Preterm birth in twins after subfertility treatment: population based
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《英国医生杂志》
1 Department of Obstetrics and Gynaecology, Ghent University Hospital 1P3, De Pintelaan, B-9000 Ghent, Belgium, 2 Department of Applied Mathematics and Informatics, Ghent University, B-9000 Ghent, 3 Center for Human Genetics, Katholieke Universiteit Leuven, University Hospital Gasthuisberg, B-3000 Leuven, Belgium, 4 Association for Scientific Research in Multiple Births, B-9070 Destelbergen, Belgium
Correspondence to: H Verstraelen hans.verstraelen@UGent.be
Objectives To assess gestational length and prevalence of preterm birth among medically and naturally conceived twins; to establish the role of zygosity and chorionicity in assessing gestational length in twins born after subfertility treatment.
Design Population based cohort study.
Setting Collaborative network of 19 maternity facilities in East Flanders, Belgium (East Flanders prospective twin survey).
Participants 4368 twin pairs born between 1976 and 2002, including 2915 spontaneous twin pairs, 710 twin pairs born after ovarian stimulation, and 743 twin pairs born after in vitro fertilisation or intracytoplasmic sperm injection.
Main outcome measures Gestational length and prevalence of preterm birth.
Results Compared with naturally conceived twins, twins resulting from subfertility treatment had on average a slightly decreased gestational age at birth (mean difference 4.0 days, 95% confidence interval 2.7 to 5.2), corresponding to an odds ratio of 1.6 (1.4 to 1.8) for preterm birth, albeit confined to mild preterm birth (34-36 weeks). The adjusted odds ratios of preterm birth after subfertility treatment were 1.3 (1.1 to 1.5) when controlled for birth year, maternal age, and parity and 1.6 (1.3 to 1.8) with additional control for fetal sex, caesarean section, zygosity, and chorionicity. Although an increased risk of preterm birth was therefore seen among twins resulting from subfertility treatment, the risk was largely caused by a first birth effect among subfertile couples; conversely, the risk of prematurity was substantially levelled off by the protective effect of dizygotic twinning.
Conclusions Twins resulting from subfertility treatment have an increased risk of preterm birth, but the risk is limited to mild preterm birth, primarily by virtue of dizygotic twinning.
One in six couples attempting pregnancy fail to conceive naturally after 12 months of regular unprotected intercourse. Most of these couples eventually succeed, about half of them through subfertility treatment.1 Efforts to increase the success rates of subfertility treatment have been accompanied by an insidious rise in the rate of multifetal pregnancies.2 About half of medically conceived babies in the United States and Europe are now born as twins,3 4 and almost half of all twins result from subfertility treatment.2
In the face of this "multiple birth epidemic," and despite widespread concern about the effects of medically aided conception on perinatal outcome, few studies have investigated outcomes in twins,5 and largely conflicting results have been reported.6 Fuller and more consistent data are needed to assess the impact of ovarian stimulation and assisted reproduction on pregnancy outcome.5
Twins tend to fare considerably worse than singletons, with much higher rates of perinatal mortality, neonatal morbidity, and long term neurological impairment.2 Adverse pregnancy outcome in turn relates to the high prevalence of preterm birth among twins and is exacerbated by monozygotic and monochorionic twinning.7-9 Whether subfertility treatment also impinges on gestational length in twins, as has been established among singletons,6 10 is unclear, as is the extent to which type of twinning interferes with perinatal outcome after subfertility treatment.11
In a population based cohort we compared gestational length and preterm birth rates between naturally and medically conceived twins. We also assessed the role of zygosity and chorionicity.
