Hum. Reprod. Advance Access originally published online on October 5, 2006
Human Reproduction 2006 21(12):3228-3234; doi:10.1093/humrep/del311
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Does subfertility explain the risk of poor perinatal outcome after IVF and ovarian hyperstimulation?
1 Division of Reproductive Medicine, Department of Gynaecology, Leiden University Medical Center, Leiden 2 Department of Epidemiology, Netherlands Cancer Institute, Amsterdam 3 Department of Gerontology and Geriatrics 4 Department of Obstetrics and Gynaecology, Erasmus Medical Centre, Rotterdam and 5 Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
6 To whom correspondence should be addressed at: Division of Reproductive Medicine, Department of Gynaecology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands. E-mail: f.m.helmerhorst{at}lumc.nl
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Abstract |
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BACKGROUND: The primary objective of this study was to investigate whether subfertility explains poor perinatal outcome after assisted conception. A secondary objective was to test the hypothesis that ovarian hyperstimulation rather than the IVF procedure may influence the perinatal outcome. METHODS: Using data from a Dutch population-based historical cohort of women treated for subfertility, we compared perinatal outcome of singletons conceived after controlled ovarian hyperstimulation (COHS) and IVF (IVF + COHS; n = 2239) with perinatal outcome in subfertile women who conceived spontaneously (subfertile controls; n = 6343) and in women who only received COHS (COHS only; n = 84). Furthermore, we compared perinatal outcome of singletons conceived after the transfer of thawed embryos with (Stim + Cryo; n = 66) and without COHS (Stim – Cryo; n = 73). RESULTS: The odds ratios (ORs) for very low birthweight (<1500 g) and low birthweight (1500–2500 g) were 2.8 [95% confidence interval (95% CI) 1.9–3.9] and 1.6 (95% CI 1.2–1.8) in the IVF + COHS group compared with the subfertile control group. The ORs for very preterm birth (<32 weeks) and for preterm birth (32–37 weeks) were 2.0 (95% CI 1.4–2.9) and 1.5 (95% CI 1.3–1.8), respectively. Adjustment for confounders did not materially change these risk estimates. The difference in risk between the COHS-only group and the subfertile group was significant only for very low birthweight (OR 3.5; 95% CI 1.1–11.4), but the association became weaker after adjustment for maternal age and primiparity (OR 3.1; 95% CI 1.0–10.4). No significant difference in birthweight and preterm delivery was found between the group of children conceived after ovarian stimulation/ovulation induction and (Stim + Cryo) and the group of children conceived after embryo transfer of thawed embryos in a spontaneous cycle without ovarian stimulation/ovulation induction (Stim – Cryo). CONCLUSIONS: The poor perinatal outcome in this database could not be explained by subfertility and suggests that other factors may be important in the known association between assisted conception and poor perinatal outcome.
Key words: adverse effects/low birthweight/ovulation induction/pregnancy outcome/premature infant
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Introduction |
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Although the prevalence of very low birthweight and very preterm birth is low, singleton pregnancies from assisted conception have a significantly higher risk of (very) low birthweight and (very) preterm birth as compared with naturally conceived controls. Confounding factors such as maternal age and parity do not change this outcome (Helmerhorst et al., 2004
). Factors such as social economic status, sex of the fetus, delivery date and site also seem unable to explain the difference (Helmerhorst et al., 2004; Jackson et al., 2004). However, a history of subfertility, irrespective of infertility treatment, has also been found to be associated with perinatal death in a case–control study (Draper et al., 1999). Jackson et al. (2004) has summarized the different trials and advised for future research in which treatment biases can be addressed.
