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Trends and Correlates of Monozygotic Twinning After Assisted Reproductive Technology
Abstract
Monozygotic twinning, associated with increased infant morbidity and mortality, is more common after assisted reproductive technology (ART) than in the general population. Although multiple factors have been proposed as contributors, studies seeking to define causality have been underpowered or inconclusive. We evaluated trends of monozygotic twinning in ART and its association with patient and treatment factors.
We analyzed 392,136 pregnancies resulting from fresh, nondonor embryo transfers conducted between 2000 and 2011 and reported to the National ART Surveillance System. We examined trends of monozygotic twin pregnancies (defined as those in which number of fetal heart tones on first trimester ultrasound exceeded number of embryos transferred) using the Cochrane-Armitage test and subsequently compared monozygotic twins with (1) singleton pregnancies (one fetal heart) and (2) other multiple-gestation pregnancies (more than one fetal heart but not more than number of embryos transferred). Modified Poisson regression models were used to estimate adjusted risk ratios (aRRs) for monozygotic twinning association with assisted hatching for both comparison groups, stratified by day-3 and day-5 transfer.
Incidence of monozygotic twinning after ART increased from 2000 to 2011 (P<.001 for trend), with greater incidence in day-5 (1.72%) than day-3 (0.48%) embryo transfers. Monozygotic twinning was associated with assisted hatching among day-3 embryo transfers when compared with both singleton (aRR 2.19, confidence interval [CI] 1.93-2.48) and other multiple-gestation (aRR 2.27, CI 2.00-2.57) pregnancies and among day-5 embryo transfers when compared with other multiple-gestation pregnancies (aRR 1.18, CI 1.05-1.32).
Monozygotic twin pregnancy incidence after ART has increased over the past decade. Day-5 transfer and assisted hatching are associated with increased monozygotic twinning risk.
IVF is now almost synonymous with all ART. Over the years the practice of IVF has become increasingly common as the treatment option for subfertility. In this field there is no lack of innovative ideas and techniques in exploring new frontiers, largely with the aim to improve pregnancy outcome. New technologies and skills researched by academic and commercial organisations have also significantly widened the scope of ART application; the discovery of ovarian tissue preservation, and the improvement in egg freezing technique have enabled many women to consider fertility preservation in certain circumstances. While these may seem promising in short term, data on long term outcomes of these techniques are limited and take time to accumulate. As more and more data are emerging, their safety for long term health of offspring born have also been questioned. In this chapter we review the evidence of laboratorial, surgical and clinical developments in ART and their impact on pregnancy outcomes as is available now and future directions.
Preimplantation genetic diagnosis and screening improves the chances of achieving a viable pregnancy, not only free of undesired single-gene defects but also aneuploidy. In addition, improvements in vitrification provide an efficient means of preserving embryos (blastocysts). By combining trophectoderm biopsy with recent improvements in vitrification methods, only those embryos that have proved themselves viable and potentially more competent are tested. Using array comparative genomic hybridization (aCGH) to assess all 24 chromosomes, aneuploidy rates were compared between day-3 blastomere biopsy and day-5 trophectoderm biopsy. Of those 1603 embryos, 31% were euploid, 62% were aneuploid and 7% not analysable. A significantly larger proportion of embryos were euploid on day-5 biopsy (42%) compared with day-3 biopsy (24%, P < 0.0001). The number of euploid embryos per patient was not significantly different. Combining extended culture, trophectoderm biopsy and aneuploidy assessment by aCGH and subsequent vitrification can provide a more efficient means of achieving euploid pregnancies in IVF.
The advent of fertility treatments has led to an increase in the rate of multiple births in the United States. However, the trends in and magnitude of the contribution of fertility treatments to the increase are uncertain.
We derived the rates of multiple births after natural conception from data on distributions of all births from 1962 through 1966 (before fertility treatments were available). Publicly available data on births from 1971 through 2011 were used to determine national multiple birth rates, and data on in vitro fertilization (IVF) from 1997 through 2011 were used to estimate the annual proportion of multiple births that were attributable to IVF and to non-IVF fertility treatments, after adjustment for maternal age. Trends in multiple births were examined starting from 1998, the year when clinical practice guidelines for IVF were developed with an aim toward reducing the incidence of multiple births.