Methods
Study population
Multiple births in the East Flanders province of Belgium are recorded by the East Flanders prospective twin survey, through a collaborative network of 19 maternity units.8 9
Data collection
Methods of data collection have previously been described in detail.8 9 Briefly, for every multiple birth, a defined set of obstetric and perinatal data were recorded and placentas were collected and examined within 48 hours of delivery according to a standardised protocol. Zygosity and chorionicity were determined through sequential analysis of fetal sex, fetal membranes, and umbilical cord blood groups and by DNA fingerprinting based on allelic similarity within a twin pair of short tandem repeat loci on nine different chromosomes. Overall, zygosity and chorionicity were determined with an accuracy of over 99%.8 9
We estimated gestational length in number of days, principally on the basis of routine gestational dating combining last menstrual period and real time ultrasonography in early pregnancy, throughout the study period. In Flanders, more than 98% of women attend early in pregnancy and gestational dating is routinely confirmed or adjusted through ultrasound examination.
Inclusion and exclusion criteria
All twins with one of the children weighing at least 500 g were registered. From 1 January 1976 to 31 December 2002, 4989 twin pairs were recorded by the survey. We excluded 621 twin gestations from all analyses because data could not be ascertained for mode of conception (n = 53), maternal age (86), parity (52), gestational length (376), zygosity (69), birth weight (19 and 23), or infant sex (2 and 3).
Definitions
We defined preterm birth as birth at less than 37 completed weeks of gestation and low birth weight as weight at birth of less than 2500 g. The ovarian stimulation group included all women who conceived in vivo after any treatment regimen involving direct or indirect stimulation of ovulation, including regulation of the menstrual cycle, artificial induction of ovulation, or ovarian hyperstimulation without a subsequent in vitro procedure. The in vitro fertilisation/intracytoplasmic sperm injection group included all women who conceived (mostly after ovarian stimulation) through an in vitro procedure, generally referred to as assisted reproduction technology. The ovarian stimulation and in vitro fertilisation/intracytoplasmic sperm injection groups together comprise the subfertility group.
Outcome measures
Primary outcome measures were gestational length and rates of preterm birth according to mode of conception.
Statistical analyses
We first compared mean differences in continuous variables by using independent samples t tests and differences in prevalence rates by using 2 tests with the Yates correction. We subsequently assessed differences in mean values and prevalence rates by fitting linear, marginal logistic, and ordinary logistic regression models. In a first set of models, we accounted for the pretreatment variables birth year, parity, and maternal age. Provided these were the only predictors associated with subfertility treatment, the resulting differences and odds ratios express the "overall effect" on the outcomes assessed. In a second set of models, we additionally removed the mediating effects of the post-treatment variables zygosity, chorionicity, intra-twin fetal sex combination, and caesarean section. Provided that no confounding variables remained that impinged on the intermediates or on the decision to apply subfertility treatment, the resulting differences and odds ratios express the "direct effect" of subfertility treatment. We corrected all analyses of birth weight for intra-twin correlation through generalised estimating equations with exchangeable working correlation.12
We used Lagrange multiplier tests for model comparisons. We used the conventional 5% level to assess significance. Analyses were done with SPSS version 12.0 and SAS version 8.02 statistical software.
Results
Study population
The population based cohort (n = 4368) comprised 2915 (66.7%) naturally conceived and 1453 (33.3%) medically conceived twin pairs, including 710 (16.3%) twin pairs born after ovarian stimulation and 743 (17.0%) twin pairs born after in vitro fertilisation or intracytoplasmic sperm injection (table 1). Women who had had subfertility treatment were on average older (P < 0.001) and less likely to have had a child previously (P < 0.001) than mothers in the natural conception group.
Table 1 Maternal and perinatal characteristics of the study population. Values are numbers (percentages) unless stated otherwise
The dizygotic:monozygotic twinning ratio was 95.2:4.8 among medically conceived twins and 53.8:46.2 in the natural conception group (P < 0.001) (table 2). The distribution of the intra-twin fetal sex combination differed significantly (P < 0.001) between naturally and medically conceived twins owing to differential zygosity, whereas the overall fetal sex distribution did not (P = 0.9).
