outcomes. Several strategies attempting to control the frequency of high order multiples have been implemented. The overriding aim of the strategies is to transfer fewer embryos of higher quality to maximize the pregnancy rate and to minimize the risk of high order multiple gestation.

Comparison of the offspring sex ratio between fresh and vitrification-thawed blastocyst transfer

There was a significant difference in the sex ratio between offspring from fresh and from vitrification-thawed blastocyst transfer. The live birth sex ratio influenced by the blastocyst-stage embryo transfer correlated with top-quality embryo morphology.

Impact of developmental stage at cryopreservation and transfer on clinical outcome of frozen embryo cycles

Although several early IVF successes were achieved after transferring fully formed blastocysts, the majority of embryos replaced worldwide over the past 30 years have been at the cleavage stage. The programme at this study centre has previously found that delaying an embryo transfer to day 5 can reduce the chance for a high-order multiple gestation without compromising the pregnancy rate because fewer embryos can be replaced. To evaluate the impact of transfer day and embryonic stage at cryopreservation on cycle outcome, 6069 fresh and 706 frozen transfers from 2000–2006 performed at this study centre were retrospectively analysed. Approximately half of the fresh transfers were performed on day 3, with a shift to day-5 transfer over the study period with no change in cryopreservation incidence. Implantation, clinical pregnancy and live birth rates were significantly higher following day-5 transfer. When frozen–thawed embryos (2-cell to day-6 blastocysts) were transferred, acceptable pregnancy and live birth rates were achieved at all stages but thawed embryos transferred as day-5 blastocysts generated consistently higher clinical pregnancy and live birth rates. Transfer of embryos frozen on day 6 had the highest miscarriage and lowest live birth rates. Barring government regulation, an IVF programme's day for cryopreservation generally depends on its management of and success with fresh embryo transfer.

Conjoined twins in a triplet pregnancy after intracytoplasmic sperm injection and blastocyst transfer: case report and review of the literature

To describe an exceptional case of conjoined twins in a triplet pregnancy after intracytoplasmic sperm injection (ICSI) and blastocyst transfer. Case report. University teaching hospital reproductive endocrinology department and infertility practice. A 34-year-old woman underwent ICSI and received two blastocysts transferred. Transvaginal ultrasonography performed sequentially during early pregnancy. Ultrasound images of the fetus in gestational sac. Two gestational sacs in the uterus were revealed at the 5th week. At the 8th week of gestation, a single fetus was seen in one sac, whereas thoracopagus conjoined twins was diagnosed in the other sac. At the 10th week, the conjoined twins had a spontaneous cardiac arrest confirmed by color Doppler. The subsequent course was uneventful, and a healthy child was born at 39th week. To date, a small number of cases of conjoined twins in IVF/ICSI pregnancies have been reported, in which most cases were treated with manipulations causing possible trauma in the zona pellucida. Our case is unique in that the transferred embryos were blastocysts that might have had additional damage on the zona pellucida from the longer culture.

Real data mathematical modeling to predict successful embryo implantation

OBJECTIVE: To develop a probabilistic model to predict successful implantation and single versus multiple gestation based on clinic success rates, age, and embryo quality. To prevent multiple gestation, reliable methods to predict individual and multiple embryo implantation are essential. DESIGN: Probabilistic modeling using real data sets. MATERIALS AND METHODS: Different predictive models were considered to determine the probability of pregnancy for different embryo cell number and grade combinations. The three most important predictive factors were considered: age, clinic, and embryo quality specific pregnancy rates. These models were developed by applying them to the study dataset. Inclusion criteria for dataset: UCSF 2003-2006: all fresh UCSF day 3 embryo transfers(ET) for women ≤ age 40. Exclusion criteria: day 2 ET; non-elective single ET; PGD; day 5 ET; age >40; >3 IVF cycles. The model was based on 1203 ET events and 700 clinical (sac) pregnancies. Clinical pregnancies were defined as presence of gestational sac to avoid missing spontaneous/selective reduction. Embryo grading per UCSF CRH IVF laboratory standards were as follows: 1) cell number 2) fragmentation: grade 1: none; 2: 1-10%; 3 10-25%; 4: 25-50%; 5> 50%; 6: 100%.The developed models were internally validated using a bootstrapping procedure. RESULTS: The model developed included a combinatoric component incorporating Bayes theorem. This probabilistic model is the most reflective of the actual data of the models considered. In particular, for this model, the highest probabilities identified were associated with cell-fragment grades 8-1 (34%), 8-2 (20%) and 8-3 (15%). Mid-level probabilities were found for 6-1, 6-2, 6-3; 7-1, 7-2, 7-3; 9-3 ;10-3. Not calculable or zero probabilities were associated with most of the other grade combinations. Similar trends were found for these probabilities when considered separately for women ≤37 years and those 38-40 years, with younger women have higher probabilities. Clinical prediction rules for singleton, twin, and higher order multiple gestation will be presented. CONCLUSIONS: The probabilistic model is the most practical and useful method for determining clinic and age-specific likelihoods of pregnancy for different combinations of embryo cell number and grade.

