Hum. Reprod. Advance Access published online on March 31, 2008
Human Reproduction, doi:10.1093/humrep/den045
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Risk factors associated with pregnancies containing a monochorionic pair following assisted reproductive technologies
1 Department of Obstetrics Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, ASB 1+3, Rm 082, Boston, 02115 MA, USA 2 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115 MA, USA 3 Department of Epidemiology, Harvard School of Public Health, Boston, 02115 MA, USA 4 Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115 MA, USA
5 Correspondence address. Tel: +1-617-732-5455; Fax: +1-617-975-0825; E-mail: cracowsky{at}partners.org
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Abstract |
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BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: ICSI and Day 5 embryo transfer synergistically increase the risk of monochorionic placentation. Patients undergoing these procedures should be counselled regarding these increased risks.
Key words: monochorionic placentation/monozygotic pregnancies/assisted hatching/ICSI/IVF
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Introduction |
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The vast majority of twins following assisted reproductive technologies (ART) are dizygotic, arising from two distinct embryos. Twins (and other higher order multiples) inherently confer a greater risk of obstetrical complication to both mother and fetuses. In recent years, there has been an increasing drive towards single-embryo transfer (SET), as a means to decrease the number of twins (and the subsequent obstetrical risk) following ART. The move towards SET has been particularly applied in Europe, with ART programs in the United States being slower to adopt this approach. Regardless, monozygotic twins, arising from a single embryo will persist in the setting of SET, therefore additional research is necessary to further understand the mechanism of monozygotic twinning and the relationship to obstetrical outcome.
Twins are classified as dizygotic if they develop from two individual embryos, or monozygotic if they derive from splitting of a single embryo. Monozygotic twins are further classified according to their chorionicity and amniocity that, in turn, are determined by the stage during development at which the splitting occurs. If the embryo splits between Day 0 and Day 4 after fertilization, the resulting twins are dichorionic, diamniotic twins, indistinguishable from dizygotic twins (arising from two embryos). If the split occurs between Day 4 and Day 8, monochorionic, diamniotic twins result and if the split occurs after Day 8, the twins will be monochorionic, monoamniotic. Splitting of the embryo after Day 12 will result in conjoined twins (Hall, 2003
), see Fig. 1.
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Several factors have been identified to predispose to an increased incidence of monozygotic twinning in ART, which encompasses both IVF as well as the ICSI procedure. Identified risk factors include: treatment regimens (Derom et al., 1987
; Schachter et al., 2001), micromanipulation of the embryo with either assisted hatching (AH) or the ICSI procedure (Alikani et al., 1994; Slotnik and Ortega, 1996; Hershlag et al., 1999; Abusheika et al., 2000; Schieve et al., 2000; Yakin et al., 2003) and Day 5 embryo transfer (Da Costa et al., 2001; Sheiner et al., 2001; Jain et al., 2004; Wright et al., 2004). However, the majority of these studies have focused on monozygosity which, in the absence of monochorionicity, does not place pregnancies at higher risk (Carroll et al., 2005) when compared with the risk of twins in general. Furthermore, the relative risks of these factors have yet to be fully established.
Monochorionic twins are at increased obstetrical risk compared with their dichorionic counterparts, due to their shared placenta. Such increased risk includes growth discordance, twin-twin transfusion syndrome, fetal loss before 24 weeks, prematurity (Sebire et al., 1997), neurologic deficits (Adegbite et al., 2004) and perinatal death (Dube et al., 2002; Hack et al., 2006). Monoamniotic twins (sharing both a placenta and an amniotic sac) are at even higher obstetrical risk, due to the risk of cord entanglement, as well as iatrogenic prematurity (Ezra et al., 2005; Cordero et al., 2006).
Monochorionic placentation (both diamniotic and monoamniotic) confers significantly greater obstetrical risk than monozygotic twinning with dichorionic placentation. Our goal was to identify the relative risks of factors associated with ART treatment that specifically lead to pregnancies containing a monochorionic pair.