Table 2 Type of twinning according to mode of conception. Values are numbers (percentages) unless stated otherwise
Differences in gestational length and risk of preterm birth
Subfertility treatment was associated with a small decrease in gestational age at birth compared with the natural conception group (tables 1 and 3; figure). This difference translated to an odds ratio of 1.6 (95% confidence interval 1.4 to 1.8) for preterm birth (table 4), albeit confined to mild preterm birth ( 34 weeks) (figure). Medically conceived twins were more likely to be preterm delivered by caesarean section (odds ratio 1.5, 1.2 to 1.9) but were also at higher risk of spontaneous preterm birth (odds ratio 1.6, 1.4 to 1.8). In agreement with the above, medically conceived twins had, on average, a slightly lower birth weight (table 1) and a slightly higher risk of low birth weight (odds ratio 1.2, 1.1 to 1.4) (table 5).
Table 3 Crude and adjusted mean differences in gestational length between ovarian stimulation and IVF/ICSI groups of women, compared with natural conception group. Values are means (95% confidence intervals) unless stated otherwise
Kaplan-Meier plot of gestational length in naturally conceived (n=2915) and medically conceived (n=1453) twins
Table 4 Crude and adjusted odds ratios (95% confidence intervals) of preterm birth in ovarian stimulation and IVF/ICSI groups of women, compared with natural conception group
Table 5 Crude and adjusted odds ratios (95% confidence intervals) of low birth weight in ovarian stimulation and IVF/ICSI groups of women, compared with natural conception group
Adjusted differences in gestational length and risk of preterm birth
We estimated the overall effect of subfertility treatment by adjusting the outcomes for birth year, maternal age, and parity. The observed differences in gestational length (table 3) and rates of preterm birth (table 4) were clearly attenuated when we accounted for confounding; lower parity among women who conceived medically was the strongest confounder. The observed effects were, however, not entirely explained by these confounding effects. Assuming that no residual confounders remained, a minor but significant overall effect of subfertility treatment on gestational length could therefore not be ruled out on the basis of the observed data (tables 3 and 4), although this was not obvious from differences in birth weight (table 5).
To assess the direct effect of subfertility treatment, we additionally accounted for zygosity, chorionicity, fetal sex, and delivery mode (caesarean versus vaginal), which act on the pathway from conception to birth as intermediate variables to the outcomes assessed. When we accounted for this defined set of confounders and intermediates, the markedly higher effect size of the direct effect on gestational length (table 3) and preterm birth (table 4) over and above the overall effect was mainly attributable to the effect of zygosity. Chorionicity had a marginal effect on gestational length beyond zygosity, and caesarean delivery showed no effect at all after confounding was accounted for. According to our analyses, dizygotic twinning pertaining to iatrogenic pregnancy therefore proves a strong and advantageous mediator of gestational length (table 4), as is also apparent from the data on birth weight (table 5).
Discussion
Taylor A. ABC of subfertility: extent of the problem. BMJ 2003;327: 434-6.
Blondel B, Kaminski M. Trends in the occurrence, determinants, and consequences of multiple births. Semin Perinatol 2002;26: 239-49.
Wright VC, Schieve LA, Reynolds MA, Jeng G. Assisted reproductive technology surveillance—United States, 2000. MMWR Surveil 2003;52: 1-16.
Nyboe Andersen A, Gianaroli L, Nygren KG, European IVF-monitoring programme, European Society of Human Reproduction and Embryology. Assisted reproductive technology in Europe, 2000: results generated from European registers by ESHRE. Hum Reprod 2004;19: 490-503.
Blondel B, Macfarlane A. Rising multiple maternity rates and medical management of subfertility: better information is needed. Eur J Public Health 2003;13: 83-6.
Helmerhorst FM, Perquin DA, Donker D, Keirse MJ. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ 2004;328: 261.
Pinborg A, Loft A, Rasmussen S, Schmidt L, Langhoff-Roos J, Greisen G, et al. Neonatal outcome in a Danish national cohort of 3438 IVF/ICSI and 10,362 non-IVF/ICSI twins born between 1995 and 2000. Hum Reprod 2004;19: 435-41.
Derom C, Derom R. The East Flanders prospective twin survey. In: Blickstein I, Keith LG, eds. Multiple pregnancy: epidemiology, gestation and perinatal outcome. 2nd ed. Oxon: Taylor and Francis, 2005: 39-47.
