Neurological sequelae in twins born after assisted conception: controlled national cohort study
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《英国医生杂志》
1 Fertility Clinic, University of Copenhagen, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark, 2 Institute of Public Health, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark, 3 Department of Neonatology, University of Copenhagen, Rigshospitalet, 4 National Board of Health, Health Statistics, Islandsbrygge 67, DK-2300 Copenhagen, Denmark
Correspondence to: A Pinborg apinborg@rh.dk
Abstract
In Denmark 5% of infants are the result of in vitro fertilisation (IVF) techniques (IVF and intracytoplasmic sperm injection, ICSI), and the latest European data from 2000 showed that 39% of IVF infants were born as twins.1 Hence assisted conception and increasing maternal age have had a great impact on the national twin birth rates.
Several studies have shown that twin pregnancies are the main reason for the overall poorer neonatal outcome in pregnancies after assisted conception.2-5
In population based studies on naturally conceived children, twins have four times the risk of cerebral palsy as singletons.6 However, the literature specifically addressing long term morbidity in twins after assisted conception is limited. A Swedish register study has found an increased risk of cerebral palsy in children after assisted conception, mainly because of the high rate of twins.7 Our recent Danish questionnaire study showed similar morbidity in twins after assisted conception and naturally conceived twins, but compared with singletons after assisted conception twins were more likely to have surgical interventions, special needs, and delayed speech development, whereas the prevalence of neurological sequelae was equal.8
To study the long term effects of IVF techniques on twins we established a database with all singletons and twins born after assisted conception between 1995 and 2000. Perinatal outcomes including prevalence rates of malformations, malignancies, mortality, and data on the use of treatments for special needs, including speech therapy, in these children have been published recently.8-10
We assessed prevalence rates of neurological sequelae in Denmark in a nationwide cohort of twins after IVF techniques and in two population based control groups of naturally conceived twins and of singletons conceived by IVF techniques. We also compared the roles of ICSI and conventional IVF in neurological sequelae in these children.
Methods
Demographic data
We included 3393 twins conceived by IVF or ICSI, 10 239 naturally conceived twins, and 5130 IVF or ICSI singletons in the study. Table 1 shows mothers' and infants' characteristics. Since 41 IVF twins and 95 control twins were survivors of a stillborn co-twin, the number of children in both twin cohorts was odd. As expected, mothers of IVF or ICSI twins were older than control twin mothers but younger than mothers of IVF or ICSI singletons. For 1676 IVF-ICSI twin pairs and for 5103 control twin pairs the sex of both twins was known. In contrast to 65.3% (3330/5103) control twin pairs with the same sex, only 50.8% (851/1676) of the IVF or ICSI twins were same sex (P < 0.001; table 1). The zygosity of twins can be determined by Weinberg's differential method.15 In our study, this estimation results in 1.6% (26/1676) monozygotic IVF or ICSI and 31% (1557/5103) monozygotic control twin pairs. We adjusted all analyses for year of birth to account for the differences in average child age at time of follow up.
Table 1 Mothers' and infants' characteristics in the three cohorts
Neurological sequelae
We observed similar prevalence rates of neurological sequelae in IVF or ICSI twins and the two control groups. The crude prevalence of children with neurological sequelae was 8.8/1000 in IVF or ICSI twins, 9.6/1000 in control twins, and 8.2/1000 in IVF or ICSI singletons. The prevalence rates of the specific diagnoses cerebral palsy and mental retardation were also similar (table 2). Odds ratios of neurological sequelae, cerebral palsy, and mental retardation with and without adjustment for a child's sex and year of birth were the same in IVF or ICSI twins and both control groups (table 3). The odds ratios of neurological sequelae in ICSI compared with IVF children were 1.3 (95% confidence interval 0.6 to 3.0) for twins and 0.5 (0.2 to 1.2) singletons.