Poor perinatal outcome has also been observed in 263 singletons born of subfertile patients conceived after only controlled ovarian hyperstimulation (COHS) relative to 5096 spontaneously conceived controls delivered in the same hospital and period; however, no difference was seen when the comparison was made between these COHS births and 162 IVF singletons (Olivennes et al., 1993). After stratification for the number of years of involuntary childlessness, Källén et al. (2002) still found a significant increased risk of preterm birth (<37 weeks) and of low birthweight (<2500 g) in singletons conceived after just COHS as compared with naturally conceived singletons. Gaudoin et al. (2003) concluded that ‘infertility’ should be added to the list of recognized factors associated with low birthweight after comparing 97 singletons whose subfertile mothers were treated with COHS and intrauterine insemination (IUI) with 35 singletons whose mothers were treated with COHS (despite normal reproductive health) and artificial insemination with donor sperm.
In this study, we investigate whether subfertility explains the poor perinatal outcome after assisted conception. We used data from a nationwide historical cohort of 26 428 women treated for subfertility in the Netherlands between 1980 and 1995 (Klip et al., 2001). Furthermore, we tried to answer the question of whether COHS with or without IVF adversely affects perinatal outcome.
The observation that birthweight of singletons conceived by implanting a cryopreserved embryo is significantly higher than birthweight after a fresh embryo transfer (Wennerholm et al., 2000; Wang et al., 2005) suggests that the cryopreservation and thawing procedure might essentially differ from the IVF and ICSI procedure in which the embryo(s) are directly and freshly transferred to the uterus. Because embryo transfer of cryopreserved embryos occurs predominantly in a natural cycle, one may hypothesize that COHS itself might influence uterine receptivity. To investigate this, we used the same database as mentioned above to compare the birthweight and preterm birth of singletons conceived after transfer of thawed embryos with and without COHS.
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Materials and methods |
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Study population
Data were obtained from an historical nationwide cohort study (OMEGA study) of 26 428 women diagnosed with subfertility in all 12 Dutch IVF clinics between 1 January 1980 and 1 January 1995. Approval of the ethics committees of all institutions was obtained. Inclusion criteria were at least 1 year of subfertility (Speroff et al., 1999
) and age 
18 years at the time of admission to one of the clinics. Women were included in the IVF group when they had completed at least one treatment cycle with COHS and IVF before 1 January 1995 (n = 19 840). A group of 6588 women unexposed to COHS, whose subfertility was diagnosed after 1980, were recruited from existing computerized databases of 4 of the 12 clinics. All clinics provided a minimal data set with names, birth dates and addresses of all eligible women. After tracing the current addresses of all women, they were contacted at their home address and were asked to fill in and return a questionnaire, as well as a written informed consent, asking each participant for permission for data abstraction from their medical records. From the initial 26 428 women, 1105 women (4.2%) were not approachable for several reasons [for more details, see Klip et al. (2001)]. Of the remaining 25 323 women, 
67% agreed to participate in the study (De Boer et al., 2005).
Some women delivered more than once during the study period. Initially, 29 148 pregnancies were reported in the returned questionnaires. As described in detail by Klip et al. (2001), 12 148 pregnancies were directly excluded (abortion <24 weeks: n = 10 291; intrauterine mortality 24 weeks: n = 524; pregnant at the time of returning questionnaire: n = 404; missing data: n = 929). This resulted in 17 000 deliveries with a minimal gestational age of 24 weeks. This group consisted of 9479 pregnancies which resulted from assisted reproductive techniques (ART) (IVF, ICSI, inseminations and fertility drug use not for IVF/inseminations), of which 5862 pregnancies achieved with IVF, and 2239 of these were IVF singletons. From the group of mothers who were treated with COHS (COHS only), 84 singletons were recruited. From the 7521 pregnancies of the subfertile controls, 6343 were singletons with a full data set.
For the first comparison in this study between the IVF group, the subfertile controls and the COHS only group, pregnancies that resulted from transfer of frozen embryos were excluded.
From the OMEGA database, 139 pregnancies were the result of cryopreserved embryo transfer. In 66 cases, embryo transfer took place after COHS and/or ovulation induction with hCG (Stim + Cryo group). In 56 cases, only hCG was administered, whereas eight received hMG or clomiphene citrate alone or in combination with hCG. In two cases, the specific type of COHS and/or ovulation induction was not known. In 73 cases (Stim – Cryo group), embryo transfer was performed in an apparently normal ovulatory cycle or before progesterone administration.