Loos R, Derom C, Vlietinck R, Derom R. The East Flanders prospective twin survey (Belgium): a population-based register. Twin Res 1998;1: 167-75.
Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol 2004;103: 551-63.
Machin GA. Why is it important to diagnose chorionicity and how do we do it? Best Pract Res Clin Obstet Gynaecol 2004;18: 515-30.
Diggle PJ, Liang K, Zeger SL. Analysis of longitudinal data. New York: Oxford University Press, 1994. (Oxford Statistical Science series, No 13.)
Basso O, Baird DD. Infertility and preterm delivery, birth weight, and caesarean section: a study within the Danish national birth cohort. Hum Reprod 2003;18: 2478-84.
Dhont M, De Sutter P, Ruyssinck G, Martens G, Bekaert A. Perinatal outcome of pregnancies after assisted reproduction: a case-control study. Am J Obstet Gynecol 1999;181: 688-95.
Hall JG. Twinning. Lancet 2003;362: 735-43.
Davies HT, Crombie IK, Tavakoli M. When can odds ratios mislead? BMJ 1998;316: 989-91.
Barrett JF. Delivery of the term twin. Best Pract Res Clin Obstet Gynaecol 2004;18: 625-30.
Kramer MS, Demissie K, Yang H, Platt RW, Sauve R, Liston R. The contribution of mild and moderate preterm birth to infant mortality. JAMA 2000;284: 843-9.
Fauser BC, Devroey P, Macklon NS. Multiple birth resulting from ovarian stimulation for subfertility treatment. Lancet 2005;365: 1807-16.
Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002;346: 731-7.
Moise J, Laor A, Armon Y, Gur I, Gale R. The outcome of twin pregnancies after IVF. Hum Reprod 1998;13: 1702-5.
Koudstaal J, Bruinse HW, Helmerhorst FM, Vermeiden JP, Willemsen WN, Visser GH. Obstetric outcome of twin pregnancies after in-vitro fertilization: a matched control study in four Dutch university hospitals. Hum Reprod 2000;15: 935-40.
Lambalk CB, van Hooff M. Natural versus induced twinning and pregnancy outcome: a Dutch nationwide survey of primiparous dizygotic twin deliveries. Fertil Steril 2001;75: 731-6.(Hans Verstraelen, research fellow1, Sylv)
Correspondence to: H Verstraelen hans.verstraelen@UGent.be
Objectives To assess gestational length and prevalence of preterm birth among medically and naturally conceived twins; to establish the role of zygosity and chorionicity in assessing gestational length in twins born after subfertility treatment.
Design Population based cohort study.
Setting Collaborative network of 19 maternity facilities in East Flanders, Belgium (East Flanders prospective twin survey).
Participants 4368 twin pairs born between 1976 and 2002, including 2915 spontaneous twin pairs, 710 twin pairs born after ovarian stimulation, and 743 twin pairs born after in vitro fertilisation or intracytoplasmic sperm injection.
Main outcome measures Gestational length and prevalence of preterm birth.
Results Compared with naturally conceived twins, twins resulting from subfertility treatment had on average a slightly decreased gestational age at birth (mean difference 4.0 days, 95% confidence interval 2.7 to 5.2), corresponding to an odds ratio of 1.6 (1.4 to 1.8) for preterm birth, albeit confined to mild preterm birth (34-36 weeks). The adjusted odds ratios of preterm birth after subfertility treatment were 1.3 (1.1 to 1.5) when controlled for birth year, maternal age, and parity and 1.6 (1.3 to 1.8) with additional control for fetal sex, caesarean section, zygosity, and chorionicity. Although an increased risk of preterm birth was therefore seen among twins resulting from subfertility treatment, the risk was largely caused by a first birth effect among subfertile couples; conversely, the risk of prematurity was substantially levelled off by the protective effect of dizygotic twinning.
Conclusions Twins resulting from subfertility treatment have an increased risk of preterm birth, but the risk is limited to mild preterm birth, primarily by virtue of dizygotic twinning.