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Materials and Methods |
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Study design
Cycle selection criteria were as follows: all cycles of patients undergoing ART at Brigham and Women's Hospital from January 1998 to December 2004 were assessed. Only one cycle per patient was chosen to eliminate possible biases when including multiple cycles from a single patient. Those cycles resulting in a monochorionic pair of fetuses were marked as index cases. Among the remaining cycles (i.e. those not resulting in a monochorionic pregnancy), the last cycle for each patient was screened to identify those resulting in a clinical pregnancy to at least 12 weeks of gestation. All monochorionic pairs were presumed to be monozygotic and further data on zygosity was not obtained. We excluded patients undergoing blastomere biopsy for preimplantation genetic diagnosis due to the small sample size within our overall population (n = 18). After appropriate institutional review board approval for chart review was obtained, a total of 2501 cycles were identified as meeting the above inclusion criteria.
We included the following parameters in our analysis: patient age, ART attempt number, day of embryo transfer, infertility diagnosis, type of stimulation protocol [including individual use of follicle stimulating hormone (FSH) and human menopausal gonadotropins (HMG)], estradiol (E2) level on the day of human chorionic gonadotropin administration (peak E2), number of stimulation days, type of culture media used, sperm parameters (total count and total motile count), number of mature and immature oocytes, number of embryos transferred, number of embryos frozen, timing of retrieval parameters (time from hCG to oocyte retrieval, time from retrieval to insemination) and number of embryos with 8 or more cells. In addition, we conducted a sub-analysis comparing our cases of pregnancies complicated by a monochorionic pair to both singleton (n = 1456) and multiple gestations (n = 1004) within the control group.
Stimulation protocols, oocyte fertilization, embryo culture, transfer and luteal support
Stimulation protocols and our methods of oocyte fertilization have been described previously (Skiadas et al., 2006). After identification of two pronuclei (PN) at the fertilization check 16–18 h after standard insemination or ICSI on Day 1, zygotes with 2 PNs were cultured individually in 25 ul microdrops of growth medium overlaid with 8 ml oil in Falcon 1007 culture dishes (Becton Dickinson Labware, Franklin Lakes, NJ). From Days 1–3, one of four growth media were used [P1 (Irvine Scientific, Santa Ana, CA; or IVF-500, G1.2 or G1.3 (Scandinavian IVF Science/Vitrolife, Gothenburg, Sweden)]. From Days 3–5, embryos were cultured in the sequential medium marketed for use with the corresponding medium used for Days 1–3 (i.e. Blastocyst Medium following P1; S2 following IVF-500; and G2.2 and G2.3, following G1.2 and G1.3, respectively).
All cultures were maintained at 37°C in a humidified atmosphere of 5% CO2 in air. On Day 3, the morphology of each embryo was assessed using standard criteria (Racowsky et al., 2003) 68–72 h post-insemination (70.7 ± 1.5 h post-insemination, mean ± SD). Embryos having the optimal cell number, the lowest percent fragmentation and lowest asymmetry in a given cohort were selected for Day 3 transfers. Other characteristics being equal, preference was given to embryos having 8 cells over those having more than 8 cells. The number of embryos transferred on Day 3 to a given patient was determined by our internal algorithm for the maximum number of embryos to transfer. This algorithm takes into consideration the age of the patient, her ART attempt number, the number and quality of embryos she had available, and her prior clinical history. For Day 5 transfers, embryos were selected for transfer based on the extent of blastocyst expansion and the integrity and number of cells in the inner cell mass and trophectoderm. The number of embryos transferred on Day 5 was determined by the number and quality of blastocysts available. With comparison with Day 3 transfers, fewer embryos were transferred on Day 5, and the percentages having 1, 2 or more than 2 embryos transferred were 0.3, 88.6 and 11.1%, respectively. More than two embryos were transferred in the absence of any blastocysts, or when only poor quality blastocysts were present.
In selected cases of Day 3 transfer (e.g. those with 2 or more failed cycles or with embryos having unusually thick or abnormally appearing zonae), all embryos chosen for transfer were subjected to AH (Cohen, 1991) using acidified Tyrode's solution. Patients undergoing Day 5 transfer were typically selected when they had at least eight zygotes with at least three good-quality embryos in their cohort on Day 3 (Racowsky et al., 2000). AH was not performed for any embryos that were transferred on Day 5.