We estimated that by 2011, a total of 36% of twin births and 77% of triplet and higher-order births resulted from conception assisted by fertility treatments. The observed incidence of twin births increased by a factor of 1.9 from 1971 to 2009. The incidence of triplet and higher-order births increased by a factor of 6.7 from 1971 to 1998 and decreased by 29% from 1998 to 2011. This decrease coincided with a 70% reduction in the transfer of three or more embryos during IVF (P<0.001) and a 33% decrease in the proportion of triplet and higher-order births attributable to IVF (P<0.001).
Over the past four decades, the increased use of fertility treatments in the United States has been associated with a substantial rise in the rate of multiple births. The rate of triplet and higher-order births has declined over the past decade in the context of a reduction in the transfer of three or more embryos during IVF. (Funded by the Centers for Disease Control and Prevention.).
STUDY QUESTION
What characteristics are associated with a Day 5 embryo transfer?
SUMMARY ANSWER
The use of the Day 5 embryo transfer has increased over time, with clinicians allowing women with typically ‘poorer’ prognostic characteristics to undergo a Day 5 embryo transfer. The mean number of embryos per Day 5 transfer decreased from 2001 to 2009, although the prevalence of the Day 5 single embryo transfer remains low and the rate of multiple births remains substantial.
WHAT IS KNOWN AND WHAT THIS PAPER ADDS
Day 5 embryo transfer may reduce the rate of multiple gestation pregnancy. US trends over time in the prevalence of the Day 5 transfer, changes in characteristics of patients receiving Day 5 transfer, and number of embryos transferred are unknown.
DESIGN
We used 2001–2009 US National assisted reproductive technology (ART) Surveillance System (NASS) data on 620 295 fresh IVF cycles derived from autologous oocytes with a Day 3 or 5 embryo transfer. Trends in the mean number of embryos transferred from 2001 to 2009 were assessed by the day of transfer. For 349 947 cycles from clinics performing both Days 3 and 5 embryo transfers, multivariable logistic regression was used to determine the characteristics associated with the Day 5 embryo transfer. We also compared the characteristics of the Day 5 embryo cycles in 2001 and 2009.
MAIN RESULTS AND THE ROLE OF CHANCE
Overall, the proportion of ART cycles using the Day 5 embryo transfer increased from 12% in 2001 to 36% in 2009 (P< 0.0001), while the mean number of embryos transferred decreased from 2.4 to 2.1 (P< 0.0001). Among Day 5 transfers, the rate of the single embryo transfer tripled from 4.5% in 2001 to 14.8% in 2009 (P< 0.0001); and the rate of multiple births decreased from 44.8 to 41.1% (P< 0.0001). In cycles initiated after 2001, maternal age
It is estimated that there is at least a 2-fold rise in the incidence of monozygotic twinning after assisted reproductive technology compared with natural conception. This can result in adverse pregnancy outcomes.
We searched MEDLINE, EMBASE and SCISEARCH for studies that estimated the risk of monozygotic twinning and its association with any particular assisted reproductive technique. Monozygotic twinning was defined by ultrasound or Weinberg criteria. A meta-analysis of the proportion of monozygotic twins was performed using both fixed and random effects models.
The search revealed 37 publications reporting on the incidence of monozygotic twins after assisted reproductive techniques. Twenty-seven studies met the inclusion criteria and were included in the meta-analysis. The summary incidence of monozygotic twins after assisted conception was 0.9% (0.8-0.9%). The incidence of monozygotic twins in natural conception is 0.4%. Blastocyst transfer and intracytoplasmic sperm injection are associated with 4.25 and 2.25 times higher risk of monozygotic twins.