One in six couples attempting pregnancy fail to conceive naturally after 12 months of regular unprotected intercourse. Most of these couples eventually succeed, about half of them through subfertility treatment.1 Efforts to increase the success rates of subfertility treatment have been accompanied by an insidious rise in the rate of multifetal pregnancies.2 About half of medically conceived babies in the United States and Europe are now born as twins,3 4 and almost half of all twins result from subfertility treatment.2
In the face of this "multiple birth epidemic," and despite widespread concern about the effects of medically aided conception on perinatal outcome, few studies have investigated outcomes in twins,5 and largely conflicting results have been reported.6 Fuller and more consistent data are needed to assess the impact of ovarian stimulation and assisted reproduction on pregnancy outcome.5
Twins tend to fare considerably worse than singletons, with much higher rates of perinatal mortality, neonatal morbidity, and long term neurological impairment.2 Adverse pregnancy outcome in turn relates to the high prevalence of preterm birth among twins and is exacerbated by monozygotic and monochorionic twinning.7-9 Whether subfertility treatment also impinges on gestational length in twins, as has been established among singletons,6 10 is unclear, as is the extent to which type of twinning interferes with perinatal outcome after subfertility treatment.11
In a population based cohort we compared gestational length and preterm birth rates between naturally and medically conceived twins. We also assessed the role of zygosity and chorionicity.
Methods
Study population
Multiple births in the East Flanders province of Belgium are recorded by the East Flanders prospective twin survey, through a collaborative network of 19 maternity units.8 9
Data collection
Methods of data collection have previously been described in detail.8 9 Briefly, for every multiple birth, a defined set of obstetric and perinatal data were recorded and placentas were collected and examined within 48 hours of delivery according to a standardised protocol. Zygosity and chorionicity were determined through sequential analysis of fetal sex, fetal membranes, and umbilical cord blood groups and by DNA fingerprinting based on allelic similarity within a twin pair of short tandem repeat loci on nine different chromosomes. Overall, zygosity and chorionicity were determined with an accuracy of over 99%.8 9
We estimated gestational length in number of days, principally on the basis of routine gestational dating combining last menstrual period and real time ultrasonography in early pregnancy, throughout the study period. In Flanders, more than 98% of women attend early in pregnancy and gestational dating is routinely confirmed or adjusted through ultrasound examination.
Inclusion and exclusion criteria
All twins with one of the children weighing at least 500 g were registered. From 1 January 1976 to 31 December 2002, 4989 twin pairs were recorded by the survey. We excluded 621 twin gestations from all analyses because data could not be ascertained for mode of conception (n = 53), maternal age (86), parity (52), gestational length (376), zygosity (69), birth weight (19 and 23), or infant sex (2 and 3).
Definitions
We defined preterm birth as birth at less than 37 completed weeks of gestation and low birth weight as weight at birth of less than 2500 g. The ovarian stimulation group included all women who conceived in vivo after any treatment regimen involving direct or indirect stimulation of ovulation, including regulation of the menstrual cycle, artificial induction of ovulation, or ovarian hyperstimulation without a subsequent in vitro procedure. The in vitro fertilisation/intracytoplasmic sperm injection group included all women who conceived (mostly after ovarian stimulation) through an in vitro procedure, generally referred to as assisted reproduction technology. The ovarian stimulation and in vitro fertilisation/intracytoplasmic sperm injection groups together comprise the subfertility group.
Outcome measures
Primary outcome measures were gestational length and rates of preterm birth according to mode of conception.
Statistical analyses
We first compared mean differences in continuous variables by using independent samples t tests and differences in prevalence rates by using 2 tests with the Yates correction. We subsequently assessed differences in mean values and prevalence rates by fitting linear, marginal logistic, and ordinary logistic regression models. In a first set of models, we accounted for the pretreatment variables birth year, parity, and maternal age. Provided these were the only predictors associated with subfertility treatment, the resulting differences and odds ratios express the "overall effect" on the outcomes assessed. In a second set of models, we additionally removed the mediating effects of the post-treatment variables zygosity, chorionicity, intra-twin fetal sex combination, and caesarean section. Provided that no confounding variables remained that impinged on the intermediates or on the decision to apply subfertility treatment, the resulting differences and odds ratios express the "direct effect" of subfertility treatment. We corrected all analyses of birth weight for intra-twin correlation through generalised estimating equations with exchangeable working correlation.12
We used Lagrange multiplier tests for model comparisons. We used the conventional 5% level to assess significance. Analyses were done with SPSS version 12.0 and SAS version 8.02 statistical software.