Luteal progesterone supplementation was initiated the day after oocyte retrieval and was achieved using one of three regimens: (i) Daily i.m. progesterone (50 mg); (ii) Daily vaginal gel [8% progesterone (Crinone; Wyeth-Ayerst, Madison, NJ)] or (iii) Twice daily progesterone suppositories (50–100 mg). Embryo transfer generally was performed with a Wallace catheter (Marlow/Cooper Surgical, Shelton, CT). For difficult transfers, a Marrs No. 4 or Marrs No. 5 embryo transfer catheter (Cook Ob/Gyn, Spencer, IN) was occasionally used.
Ultrasonographic assessment
Determination of twin chorionicity has been shown to be most accurate in the first trimester (for review, see Shetty and Smith, 2005). All patients underwent a scan at 5–6 weeks gestation and a follow-up ultrasound at 8 weeks, at which time they were transferred to obstetrical care. Patients with multiple gestations were monitored closely to assess for numbers of chorions and amnions. The number of chorions was determined by the number of separate gestational sacs. A gestational sac containing two embryos was diagnosed as a monochorionic pair. The number of amnions in the monochorionic pair was determined by assessing the developing amnions around the fetuses and the number of yolk sacs. Two yolk sacs, one adjacent to each fetus, suggested a monochorionic, diamniotic pair, and the finding was confirmed by seeing the development of the inter-twin membrane in the latter part of the first trimester. A single yolk sac suggested a monochorionic, monoamniotic pair, and the finding of monoamnionicity was confirmed later in the first trimester by seeing both fetuses and their umbilical cords within the same amniotic cavity. We only included patients who had a viable pregnancy at 12 weeks in our dataset, as these are the pregnancies, when complicated by monochorionicity, that are most likely to result in greater complications for mother or fetuses. One monochorionic pregnancy was lost between the time of ultrasound diagnosis (8 weeks) and our threshold of 12 weeks. This patient underwent an uncomplicated suction curettage; she was not included in our dataset for analysis. Pregnancies complicated by a monochorionic pair in our dataset were identified and ultrasounds were reviewed by one of the co-authors (C.B.), an experienced attending radiologist, to confirm the number of chorions and amnions in each pregnancy.
Each patient with an identified multiple gestation containing a monochorionic pair, and who had ultrasounds through our healthcare system, was reviewed to ensure accuracy in diagnosis. In cases where placental pathology was also available, pathology reports were cross-checked to confirm the ultrasound diagnosis. In cases in which no ultrasound was performed in our hospital, and no confirmatory pathology reports were available, medical records were reviewed to confirm that these pregnancies contained a monochorionic pair.
Statistical analysis
Using SAS Statistical Software Version 8.2 (SAS Institute Inc., Cary, NC), we compared the distribution of patient and cycle characteristics between women with an ongoing pregnancy that did and did not contain a monochorionic pair. Unconditional logistic regression was used to calculate the crude and multivariable odds ratios (OR) and 95% confidence intervals (CI), presented as estimates of the relative risk (Rothman and Greenland, 1998).
We included all variables as potential confounders of the association of the exposure of interest with pregnancies containing a monochorionic pair if addition of that variable to the model changed the OR by 10% or greater (Greenland, 1989). If a factor was identified as a confounder of any estimated main effect, it was kept in all models. Cycle attempt number was included a priori. Ultimately, only AH, ICSI and day of transfer were additionally included in all final models.
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Results |
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We identified 2501 women who met our inclusion criteria during the study period. There were 41 patients identified with a pregnancy containing a monochorionic pair. The distribution of twins, triplets and higher order multiples are shown in Fig. 2. Overall, three of these 41 pregnancies further contained a monoamniotic pair. Of those pregnancies not containing a monochorionic pair, 1456 were singleton pregnancies and 1004 were multiple pregnancies.
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Cycle characteristics of patients in our study dataset are shown in Table I. In unadjusted models, we did not observe a statistically significant association between monochorionic pairs and maternal age, ART attempt number, year of embryo transfer, peak E2 level, E2 level per follicle, stimulation day of hCG, total FSH or HMG per patient, sperm count, sperm motility, percent of mature (MII) oocytes, the number of immature oocytes (GV or MI), the number of embryos, the number of embryos with
8 cells, number of embryos transferred, number of embryos frozen, primary infertility diagnosis, type of culture medium or number of hours between hCG injection and oocyte retrieval or the number of hours between retrieval and transfer (Table II). However, embryo transfer on Day 5 (n = 273) and the use of ICSI (n = 930) were significantly predictive of pregnancy containing a monochorionic pair, with AH (n = 739) being not significant, but showing a borderline association.