The risk of monozygotic twins in assisted conception is 2.25 times higher than the natural conceptions. Larger studies reporting on monozygotic twinning following single-embryo transfer or after post-natal confirmation of zygosity with DNA analysis are warranted before definitive conclusions can be drawn and guidelines produced. In order to provide adequate pre-conceptional counselling, it is important to monitor the incidence of monozygotic twins in both natural and assisted conceptions. We suggest building a national multiple pregnancy database based on accurate diagnosis of zygosity.
To assess the association of zona pellucida micromanipulation and subsequent development of monozygotic twins, cases of assisted embryo hatching (AH) and intracytoplasmic sperm injection (ICSI) were identified and related to treatment type, implantation and zygosity data. Embryology records from all patients undergoing in-vitro fertilization (IVF) at this centre from January 1995 to March 1998 were reviewed. In this study, 3546 transfer cycles were completed, with clinical pregnancy established in 1911 (54% per transfer) patients undergoing a single IVF cycle. These pregnancies occurred in 1674 (88%) IVF cycles, 120 (6%) donor oocyte cycles (DER), and 117 (6%) frozen embryo transfer (FET) cycles. During the study period, 23 cases of monozygotic (MZ) twins were identified, representing an overall frequency of 1.2%. Chorionicity was determined by transvaginal ultrasound at 7 weeks when the number of embryos transferred was less than the number of fetal heart-beats, or when >1 fetal heartbeat per gestational sac was seen. Zygosity was confirmed by placental evaluation at delivery, and corroborated the antenatal diagnosis in all cases. Among IVF study patients the frequency of MZ twinning was not statistically different between zona manipulated and zona intact subgroups. While this investigation is the largest to date describing the relationship between MZ twins and zona procedures, studies with even greater statistical power are needed to clarify it more precisely, particularly in DER and FET settings. A greater overall frequency of MZ twinning for IVF patients may be a function of the higher number of embryos transferred in IVF, rather than discrete zona manipulations.
Monozygotic twinning is a relatively rare event in in-vivo conception, being estimated to occur in 0.42% of all births. The underlying mechanism for monozygotic twin formation is the division of the embryo early in its development. Separation of cells may theoretically occur before or after inner cell mass formation. In this analysis we report 11 cases of monozygotic twins resulting from IVF or intracytoplasmic sperm injection (ICSI) treatment cycles performed between 1991 and 1998 at St James's University Hospital, Leeds, and Bourn Hall Clinic, Cambridge, UK. Six cases (55%) followed treatment with ICSI and seven cases (64%) were in women aged > or = 35 years. This article also reviews the scientific literature discussing information pertaining to frequency, aetiology and potential complications of the monozygotic twinning phenomenon. We conclude that patients at risk of monozygotic twinning are those aged >35 years of age and those who had artificial opening in the zona pellucida by application of micromanipulation techniques. Women undergoing assisted conception treatment, particularly those with these two risk factors, must be informed of the low but definite risk of monozygotic twinning when counselled regarding the number of embryos to be transferred and chances of multiple births.
Assisted reproduction technique (ART) is an efficacious treatment in subfertile couples. So far little attention has been
paid to the safety of ART, i.e. to its adverse events and complications. The consensus meeting on Risks and Complications
in ART held in Maastricht in May 2002 focused on four topics: multiple pregnancies, long‐term effects of ART on women, effects
of ART on offspring, and morbidity/mortality registries.
This study examines the association between day of embryo transfer and monozygotic (MZ) twinning.
We used a population-based sample of 108,36 IVF/embryo transfer procedures in which the patients oocytes' were freshly fertilized (non-frozen; non-donor) and 39,98 resultant pregnancies from US clinics in 1999 and 2000. Cases were pregnancies for which the number of fetal hearts observed on ultrasound exceeded the number of embryos transferred. These pregnancies were considered to contain at least one set of MZ twins. A total of 226 MZ pregnancies were compared with two control groups: 23,880 singleton pregnancies (one fetal heart) and 15,092 other multiple-gestation pregnancies (> or = 2 fetal hearts but the number of fetal hearts on ultrasound was less than or equal to the number of embryos transferred).