Results
Study population
The population based cohort (n = 4368) comprised 2915 (66.7%) naturally conceived and 1453 (33.3%) medically conceived twin pairs, including 710 (16.3%) twin pairs born after ovarian stimulation and 743 (17.0%) twin pairs born after in vitro fertilisation or intracytoplasmic sperm injection (table 1). Women who had had subfertility treatment were on average older (P < 0.001) and less likely to have had a child previously (P < 0.001) than mothers in the natural conception group.
Table 1 Maternal and perinatal characteristics of the study population. Values are numbers (percentages) unless stated otherwise
The dizygotic:monozygotic twinning ratio was 95.2:4.8 among medically conceived twins and 53.8:46.2 in the natural conception group (P < 0.001) (table 2). The distribution of the intra-twin fetal sex combination differed significantly (P < 0.001) between naturally and medically conceived twins owing to differential zygosity, whereas the overall fetal sex distribution did not (P = 0.9).
Table 2 Type of twinning according to mode of conception. Values are numbers (percentages) unless stated otherwise
Differences in gestational length and risk of preterm birth
Subfertility treatment was associated with a small decrease in gestational age at birth compared with the natural conception group (tables 1 and 3; figure). This difference translated to an odds ratio of 1.6 (95% confidence interval 1.4 to 1.8) for preterm birth (table 4), albeit confined to mild preterm birth ( 34 weeks) (figure). Medically conceived twins were more likely to be preterm delivered by caesarean section (odds ratio 1.5, 1.2 to 1.9) but were also at higher risk of spontaneous preterm birth (odds ratio 1.6, 1.4 to 1.8). In agreement with the above, medically conceived twins had, on average, a slightly lower birth weight (table 1) and a slightly higher risk of low birth weight (odds ratio 1.2, 1.1 to 1.4) (table 5).
Table 3 Crude and adjusted mean differences in gestational length between ovarian stimulation and IVF/ICSI groups of women, compared with natural conception group. Values are means (95% confidence intervals) unless stated otherwise
Kaplan-Meier plot of gestational length in naturally conceived (n=2915) and medically conceived (n=1453) twins
Table 4 Crude and adjusted odds ratios (95% confidence intervals) of preterm birth in ovarian stimulation and IVF/ICSI groups of women, compared with natural conception group
Table 5 Crude and adjusted odds ratios (95% confidence intervals) of low birth weight in ovarian stimulation and IVF/ICSI groups of women, compared with natural conception group
Adjusted differences in gestational length and risk of preterm birth
We estimated the overall effect of subfertility treatment by adjusting the outcomes for birth year, maternal age, and parity. The observed differences in gestational length (table 3) and rates of preterm birth (table 4) were clearly attenuated when we accounted for confounding; lower parity among women who conceived medically was the strongest confounder. The observed effects were, however, not entirely explained by these confounding effects. Assuming that no residual confounders remained, a minor but significant overall effect of subfertility treatment on gestational length could therefore not be ruled out on the basis of the observed data (tables 3 and 4), although this was not obvious from differences in birth weight (table 5).
To assess the direct effect of subfertility treatment, we additionally accounted for zygosity, chorionicity, fetal sex, and delivery mode (caesarean versus vaginal), which act on the pathway from conception to birth as intermediate variables to the outcomes assessed. When we accounted for this defined set of confounders and intermediates, the markedly higher effect size of the direct effect on gestational length (table 3) and preterm birth (table 4) over and above the overall effect was mainly attributable to the effect of zygosity. Chorionicity had a marginal effect on gestational length beyond zygosity, and caesarean delivery showed no effect at all after confounding was accounted for. According to our analyses, dizygotic twinning pertaining to iatrogenic pregnancy therefore proves a strong and advantageous mediator of gestational length (table 4), as is also apparent from the data on birth weight (table 5).