Table 2 Numbers of children in the three cohorts with neurological sequelae. Diagnoses were counted per child. The primary diagnoses were classified according to severity in the ranking order system. Diagnoses were recorded from 1 January 1995 to 31 December 2002
Table 3 Odds ratio of neurological sequelae, cerebral palsy and mental retardation in IVF-ICSI twins versus control twins and IVF-ICSI singletons. Results are presented as odds ratios and adjusted odds ratios for child sex and year of birth with 95% confidence intervals
We identified one twin pair with neurological sequelae in 30 IVF or ICSI twins and six in 98 control twins, all of the same sex. The concordance rates were therefore 3.3% and 6.1%, respectively.
The role of zygosity
To account for the higher monozygotic rate among naturally conceived twins, we computed odds ratios of neurological sequelae in IVF or ICSI twins of the opposite sex compared with twins of the same sex (0.7, 0.3 to 1.4) and in control twins (1.0, 0.8 to 1.4). To exclude the monozygotic twins we restricted our analyses to twins of the opposite sex. The odds ratios for neurological sequelae were 1.1 (0.6 to 2.3), mental retardation 1.1 (0.4 to 2.6), and cerebral palsy 1.3 (0.4 to 4.0) in twins of the opposite sex conceived by IVF or ICSI compared with control twins of the opposite sex.
Factors influencing the risk of neurological sequelae
We performed multiple logistic regression analyses for all children in the three cohorts and for twins alone to explore the effect of relevant confounders on the risk of neurological sequelae. In each of the analyses we tested separately the risk of the two outcomes, neurological sequelae and cerebral palsy. Table 4 shows that low birth weight or prematurity and male sex were strong risk factors for both outcome measures. After adjustment for low birth weight or prematurity, we observed that IVF and maternal age > 35 years had no independent effect on the risk of neurological sequelae, and neither had being a twin. In the analyses restricted to twins, IVF or ICSI twins had no greater risk of neurological sequelae than naturally conceived twins (table 4). We adjusted all data in the logistic regression analysis for children's year of birth.
Table 4 Multiple logistic regression analysis showing independent effects of being a twin infant, assisted conception (IVF and ICSI), maternal age 35 years, male sex, and low birth weight (<2500 g) (upper panel) or low gestational age (<37 weeks) (lower panel) on the risk of neurological sequelae and cerebral palsy. Results are presented as odds ratios (95% confidence intervals), adjusted for child sex and year of birth
To study the effect of ICSI, we performed regression analyses restricted to IVF or ICSI children. ICSI children had similar odds ratios as IVF children for neurological sequelae (0.9, 0.5 to 1.6) and cerebral palsy (0.8, 0.3 to 2.4). Also in these analyses male sex and low birth weight or prematurity independently affected the risk of both outcomes, and we found no difference between twins and singletons in the risk of any of the outcomes.
Discussion
Nyboe Andersen A, Gianaroli L, Nygren KG. Assisted reproductive technology in Europe, 2000. Results generated from European registers by ESHRE. Hum Reprod 2004;19: 490-03.
Bergh T, Ericson A, Hillensj? T, Nygren KG, Wennerholm UB. Deliveries and children born after in-vitro fertilisation in Sweden 1982-95: a retrospective cohort study. Lancet 1999;354: 1579-85.
Dhont M, Sutter PD, 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.
Westergaard HB, Johansen AMT, Erb K, Nyboe Andersen A. Danish national in-vitro fertilization registry 1994 and 1995: a controlled study of birth, malformations and cytogenetic findings. Hum Reprod 1999;14: 1896-902.
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: 731-37.
Scher AI, Petterson B, Blair E, Ellenberg JH, Grether JK, Haan E, et al. The Risk of mortality or cerebral palsy in twins: a collaborative population-based study. Pediatr Res 2002;52: 671-81.
Str?mberg B, Dahlquist G, Ericson A, Finnstr?m O, K?ster M, Stjernquist, K. Neurological sequelae in children born after in-vitro fertilisation: a population based study. Lancet 2002;359: 461-65.