Cases of presumed MZ multiple-gestation pregnancies were more likely to have had a day 5 embryo transfer compared with day 3 embryo transfers than singleton pregnancies [adjusted odds ratio (AOR) = 3.92, 95% confidence interval (CI) = 2.97-5.17] or other multiple-gestation pregnancies (AOR = 3.91, 95% CI = 2.96-5.17) conceived with IVF/embryo transfer.
Day 5 embryo transfer may be associated with increased MZ twinning.
Although several factors have been identified to predispose to an increased incidence of monozygotic twinning in assisted reproductive technologies (ART), the relative risks associated with each have yet to be fully established. Moreover, the focus has been predominantly on monozygosity, which, in the absence of monochorionicity, does not increase perinatal risk. The present objective was to undertake an analysis of the relative risks of factors associated with monochorionic pairs resulting from ART.
Study cycles included the last cycle, of each patient undergoing ART at Brigham and Women's Hospital from January 1998 to December 2004, that resulted either in a pregnancy with a monochorionic pair (n = 41) or a pregnancy without a monochorionic pair at 12 weeks (n = 2460). We used multivariable logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) to identify factors significantly associated with a monochorionic pair.
Independent predictors of a monochorionic pair were assisted hatching (OR 2.23, 95% CI 1.06-4.67), ICSI (OR 2.42, 95% CI 1.22-4.83) and Day 5 embryo transfer (OR 2.48, 95% CI 1.62-3.80). The effects of ICSI and Day 5 transfer were amplified when cycles involved both interventions.
ICSI and Day 5 embryo transfer synergistically increase the risk of monochorionic placentation. Patients undergoing these procedures should be counselled regarding these increased risks.
Twin birth rates have increased markedly in developed countries since the 1970s for two primary reasons: increasing maternal age and the advent and increasing use of fertility treatments. In addition, monozygotic (MZ) twin pregnancies have been reported to occur at a significantly higher rate following assisted reproductive technologies (ART) procedures compared with the natural incidence. Twin pregnancies are of concern due to a dramatically increased risk of associated complications. Monozygotic twin pregnancies carry a 10-20% risk of twin-twin transfusion syndrome, and monoamniotic monochorionic twins are additionally at risk for cord entanglement. While the mechanisms and contributory factors for dizygotic twinning are well established, very little is known about the mechanisms involved in MZ twinning or the factors that contribute to its occurrence. In this review, we will discuss a number of potential mechanisms involved in MZ twinning and explore factors that may be contributing to the increased incidence of ART-associated MZ twins. An improved understanding of the factors that contribute to increased MZ twinning associated with ART will help to elucidate the poorly understood mechanisms involved in the process and will further aid in reducing the overall incidence of multiple pregnancies with their associated risks following ART procedures.
To evaluate factors associated with monozygosity (MZ) (number of fetal heartbeats on early ultrasound greater than the number of embryos transferred) and the risk of recurrence in subsequent pregnancies using a national assisted reproduction database.
Historical cohort study.
Clinic-based data.
197,327 pregnancies (including 2,824 with evidence of MZ) from cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) between 2004 and 2010.
None.
Evidence of MZ, adjusted odds ratios and their 95% confidence intervals computed from logistic regression models.
In the univariate analysis, the risk of MZ was increased with ovulation disorders, donor oocytes, gonadotropin-releasing hormone agonist (GnRH-a) suppression, assisted hatching (AZH), and day 5-6 transfer, and was decreased with higher follicle-stimulating hormone (FSH) doses (≥3,000 IU). In the multivariate analysis, the risk of MZ was increased with GnRH-a suppression, AZH, and decreased with intracytoplasmic sperm injection (ICSI) and higher FSH dose. The interaction showed that although MZ was more likely with day 5-6 embryos, AZH had a minimal nonsignificant effect, whereas in day 2-3 embryos, AZH had a substantial statistically significant effect. Only one woman had a recurrence of MZ in a subsequent assisted reproduction pregnancy, which is consistent with randomness.