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When these significant predictors were included together in a multivariable model to evaluate independent effects, AH was observed to have been negatively confounded, and this factor joined day of embryo transfer and ICSI as a significant predictor of a pregnancy containing a monochorionic pair (Table III). In fact, the presence of each more than doubled the likelihood of a pregnancy containing a monochorionic pair independently compared with the reference group comprised of ART cycles having a Day 3 transfer without ICSI or AH. Specifically, women undergoing a Day 5 embryo transfer were 2.48 times more likely to have a pregnancy complicated by a monochorionic pair when compared with women undergoing a Day 3 transfer. Patients who had ICSI were 2.42 times more likely to have a monochorionic pair, regardless of day of transfer or AH and patients who had AH were 2.23 times more likely to have a monochorionic pair, again, independent of day of transfer or ICSI.
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In addition, we also conducted a sub-analysis of our data to compare our cases to both singleton and multiple pregnancies within the control group to ensure that the increased risks seen were not related to factors associated with multiple pregnancies alone. When compared with singleton pregnancies, Day 5 transfer and ICSI remained statistically significantly predictive of increased likelihood of monochorionic twinning with Day 5 embryo transfer conferring a 2.54-fold increase in likelihood (95% CI 1.66–3.88) and ICSI conferring a 2.52-fold increased likelihood (95% CI 1.06–4.36). Although AH had an OR of 1.90, the 95% CI did cross one (0.87–4.18). Compared with all multiple pregnancies, again Day 5 transfer and ICSI remained significantly predictive [Day 5 embryo transfer OR 2.50 (95% CI 1.60–3.90) and ICSI OR 2.14 (95% CI 1.03–4.46)]. AH, in this comparison, had an OR of 2.07, but the 95% CI again crossed one (0.93–4.68).
As patients may have a combination of ICSI with a Day 5 embryo transfer, each of which were found independently to increase risk, we conducted a further analysis of the combined effect of day of transfer with or without ICSI [having adjusted for AH and cycle attempt number using, as the referent group, those patients who underwent a Day 3 transfer without ICSI (Table IV)]. Patients undergoing ICSI followed by a Day 3 transfer had an increased risk (OR 1.87, 95% CI 0.88–3.97) of a pregnancy containing a monochorionic pair, although this risk was not statistically different without ICSI followed by a Day 3 transfer. However, patients undergoing Day 5 transfers without ICSI had a statistically significantly increased risk (OR 4.31, 95% CI 1.59–11.68) of a monochorionic pair, while among patients undergoing both ICSI and a Day 5 transfer, the risk of was more than 20 times greater (OR 24.42, 95% CI 7.03–84.82).
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We also evaluated the combined effect of AH and day of transfer, controlling for ICSI. The referent group for this analysis was comprised of patients undergoing a Day 3 transfer without AH (Table V). We again observed that the presence of AH with a Day 3 transfer conferred an increased risk of a monochorionic pair (OR 2.23, 95% CI 1.06–4.67). Patients undergoing a Day 5 transfer without AH were observed to have 6 times the risk (OR 6.17, 95% CI 2.64–14.41) compared to this referent group.
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Discussion |
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Several studies have confirmed that adverse fetal outcome in monozygotic twins is related primarily to monochorionicity, rather than monozygosity. Indeed monozygotic, dichorionic twins have similar perinatal outcomes to those associated with dizygotic twins (Machin et al., 1995
; Dube et al., 2002; Carroll et al., 2005).
The majority of twins and higher order multiple gestations from ART result from multiple embryos being transferred, and with each fetus arising from an individual embryo. However, as early as the mid-1980s, investigators began noticing an increased incidence of monozygotic twins after IVF (Yovich et al., 1984; Edwards et al., 1986), which some authors have suggested may be up to ten times higher than the natural incidence of monozygotic twins (Behr et al., 2000). Although the exact mechanism leading to this increased incidence has yet to be fully elucidated, authors have linked monozygotic twinning to ovulation induction (Derom et al., 1987), gonadotropin treatment (Schachter et al., 2001), maternal age [either younger (Schieve et al., 2000) or older (Abusheika et al., 2000)], culture conditions (Cassuto et al., 2003) and Day 5 embryo transfer (Da Costa et al., 2001; Sheiner et al., 2001; Jain et al., 2004; Wright et al., 2004). Prolonged culture also may artificially induce twins due to abnormal hatching (Malter and Cohen, 1989) or apoptosis in the embryo (Menezo and Sakkas, 2002).