Discussion
Taylor A. ABC of subfertility: extent of the problem. BMJ 2003;327: 434-6.
Blondel B, Kaminski M. Trends in the occurrence, determinants, and consequences of multiple births. Semin Perinatol 2002;26: 239-49.
Wright VC, Schieve LA, Reynolds MA, Jeng G. Assisted reproductive technology surveillance—United States, 2000. MMWR Surveil 2003;52: 1-16.
Nyboe Andersen A, Gianaroli L, Nygren KG, European IVF-monitoring programme, European Society of Human Reproduction and Embryology. Assisted reproductive technology in Europe, 2000: results generated from European registers by ESHRE. Hum Reprod 2004;19: 490-503.
Blondel B, Macfarlane A. Rising multiple maternity rates and medical management of subfertility: better information is needed. Eur J Public Health 2003;13: 83-6.
Helmerhorst FM, Perquin DA, Donker D, Keirse MJ. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ 2004;328: 261.
Pinborg A, Loft A, Rasmussen S, Schmidt L, Langhoff-Roos J, Greisen G, et al. Neonatal outcome in a Danish national cohort of 3438 IVF/ICSI and 10,362 non-IVF/ICSI twins born between 1995 and 2000. Hum Reprod 2004;19: 435-41.
Derom C, Derom R. The East Flanders prospective twin survey. In: Blickstein I, Keith LG, eds. Multiple pregnancy: epidemiology, gestation and perinatal outcome. 2nd ed. Oxon: Taylor and Francis, 2005: 39-47.
Loos R, Derom C, Vlietinck R, Derom R. The East Flanders prospective twin survey (Belgium): a population-based register. Twin Res 1998;1: 167-75.
Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol 2004;103: 551-63.
Machin GA. Why is it important to diagnose chorionicity and how do we do it? Best Pract Res Clin Obstet Gynaecol 2004;18: 515-30.
Diggle PJ, Liang K, Zeger SL. Analysis of longitudinal data. New York: Oxford University Press, 1994. (Oxford Statistical Science series, No 13.)
Basso O, Baird DD. Infertility and preterm delivery, birth weight, and caesarean section: a study within the Danish national birth cohort. Hum Reprod 2003;18: 2478-84.
Dhont M, De Sutter P, Ruyssinck G, Martens G, Bekaert A. Perinatal outcome of pregnancies after assisted reproduction: a case-control study. Am J Obstet Gynecol 1999;181: 688-95.
Hall JG. Twinning. Lancet 2003;362: 735-43.
Davies HT, Crombie IK, Tavakoli M. When can odds ratios mislead? BMJ 1998;316: 989-91.
Barrett JF. Delivery of the term twin. Best Pract Res Clin Obstet Gynaecol 2004;18: 625-30.
Kramer MS, Demissie K, Yang H, Platt RW, Sauve R, Liston R. The contribution of mild and moderate preterm birth to infant mortality. JAMA 2000;284: 843-9.
Fauser BC, Devroey P, Macklon NS. Multiple birth resulting from ovarian stimulation for subfertility treatment. Lancet 2005;365: 1807-16.
Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002;346: 731-7.
Moise J, Laor A, Armon Y, Gur I, Gale R. The outcome of twin pregnancies after IVF. Hum Reprod 1998;13: 1702-5.
Koudstaal J, Bruinse HW, Helmerhorst FM, Vermeiden JP, Willemsen WN, Visser GH. Obstetric outcome of twin pregnancies after in-vitro fertilization: a matched control study in four Dutch university hospitals. Hum Reprod 2000;15: 935-40.
Lambalk CB, van Hooff M. Natural versus induced twinning and pregnancy outcome: a Dutch nationwide survey of primiparous dizygotic twin deliveries. Fertil Steril 2001;75: 731-6.(Hans Verstraelen, research fellow1, Sylv)