The risk of MZ was higher with fresh day 5-6 embryos, donor oocytes, GnRH-a suppression, lower FSH doses, and AZH (particularly with day 2-3 embryos).
Objective:
To assess trends in elective single ET and identify factors associated with a good perinatal outcome.
Design:
Retrospective cohort study.
Setting:
Clinic-based data.
Patient(s):
A total of 886,686 fresh, nondonor cycles reported to the National Assisted Reproductive Technology Surveillance System during 1999-2010, of which 17,166 met criteria for elective single ET.
Intervention(s):
None.
Main outcome measure(s):
Rates of elective single ET and good perinatal outcome (term, singleton infant with normal birth weight).
Result(s):
In 2010, elective single ET comprised 5.6% of all fresh transfers, representing an eightfold increase since publication of first guidelines in 2004 recommending elective single ET. Compared with other ETs, elective single ETs were nearly twice as likely to result in a good perinatal outcome (37.1% vs. 18.9%, respectively). Among women using elective single ET, those aged <35 and 35-37 years had a good perinatal outcome (40.2% and 32.5%, respectively). In multivariable, log-binomial analyses, factors positively associated with a good perinatal outcome included male factor infertility, day 5 ET, and having ≥3 supernumerary embryos for cryopreservation.
Conclusion(s):
Between 1999 and 2010, national rates of elective single ET increased. Given the frequency of good perinatal outcomes among women aged 35-37 years, guidelines for elective single ET could be expanded to include patients in this age group with favorable prognoses.
Background:
Failure of implantation and conception may result from an inability of the blastocyst to escape from its outer coat, which is known as the zona pellucida. Artificial disruption of this coat is known as assisted hatching and has been proposed as a method for improving the success of assisted conception by facilitating embryo implantation.
Objectives:
To determine the effect of assisted hatching (AH) of embryos from assisted conception on live birth and multiple pregnancy rates.
Search methods:
We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register (August 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (August 2012), MEDLINE (1966 to August 2012) and EMBASE (1980 to August 2012).
Selection criteria:
Three authors identified and independently screened trials. We included randomised controlled trials (RCTs) of AH (mechanical, chemical or laser disruption of the zona pellucida prior to embryo replacement) versus no AH that reported live birth or clinical pregnancy.
Data collection and analysis:
Three authors independently performed quality assessments and data extraction.
Main results:
Thirty-one trials reported clinical pregnancy data, including 1992 clinical pregnancies in 5728 women. There was no significant difference in the odds of live birth in the AH group compared with the control group (9 RCTs; odds ratio (OR) 1.03, 95% confidence interval (CI) 0.85 to 1.26, moderate quality evidence), with no evidence of significant heterogeneity (P = 0.38) or inconsistency (I(2) = 6%). Analysis of the clinical pregnancy rates from the nine studies which reported live birth showed a non-significant result (OR 1.03, 95% CI 0.85 to 1.25 ).Analysis of all of the studies included in this update (31 RCTs) showed that the clinical pregnancy rate in women who underwent AH was slightly improved, but the level only just reached statistical significance (OR 1.13, 95% CI 1.01 to 1.27, moderate quality evidence). However, it is important to note that the heterogeneity for this combined analysis for clinical pregnancy rate was statistically significant (P = 0.001) and the I(2) was 49%. Subgroup analysis of women who had had a previous failed attempt at IVF found improved clinical pregnancy rates in the women undergoing AH compared with the women in the control group (9 RCTs, n = 1365; OR 1.42, 95% CI 1.11 to 1.81) with I(2) = 20%. Miscarriage rates per woman were similar in both groups (14 RCTs; OR 1.03, 95% CI 0.69 to 1.54, P = 0.90, moderate quality evidence). Multiple pregnancy rates per woman were significantly increased in women who were randomised to AH compared with women in the control groups (14 RCTs, 3447 women; OR 1.38, 95% CI 1.11 to 1.70, P = 0.004, low quality evidence).