In each participating clinic, research assistants specifically trained for data collection for the OMEGA study abstracted detailed information from the medical records. For each reported child, the questionnaire, completed by the study participants, provided detailed information on the maternal characteristics, method of conception, the duration of gestation in weeks, birth data, gender and birthweight (Klip et al., 2001).
Definitions
Although the National Institute for Clinical Excellence (National Institute for Clinical Excellence, NHS, 2004) defines subfertility as failure to conceive after regular unprotected sexual intercourse for 2 years in the absence of known reproductive pathology, the definition currently used in the Netherlands during the period of the cohort followed the one given in the textbook Clinical Gynaecologic Endocrinology and Infertility (Speroff et al., 1999): ‘one year unprotected coitus without conception’.
Gestational age (duration of pregnancy) at birth in case of IVF pregnancies was determined by adding 14 days to the interval between LH administration and delivery. For the control pregnancies, it was calculated as the interval between the first day of the last menstrual period and delivery. International definitions were followed for preterm (<37 weeks), very preterm (<32 weeks), low birthweight (<2500 g) and very low birthweight (<1500 g) deliveries.
Statistics
Differences between groups were assessed by t-tests for continuous variables and by chi-square tests for ordinal variables. Logistic regression analyses were used to determine the odds ratios (ORs) of (very) low birthweight and (very) preterm birth between the groups. Crude ORs were calculated and first adjusted for the confounders, maternal age and primiparity and thereafter for each of the following potential confounders: body mass index (BMI), race, education level, smoking, diabetes mellitus and sex of infant. The unit of analysis was one birth. Because some women contributed more than one birth to the analyses, robust confidence intervals (CIs) around the ORs were computed. Robust CIs are generally wider in case the observations, in our study the births, are not independent from each other. Moreover, all analyses were also repeated in a restricted sample of women, with only their first births occurring within the time frame of the study. Significance level was set at 5% two-tailed. Analyses were performed with Statistics Package for Social Sciences (SPSS) 12.0.1, and STATA 9.0 was used to calculate the robust CIs.
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Results |
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A total of 1576 women had their first birth after IVF + COHS; 898 of them contributed one birth to the analysis, 497 contributed two births and 111 contributed three or more births. There were 3754 subfertile controls; 2757 of them had one birth, 1189 had two births and 371 had three or more births. There were 68 women who had their first birth after COHS only; 54 of them contributed one birth to the analysis, 12 contributed two births and 2 contributed three births. Hence, complete perinatal data were obtained from 2239 singleton IVF + COHS pregnancies, from 6343 pregnancies in subfertile controls and from 84 COHS-only pregnancies.
Maternal characteristics
In the IVF + COHS group, the mean maternal age was significantly higher as compared with COHS-only and subfertile controls (Table I). The proportion of women with pre-existing diabetes mellitus (for which women used medication during pregnancy) was found to be significantly higher in the IVF + COHS group as compared with the subfertile control group (Table I). The mean BMI was significantly lower, and the education level was significantly higher in the IVF + COHS group as compared with the control group. In the COHS-only group, primiparity was significantly more prevalent as compared with the IVF + COHS group and the subfertile controls, whereas there were significantly less women who smoked as compared with the IVF + COHS and subfertile control group. In Table II, the maternal characteristics are expressed for women at the time when their first birth occurred within the time frame of the study.