Going towards single embryo transfer

The chance for conception with IVF is improved by transferring more than one embryo to the uterus but this practice carries the risk of high order multiple gestation (HOMG). Effective 2000, we decided to transfer one fewer embryo on day 5, post-oocyte retrieval (D5ET) than the traditional number on day 3. From 1999 to 2003, this resulted in a 58% decline in HOMG, while maintaining the overall clinical pregnancy (CP, +fetal heartbeat) rate at 47%. The current data extends our results through 2006.

Infertility Case Management

Infertility is a growing medical condition as more women are desirous of having children at an older age. It is estimated to be a $3 billion business, and, while infertility treatment is a for-profit commercial endeavor, the product is noncommercial (baby or babies). The treatment process may be complicated with overutilization, drug wastage, and adverse outcomes. High-order multiple gestations may result in preterm births, chronic adult diseases, and lifelong neurological impairments (such as cerebral palsy). The total national cost of infertility treatment unfortunately equals the cost of providing care to these babies in the nursery and neonatal intensive care unit. This article explores the potential benefit of the integration of information technology with clinical case management to reduce overall cost and improve provider accuracy. Office-based telephonic nurse case management and pharmacology management practice. The article demonstrates that the challenging integration of information technology with clinical case management is very effective and improves provider accuracy, resulting in the best transfer of real-time information. The case management program at Women's Integrated Network Healthcare has been shown to lower infertility treatment costs by 30% to 40% and lower the numbers of high-order multiple gestations. Eighty-one percent of the cost reduction is related directly to case management, not reduction in physician fees or unit pharmaceutical costs. Case management can improve effectiveness and quality of conception, and there is a reduction in high-order multiple gestations. It was also found that, by expanding infertility benefits and including case management as the pivotal element, payers and employers could recognize significant savings and, more importantly, the women and families would benefit.

Programmatic implementation of blastocyst transfer in a university-based in vitro fertilization clinic: maximizing pregnancy rates and minimizing triplet rates

To assess whether the use of extended embryo culture can reduce the incidence of high-order multiple gestations, a retrospective analysis of 7,418 fresh ETs performed in a university-based IVF clinic from 1997-2003 was conducted, comparing program results before and after institution of a protocol to select patients for extended culture of in vitro fertilized embryos. The incidence of triplet pregnancies was significantly reduced in patients at highest risk for high-order multiple gestations, i.e., those at <35 years of age (16.8% versus 6.8%), those at 35-37 years of age (13.0% versus 5.6%), and recipients of donated oocytes (11.2% versus 4.5%).

Infertility, Assisted Reproductive Technology, and Adverse Pregnancy Outcomes

The National Institute of Child Health and Human Development held a workshop on September 12-13, 2005, to summarize the risks for adverse pregnancy outcomes after assisted reproductive technology (ART), develop an approach to counseling couples regarding these risks, and establish a research agenda. Although the majority of ART children are normal, there are concerns about the increased risk for adverse pregnancy outcomes. More than 30% of ART pregnancies are twins or higher-order multiple gestations (triplets or greater) and more than one half of all ART neonates are the products of multifetal gestations, with an attendant increase in prematurity complications. Assisted reproductive technology singleton pregnancies also demonstrate increased rates of perinatal complications-small for gestational age infants, preterm delivery, and perinatal mortality-as well as maternal complications, such as preeclampsia, gestational diabetes, placenta previa, placental abruption, and cesarean delivery. Although it is not possible to separate ART-related risks from those secondary to the underlying reproductive pathology, the overall increased frequency of obstetric complications, including preterm birth and small for gestational age neonates, should be discussed with the couple. Significant gaps in knowledge were identified, and the basic science and clinical and epidemiologic research required to address these gaps is outlined.