Authors' conclusions:
This update has demonstrated that whilst assisted hatching (AH) does appear to offer a significantly increased chance of achieving a clinical pregnancy, the extent to which it may do so only just reaches statistical significance. The 'take home' baby rate was still not proven to be increased by AH. The included trials provided insufficient data to investigate the impact of AH on several important outcomes. Most trials still failed to report on live birth rates.
Advances in cell culture media have led to a shift in in vitro fertilization (IVF) practice from early cleavage embryo transfer to blastocyst stage transfer. The rationale for blastocyst culture is to improve both uterine and embryonic synchronicity and enable self selection of viable embryos thus resulting in higher implantation rates.
To determine if blastocyst stage (Day 5 to 6) embryo transfers (ETs) improve live birth rate and other associated outcomes compared with cleavage stage (Day 2 to 3) ETs.
Cochrane Menstrual Disorders and Subfertility Group Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE and Bio extracts. The last search date was 21 February 2012.
Trials were included if they were randomised and compared the effectiveness of early cleavage versus blastocyst stage transfers.
Of the 50 trials that were identified, 23 randomised controlled trials (RCTs) met the inclusion criteria and were reviewed (five new studies were added in this update). The primary outcome was rate of live birth. Secondary outcomes were rates per couple of clinical pregnancy, cumulative clinical pregnancy, multiple pregnancy, high order pregnancy, miscarriage, failure to transfer embryos and cryopreservation. Quality assessment, data extraction and meta-analysis were performed following Cochrane guidelines.
Twelve RCTs reported live birth rates and there was evidence of a significant difference in live birth rate per couple favouring blastocyst culture (1510 women, Peto OR 1.40, 95% CI 1.13 to 1.74) (Day 2 to 3: 31%; Day 5 to 6: 38.8%, I(2) = 40%). This means that for a typical rate of 31% in clinics that use early cleavage stage cycles, the rate of live births would increase to 32% to 42% if clinics used blastocyst transfer.There was no difference in clinical pregnancy rate between early cleavage and blastocyst transfer in the 23 RCTs (Peto OR 1.14, 95% CI 0.99 to 1.32) (Day 2 to 3: 38.6%; Day 5 to 6: 41.6%) and no difference in miscarriage rate (13 RCTs, Peto OR 1.18, 95% CI 0.86 to 1.60). The four RCTs that reported cumulative pregnancy rates (266 women, Peto OR 1.58, 95% CI 1.11 to 2.25) (Day 2 to 3: 56.8%; Day 5 to 6: 46.3%) significantly favoured early cleavage. Embryo freezing rates (11 RCTs, 1729 women, Peto OR 2.88, 95% CI 2.35 to 3.51) and failure to transfer embryos (16 RCTs, 2459 women, OR 0.35, 95% CI 0.24 to 0.51) (Day 2 to 3: 3.4%; Day 5 to 6: 8.9%) favoured cleavage stage transfer.
This review provides evidence that there is a small significant difference in live birth rates in favour of blastocyst transfer (Day 5 to 6) compared to cleavage stage transfer (Day 2 to 3). However, cumulative clinical pregnancy rates from cleavage stage (derived from fresh and thaw cycles) resulted in higher clinical pregnancy rates than from blastocyst cycles. The most likely explanation for this is the higher rates of frozen embryos and lower failure to transfer rates per couple obtained from cleavage stage protocols. Future RCTs should report miscarriage, live birth and cumulative live birth rates to enable ART consumers and service providers to make well informed decisions on the best treatment option available.