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Perinatal outcome
The mean birthweight and the mean gestational periods of the singletons born to the IVF + COHS group were significantly lower and shorter, respectively, as compared with children born to the subfertile control group (Table III). The ORs for very preterm birth and very low birthweight in the IVF + COHS group in comparison with the subfertile controls were 2.0 and 2.8, respectively, whereas the ORs for preterm birth and low birthweight groups were not as high: 1.5 and 1.6, respectively. Only minor changes in the aforementioned ORs were seen after adjustment for potential confounders (maternal age and primiparity as well as BMI, race, education, smoking, diabetes mellitus and sex of infant) that may influence birthweight and/or gestational age (data not shown). When we computed robust CIs around the ORs and therewith adjusted for the fact that some women contributed more than one birth to the analyses, the CIs did not change (data not shown). Furthermore, when we excluded the multiple births of women and only looked at their first births occurring within the time frame of the study, the ORs and their CIs did not materially change (data not shown).
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The ORs for very preterm birth and very low birthweight in the COHS-only group in comparison with the subfertile controls were 2.0 and 3.5, respectively, although after adjustment for maternal age and primiparity, the associations became slightly weaker (Table IV). The ORs for birthweight and gestational age categories in the IVF + COHS group (data as represented in Table III) compared with the COHS-only group (data as represented in Table IV were not significantly different): OR for 1500–2500 g 1.7 (95% CI 0.7–4.3), ORadj 1.7 (95% CI 0.7–4.5); OR for <1500 g 0.8 (95% CI 0.2–2.6), ORadj 0.8 (95% CI 0.3–2.7); OR for 32–37 weeks 2.9 (95% CI 0.9–9.3), ORadj 2.7 (95% CI 0.9–8.8) and OR for <32 weeks 1.0 (95% CI 0.2–4.1), ORadj 0.9 (95% CI 0.2–3.8).
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Cryopreservation
Complete perinatal data were obtained from 66 singleton pregnancies derived from cryopreserved embryo transfer after COHS (Stim + Cryo group) and from 73 singleton pregnancies in which the embryo transfer was performed in a natural cycle (Stim – Cryo group). When we compared maternal characteristics of the Cryo+ and Cryo– groups, no significant differences were found in this small group: mean age 34.1 versus 33.8 years, mean height 168.3 versus 167.5 cm, mean weight 67.7 versus 65.2 kg, mean BMI 24.0 versus 23.3, mean percentage Caucasian 97.0 versus 98.6, mean percentage women with only primary school education 43.9 versus 47.9, mean percentage primiparous women 36.4 versus 41.1, mean percentage of women who smoked during pregnancy 37.9 versus 30.1, and in both groups, nobody was indicated to suffer from pre-existent diabetes mellitus. The group Stim + Cryo-treated women did not have a significantly higher risk of singleton birth, with a low birthweight and/or of preterm delivery as compared with when embryo transfer had taken place in a natural or progesterone-treated cycle (Table V). Correction for the already mentioned confounders did not materially change the results. In the Stim + Cryo group, significantly fewer boys were born (48.5 versus 65.8%, P = 0.03).
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Discussion |
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In this large database of Dutch IVF clinics, singleton IVF pregnancies have significantly worse perinatal outcomes than those of spontaneously conceived pregnancies in subfertile women. The risk is more pronounced for very preterm birth and very low birthweight than for preterm birth and low birthweight. The estimates did not materially change after adjustment for maternal age, primiparity or other potential confounders.
Randomization is the proper way to evaluate the effect of treatment for subfertility on the perinatal outcome (Buck Louis et al., 2005); however, it is difficult and unethical (Jackson et al., 2004) to conduct. Alternative methodological approaches have been followed with different outcomes. In a population-based case–control study, Draper et al. (1999) showed that history of subfertility, irrespective of treatment, increased the risk of perinatal death, whereas Basso and Olsen (2005) found that the odds of neonatal (and not intrauterine) death among firstborn singletons were significantly increased in the group of non-treated mothers with >12 months of subfecundity, relative to mothers who became pregnant within 3 months. McElrath and Wise (1997), using logistic regression models, found the risk of very low birthweight among subfertile, non-treated women to be 1.4 (95% CI 1.1–1.9) and among subfertile, treated women 2.6 (95% CI 2.1–3.2) compared with a national US control group gathered in 1988. Both estimates were slightly lower, but still significantly increased, when they were adjusted for effects of multiple gestation, maternal age and a history of miscarriage.