In the present study, we were unable to show an association between type of culture medium used and risk of a monochorionic pair (Table II). This observation is inconsistent with the recent suggestion that the progressive decrease in the incidence of monozygotic twins from Day 5 transfers, may perhaps reflect a ‘learning curve’ in the development of extended culture media (Moayeri et al., 2007). While this is an important observational study, the analysis did not control for other factors that may have changed in the two study populations, including rates of ICSI or AH between the two time periods addressed. Moreover, it was not possible to compare our incidence of monozygotic twinning with that of Moayeri's over time. Our study focused specifically on monochorionic pairs, whereas the Moayeri study investigated monozygotic twins.
Monozygotic twinning has also been linked with micromanipulation of the embryo, including both AH and ICSI (Alikani et al., 1994; Slotnik and Ortega, 1996; Hershlag et al., 1999; Abusheika et al., 2000; Schieve et al., 2000; Yakin et al., 2003). Although this relationship has not been identified in all studies (Scott Sills et al., 2000; Wright et al., 2004), our analyses do, indeed, support zona pellucida manipulation and Day 5 embryo transfer as risk factors for monozygotic twinning. Furthermore, we have identified these as specific risk factors for monochorionic placentation. Interestingly, however, we did not find any association with other previously suggested factors (such as maternal age, culture media and type of gonadotropins used during the cycle).
The current study has several additional limitations. First, despite using six years of collected data, the number of pregnancies containing a monochorionic pair reaching 12 weeks was only 41. Therefore, as our data are stratified to evaluate combined risks, the number of cases in each subset remains small and follow-up studies are indicated to evaluate further these identified risk factors. Second, as we chose only to evaluate monochorionic pairs, as opposed to monozygotic pairs (as undertaken in the majority of previous other studies), our data may not be directly comparable to the monozygotic pair literature. There may be different mechanisms leading to monozygotic twins resulting from an early embryonic split (i.e. Day 0–4) compared with those leading to a later embryonic split (Day 4–8), resulting in monochorionic twins. Third, although we found a relationship between ICSI, AH and day of embryo transfer increasing the risk of monochorionic placentation, it is possible that the underlying risk factors leading to these procedures could predispose a patient to a monochorionic pair, as opposed to the techniques employed. Fourth, there is some literature suggesting familial clustering of monozygotic twinning, which we did not address as a possible contributing risk factor (Harvey et al., 1977; Steinman, 2003). Finally, all of our patients underwent ART for infertility treatment; it is unknown whether our findings would pertain in a fertile population.
In conclusion, our study has enabled us to identify the interactions between characteristics associated with an ART cycle, such as the interaction between ICSI and Day 5 transfer, to estimate a combined relative risk of pregnancies containing a monochorionic pair. The data indicate that micromanipulation involving either ICSI or AH, as well as a Day 5 transfer, lead to an increased risk of monochorionic placentation. This is particularly true for the combined use of ICSI with a Day 5 transfer, which results in a 24-fold increased risk of this unfortunate obstetrical condition, associated with increased perinatal morbidity. Although the literature suggests that the overall incidence of ART pregnancies containing a monochorionic pair remains <5% (Behr et al., 2000; Moayeri et al., 2007), patients should be counselled regarding their individual risks in the setting of optimizing their ART success.
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Acknowledgements |
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The BWH embryology team, Anne Fladger, Meaghan Muir and the staff of the BWH Medical Library.
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References |
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Submitted on August 30, 2007; resubmitted on January 16, 2008; accepted on January 30, 2008.
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  K I Aston, C M Peterson, and D T Carrell Monozygotic twinning associated with assisted reproductive technologies: a review Reproduction, October 1, 2008; 136(4): 377 - 386. [Abstract] [Full Text] [PDF]
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