The number of twins has doubled and the rate of twin births has risen by more than three-fourths over the three decades 1980–2009. Increases in twin birth rates averaged more than 2 percent annually from 1980 to 2004, but the pace of increase slowed to less than 1 percent from 2005 to 2009. The increase in twinning over the three decades has been widespread, occurring across age and race and Hispanic origin groups, and in all states within the United States. The largest increases have been among non-Hispanic white women and mothers aged 30 and over. Older maternal age accounts for about one-third of the growth in the twinning rate over this period. The increased availability and use of infertility treatments likely explains much of the remainder of the rise (9,10). Similar increasing trends in multiple births associated with both maternal age and infertility therapies have been observed in Western Europe and other countries during the 1980s and 1990s (10,12). The study of multiple births is important because of their elevated health risks and accompanying greater health care costs (6). The rise in twinning has influenced the upward trend in key infant health indicators such as preterm and low birthweight rates during the 1980s and 1990s (8). An estimated additional 865,000 twins were born in the United States over the study period due to rising rates; more than one-half of these infants were low birthweight, and 1 in 10 were very low birthweight (3,4,13). New information soon to be available from the 2003 revision of the U.S. Standard Certificate of Live Birth and the U.S. Standard Report of Fetal Death on topics such as use of infertility treatment and admission to a neonatal intensive care unit, will further expand understanding of the causes and risks of multiple-gestation pregnancies.
To investigate whether cryopreservation of supernumerary embryos is a good surrogate for embryo quality.
Retrospective study of 6,859 assisted reproductive technology (ART) cycles from women aged <35 years with two fresh day 3 embryos transferred.
National Society for Assisted Reproductive Technology Clinic Outcome Reporting System data from 2006-2008.
Women undergoing ART.
None.
Embryo quality (good, fair, or poor), cell number, and live births were compared for cycles with and without cryopreservation, using χ(2) to evaluate statistical significance. The association of freezing with embryo quality was examined using multiple logistic regression after adjusting for confounders (patient age, oocyte yield, intracytoplasmic sperm injection [ICSI], assisted hatching, male factor infertility).
Cycles with cryopreservation were more likely to have two embryos of good quality transferred (81.3% vs. 48.5%) and had more 8-cell embryos transferred (76.0% vs. 50.1%). Relative to cycles with two good embryos (good-good), the adjusted odds ratios (OR) for cryopreservation were: good-fair (OR = 0.301, 95% confidence interval [CI] = 0.257-0.354), fair-fair (OR = 0.308, 95% CI = 0.258-0.367), and any poor (OR = 0.058, 95% CI = 0.040-0.083). The live birth rate was 52.4% for cycles with freezing and 40.6% for cycles without.
Embryo quality and cell number were both associated with embryo cryopreservation. However, although cryopreservation was a strong marker for good quality, not having cryopreservation did not reliably indicate poor quality, as almost half of those cycles had two good quality embryos.
In a 7-year (2002-2008) retrospective study of a large IVF program based on minimal ovarian stimulation and single ET (47,841 single ETs), monozygotic twinning occurred in 1.01% of 14,956 clinical pregnancies. Blastocyst culture was associated with a significantly increased monozygotic twinning risk (adjusted odds ratio, 2.04; 95% confidence interval, 1.29-4.48), whereas embryo freezing, type of stimulation protocol used, intracytoplasmic sperm injection fertilization, or zona removal did not influence its incidence.
To characterize incidence, chorionicity, amnionicity, and pregnancy outcome for monozygotic twin pregnancy (MZT) after IVF.
Retrospective review.
University-based fertility center.
Autologous and oocyte donation IVF cycles eventuating in 4,976 clinical gestations from 2000 to 2007.
None.
MZT incidence, chorionicity, zygosity, pregnancy outcome.
Ninety-eight MZTs were diagnosed after first-trimester ultrasound evaluation (2% incidence). The incidence in cycles transfering autologous oocytes was 1.7% but was 3.3% with donor oocytes; however, women <35 years old using their own oocytes displayed a similar rate (3.1%) to women using donor oocytes. Eighty MZTs occurred after fresh day-5 transfer; only 14 followed fresh day-3 transfer (2.6% vs. 1.2%). The MZT incidence in day-3 transfers without hatching was not different from those with hatching (1.3% vs. 1.1%). In addition, MZT incidence did not differ significantly whether or not ICSI was performed (2.4% vs. 2.0%). Four MZTs occurred after frozen-thawed embryo transfer (0.8% incidence). Ninety-five percent of all placental arrangements were confirmed as monochorionic-diamniotic on obstetric ultrasounds.