Cumulus coculture and cumulus-aided embryo transfer increases pregnancy rates in patients undergoing in vitro fertilization

To evaluate the effect of the use of cumulus-aided embryo transfer on pregnancy rates. To study the proximity of expanded cumulus cells to the developing embryo. To document by light microscopy the anchoring of day 3 to day 4 embryos by the expanded cumulus cells. To demonstrate by transmission electron microscopy the cellular activity of the expanded cumulus cells. To evaluate the expression of growth factors (vascular endothelial growth factor, interleukin-6, insulin-like growth factor I) that are secreted by the cumulus cells. A comparative study of a group of women undergoing cumulus coculture and cumulus-aided embryo transfer, with those who underwent cumulus coculture but did not undergo cumulus-aided embryo transfer. The endpoint was the achievement of pregnancy. Department of Infertility Management and Assisted Reproduction, Jaslok Hospital and Research Centre, Mumbai, India. Five hundred seventeen women undergoing treatment for infertility using intracytoplasmic sperm injection and embryo transfer and fulfilling set criteria. To validate our initial results, we conducted a similar study on 208 women where randomization was performed. Embryos were cocultured with the patient's own cumulus cells and were transferred into the uterus with approximately 30 microL of the expanded cumulus cells. Pregnancy, implantation, and multiple gestation rates. Our study demonstrated a significant increase in the implantation rate in the study group (group A) of 25.6% versus 14.5% in the control group (group B) and a significant increase in the pregnancy rate in the study group (group A) of 47.6% versus 34% achieved in the control group (group B). Although the incidence of multiple gestation was similar (38.6% in the study group and 32.9% in the control group), the higher-order multiple gestation rate was significantly more in the study group as compared with the control group (18.1% vs. 2.4%). Similar pregnancy and implantation rates were observed in the randomized study. This study demonstrates the efficacy of cumulus-aided embryo transfer, using autologous cumulus cells. It indicates a significant increase in implantation and pregnancy rates. The results suggest that cumulus cells play an important role in embryonic development, and that they may provide a mechanism to improve embryo-uterine adhesion by physical proximity, and by secreting cytokines and growth factors required to aid the implantation process.

O-15: Anovulation may be a risk factor for major birth defects in children born after infertility treatment

We recently reported a slight but significant increase in major birth defects in infants conceived by IVF procedures and a slight and non-significant increase in infants born after IUI procedures compared to matched controls. Our purpose was to further evaluate the same database for risk factors for birth defects after infertility treatments. Retrospective analysis of 1805 infants born to 1134 women following infertility treaments (both IVF and IUI) with 107 of these infants being diagnosed with at least one major birth defect by one year of age. The generalized logit model fitted using the generalized estimating equations method was used to identify risk factors associated with major birth defects while accounting for the correlation among births from the same mother. Individual risk factors were then fitted into a multi-factor model to determine significant independent variables. Variables examined included infertility treatments used, parental demographic data, sex and plurality of the infant, maternal BMI, and infertility diagnoses. Attending physicians made infertility diagnoses prior to the IVF cycle and these included tubal factor, male factor, endometriosis, cervical factor, polycystic ovarian syndrome (PCOS), and ovulatory factor not otherwise specified. For the infertility diagnosis variable, 28 infants had to be excluded due to missing data. By univariate analysis, factors that were significantly associated with an increased risk of a major birth defect were high order multiple gestations (but not twins), male gender, and the combined infertility diagnostic categories of ovulatory factor/PCOS (see table). The 73 infants born to mothers with a definite diagnosis of PCOS had a 13% incidence of birth defects with an odds ratio of 2.53 (95% CI of 1.20, 5.34, p=0.02), although the numbers in this group were small. Maternal BMI was not a risk factor. The diagnosis of endometriosis did not quite reach statistical significance as a risk factor. By multivariate analysis, high order multiple birth, male gender and PCOS/ovulatory factor remained as significant risk factors for birth defects following infertility treatments.Tabled 1 This is the first study to link birth defects with a maternal infertility diagnosis. Ovulatory dysfunction and PCOS appear to contribute to the risk for birth defects following treament. As we seek safe outcomes from infertility care, reducing multiple gestations should be a priority for many reasons including the avoidance of birth defects.