Another approach is to compare different treatments among subfertile couples, with the difficulty of the difference in treatment. Olivennes et al. (1993) found no difference in the prevalence of (very) preterm birth and (very) low birthweight among 162 IVF and 263 COHS singletons, and Bonduelle et al. (2002) also showed no differences among 1499 ICSI and 1556 IVF singletons. However, the analysis of Ombelet et al. (2005) showed only a significantly higher risk of preterm birth among 3974 IVF singletons relative to 1655 ICSI singletons. The authors hypothesized that the indication for ICSI is predominantly a male factor. Remarkable is that the two latter studies have been conducted in the relatively circumscriptive, Dutch-speaking part of Belgium. The Ombelet study gathered all deliveries in Flanders in the period 1997–2003, whereas the Bonduelle study collected the data of one reproductive centre in the period 1991–1999 for ICSI and 1983–1999 for IVF. Part of these data has been included in the Ombelet study. An explanation for the difference has not been offered by Ombelet et al. (2005). In another study (Wang et al., 2002), preterm birth was significantly more often observed in the high-technology group [IVF, ICSI and gamete intra-Fallopian transfer (GIFT)] than in the low-technology group (IUI, donor insemination), with ORs of 2.39 and 1.50, respectively, compared with naturally conceived controls. Two similar studies comparing IVF with IUI singletons (Nuojua-Huttunen et al., 1999; De Sutter et al., 2005) found no differences in the prevalence of preterm birth and low birthweight.
Our study might suffer from some information bias through the use of a mailed questionnaire to collect perinatal outcome and might be limited by not taking into account pregnancy complications, fetal malformations and a history of previous pregnancy loss, all factors that may be associated with adverse pregnancy outcome. However, it is unlikely that the IVF + COHS group would report systematically different from the subfertile controls, if there was no effect of the treatment. Therefore, we suggest, based on our data and the results of the above-mentioned studies, that subfertility might explain part of the association between assisted conception and poor perinatal outcome of singletons, but that there remains an important effect of assisted reproduction itself. Is the COHS, as part of the assisted technology methods, the culprit or the technique itself as suggested by Olivennes et al. (1993)? In our study, the risk estimates comparing singletons conceived after COHS and IVF versus singletons conceived after COHS only did not differ significantly. In a retrospective cohort study of Australian data of infants conceived through assisted reproduction, Wang et al. (2005) found that preterm birth and low-weight birth were more likely to occur among singletons conceived by transfer of fresh embryos, relative to those conceived by with transfer of frozen embryos. We are not informed in their study whether the transfer of thawed embryo(s) in their study was performed in a natural or stimulated cycle. Unfortunately, in our study, we were not able to test the hypothesis that COHS before embryo transfer affects uterine receptivity due to the small number of patients in this database. As female-factor subfertility increased the likelihood of preterm birth and low birthweight significantly more than male-factor subfertility, Wang et al. (2005) suggested that uterine receptivity might offer us a biological plausibility for the phenomenon; however, no difference in the prevalence of preterm birth and low birthweight was seen among singletons born after ICSI, which is possibly more likely to be used for male factor subfertility (Bonduelle et al., 2002; Ombelet et al., 2005).
If ovarian stimulation by itself has a negative effect on the pregnancy outcome, it may influence oocyte/embryo quality, resulting in impaired implantation and embryonic/fetal development (Rao, 2001). Other studies suggest that ovarian stimulation is rather associated with an unbalanced endometrium and/or oviductal environment (Walton et al., 1982; Walton and Armstrong, 1983; Fossum et al., 1989; Ertzeid et al., 1993). Supra-physiological concentrations of oestradiol (E2) and progesterone during ovarian stimulation may modulate growth factors, cell-adhesion molecule profiles, steroid receptors and the expression of pinopodes in the endometrium (Kolb et al., 1997; Paulson et al., 1997; Macklon and Fauser, 2000), influencing endometrial receptivity (Paulson et al., 1990, 1997; Kolb et al., 1997). Sibug et al. (2002, 2005) suggested that the effect of ovarian stimulation on pregnancy outcome might be explained by the modulation of vascular endothelial growth factor (VEGF) affecting angiogenesis during implantation and placentation (Smith, 1998; Kapiteijn et al., 2001; Koolwijk et al., 2001).