These findings confirm a higher incidence of MZT after IVF. Monochorionic-diamniotic implantations were increased, whereas monochorionic-monoamniotic were not. The MZT risk factors included young age and extended culture, but not zona penetration or cryopreservation.
To determine whether the transfer of blastocysts on day 5, developed in sequential culture media, resulted in an increase in implantation rate compared with embryos transferred on day 3.
Comparative study of embryo culture regimes.
Private practice assisted reproductive technology center.
Twenty-three patients undergoing routine IVF cycles.
Culture of embryos to day 3 in either standard culture conditions or a serum-free chemically defined medium. One hundred one embryos were subsequently cultured from day 3 to day 5 in a second serum-free medium specifically designed to support development of the blastocyst.
Embryo cell number and quality on day 3. Blastocyst development on day 5. Implantation rate (determined by fetal heart) and ongoing pregnancy rate (PR).
Implantation rates for embryos transferred at the blastocyst stage of development were twice that observed for embryos transferred on day 3, around the eight-cell stage. Significantly more embryos were required for transfer on day 3, compared with day 5, to establish similar PRs.
Viable human blastocysts can be obtained in sequential culture media in the absence of coculture and serum. Transfer of blastocysts in IVF will facilitate high PRs while limiting the number of embryos transferred and therefore minimizes the risk of multiple gestation.
To examine the association between assisted hatching and monozygotic (MZ) twinning.
Case-control.
Population-based sample of IVF-ET cycles initiated in U.S. clinics, 1996.
The IVF-ET (n = 35,503) cycles and 11,247 resultant pregnancies.
Use of an assisted hatching procedure on embryos transferred.
Cases were pregnancies for which number of fetal hearts observed on ultrasound exceeded number of embryos transferred. These pregnancies were considered to contain at least one MZ set of twins. Cases were compared with two control groups: other multiple-gestation pregnancies (>/=2 fetal hearts but number of fetal hearts </= number of embryos transferred); and singleton pregnancies (1 fetal heart).
Women with a case pregnancy were more likely to have received embryos treated with assisted hatching procedures than were women in either control group. After adjustment for patient age, number of embryos transferred, prior cycles, infertility diagnosis, intracytoplasmic sperm injection, and whether embryos from the current cycle were cryopreserved for later use, odds ratios and 95% CIs for use of assisted hatching were 3.2 (1.2-8.0), compared with other multiple-gestation pregnancies, and 3.8 (1.8-9.8), compared with singleton pregnancies.
Assisted hatching may pose a risk for MZ twinning.
Advances in assisted reproductive technology and increases in the proportion of maternities in older women have both contributed to the steep increase in the incidence of twin pregnancies since the 1980s. Maternal and perinatal complications are higher in twins than in singleton pregnancies. A significant proportion of perinatal mortality and morbidity among twins is due to the high incidence of preterm delivery and the added complication of twin-to-twin transfusion syndrome (TTTS) in monochorionic twins. Monochorionic twins also have a much higher rate of perinatal mortality than dichorionic twins, the greatest risk being before fetal viability (<24 weeks gestation). Early diagnosis of twins and their chorionicity, close fetal surveillance, particularly of monochorionic twins, and prompt therapeutic intervention in TTS are necessary to reduce perinatal mortality. Intrapartum management in the hospital setting with anaesthetic and neonatal facilities, as well as critical assessment of mode of delivery, have led to better outcomes. Ultrasonography is a valuable tool in the management of twin pregnancy. This chapter briefly summarises these topics, with a particular focus on recent literature.
Over the past two decades there has been an association between assisted reproductive technologies and increased monozygotic twinning. The association is not clear nor are the causes of assisted reproductive technology-related monozygotic twinning understood, although there are several theories as to the possible mechanisms involved. This review looks at some of the assisted reproductive technologies which may be associated with an increased risk of monozygotic twinning such as intracytoplasmic sperm injection, assisted hatching and blastocyst transfers. Determining the true incidence of monozygotic twinning after assisted reproductive technologies is important as there is a well-documented increase in perinatal morbidity and mortality of monozygotic twins compared to singleton and dizygotic pregnancies.
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