In conclusion, our study suggests that the association between assisted conception and poor perinatal outcome may not be completely explained by subfertility.
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Acknowledgements |
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The OMEGA project group included the following persons: M. Kortman and E.R. te Velde (University Medical Center Utrecht), N. Macklon (Academic Hospital Dijkzigt, Rotterdam), C.A.M. Jansen (Diaconessenhuis, Voorburg), R.A. Leerentveld (Isala Clinics, Zwolle), W.N.P. Willemsen (Academic Hospital Nijmegen, St. Radboud), R. Schats (Academic Hospital Free University, Amsterdam), N. Naaktgeboren (Leiden University Medical Center), R.S.G.M. Bots (St. Elisabeth Hospital, Tilburg), A.H.M. Simons (Academic Hospital Groningen), H.V. Hogerzeil (Academic Medical Center, Amsterdam), J.L.H. Evers (Academic Hospital Maastricht) and P.A. van Dop (Catharina Hospital, Eindhoven).
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Footnotes |
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E.de Boer, C.W.Burger and F.E.van Leeuwen: On behalf of the OMEGA project group of which members are listed in the Acknowledgement section.
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Submitted on May 8, 2005; resubmitted on March 9, 2006; resubmitted on May 2, 2006; resubmitted on June 19, 2006; accepted on July 7, 2006.
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 M.F.G. Verberg, N.S. Macklon, G. Nargund, R. Frydman, P. Devroey, F.J. Broekmans, and B.C.J.M. Fauser Mild ovarian stimulation for IVF Hum. Reprod. Update, January 1, 2009; 15(1): 13 - 29. [Abstract] [Full Text] [PDF]
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G. Griesinger, E.M. Kolibianakis, K. Diedrich, and M. Ludwig Ovarian stimulation for IVF has no quantitative association with birthweight: a registry study Hum. Reprod., November 1, 2008; 23(11): 2549 - 2554. [Abstract] [Full Text] [PDF]
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 C. H. Ramlau-Hansen, A. M. Thulstrup, J. Olsen, and J. P. Bonde Parental Subfecundity and Risk of Decreased Semen Quality in the Male Offspring: A Follow-up Study Am. J. Epidemiol., June 15, 2008; 167(12): 1458 - 1464. [Abstract] [Full Text] [PDF]
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B.C. Jacod, K.D. Lichtenbelt, G.H. Schuring-Blom, J.S.E. Laven, D. van Opstal, M.J.C. Eijkemans, N.S. Macklon, and on behalf of the IVF-CPM Study Group Does confined placental mosaicism account for adverse perinatal outcomes in IVF pregnancies? Hum. Reprod., May 1, 2008; 23(5): 1107 - 1112. [Abstract] [Full Text] [PDF]
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G. M. Chambers, M. G. Chapman, N. Grayson, M. Shanahan, and E. A. Sullivan Babies born after ART treatment cost more than non-ART babies: a cost analysis of inpatient birth-admission costs of singleton and multiple gestation pregnancies Hum. Reprod., December 1, 2007; 22(12): 3108 - 3115. [Abstract] [Full Text] [PDF]
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P. Poikkeus, M. Gissler, L. Unkila-Kallio, C. Hyden-Granskog, and A. Tiitinen Obstetric and neonatal outcome after single embryo transfer Hum. Reprod., April 1, 2007; 22(4): 1073 - 1079. [Abstract] [Full Text] [PDF]
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