Pinborg A, Loft A, Schmidt L, Nyboe Andersen A. Morbidity in a Danish national cohort of 472 IVF/ICSI twins, 1132 non-IVF/ICSI twins and 634 IVF/ICSI singletons: health-related and social implications for the children and their families. Hum Reprod 2003;18: 1234-43.
Pinborg A, Loft A, Rasmussen S, Schmidt L, Langhoff-Roos J, Greisen G, Nyboe Andersen A. Neonatal outcome in a Danish national cohort of 3438 IVF/ICSI twins and 10362 non-IVF/ICSI twins born in 1995 to 2000. Hum Reprod 2004;19: 435-41.
Pinborg A, Loft A, Nyboe Andersen A. Neonatal outcome in a Danish national cohort of 8602 children born after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI): the role of twin pregnancy. Acta Gynecol Obstet Scand 2004 (in press).
Knudsen L, Olsen J. The Danish Medical Birth Registry. Dan Med Bull 1998;45: 320-3.
Nyboe Andersen A, Westergaard HB, Olsen J. The Danish in vitro fertilisation (IVF) registry. Dan Med Bull 1999;46: 357-60.
Andersen TF, Madsen M, Jorgensen J, Mellemkjaer L, Olsen J. The Danish hospital register. A valuable source of data for modern health sciences. Dan Med Bull 1999;46: 263-68.
Munk-Jorgensen P, Mortensen PB. The Danish psychiatric central register. Dan Med Bull 1997;44: 82-4.
Weinberg W. Beitr?ge zur Physiologie und Pathologie der Mehrlingsgebuhrten beim Menschen . Archiv Gesamte Physiol Menschen Tiere 1902;88: 346-430.
Daniel Y, Ochshorn Y, Fait G, Geva E, Bar-Am A, Lessing JB. Analysis of 104 twin pregnancies conceived with assisted reproductive technologies and 193 spontaneously conceived twin pregnancies. Fertil Steril 2000;74: 683-89.
K?llen B, Olausson PO, Nygren KG. Neonatal outcome in pregnancies from ovarian stimulation. Obstet Gynecol, 2002;100: 414-9.
Sutcliffe AG, Taylor B, Saunders K, Thornton S, Lieberman BA, Grudzinskas JG. Outcome in the second year of life after in-vitro fertilisation by intracytoplasmic sperm injection: a UK case-control study. Lancet 2001;357: 2080-84.
Leslie GI, Gibson FL, McMahon C, Cohen J, Saunders DM, Tennant C. Children conceived using ICSI do not have an increased risk of delayed mental development at 5 years of age. Hum Reprod 2003;18: 2067-72.
Minakami H, Sayama M, Honma Y, Matsubara S, Koike T, Sato I, et al. Lower risk of adverse outcome in twins conceived by artificial reproductive techniques compared with spontaneously conceived twins. Hum Reprod 1998;13: 2005-8.
Koivurova S, Hartikainen AL, Sovio U, Gissler M, Hemminki E, J?rvelin MR. Growth, psychomotor development and morbidity up to 3 years of age in children born after IVF. Hum Reprod 2003;18: 2328-36.
Hagberg B, Hagberg G, Beckung E, Uvebrandt P. Changing panorama of cerebral palsy in Sweden. VIII. Prevalence and origin in the birth year period 1991-94. Acta Paediatr 2001;90: 271-7.
Topp M, Uldall P, Greisen G. Cerebral palsy births in eastern Denmark, 1987-1990: implications for neonatal care. Pediatr Perinat Epidemiol 2001;15: 271-7.(Anja Pinborg, research fe)
Correspondence to: A Pinborg apinborg@rh.dk
Abstract
In Denmark 5% of infants are the result of in vitro fertilisation (IVF) techniques (IVF and intracytoplasmic sperm injection, ICSI), and the latest European data from 2000 showed that 39% of IVF infants were born as twins.1 Hence assisted conception and increasing maternal age have had a great impact on the national twin birth rates.
Several studies have shown that twin pregnancies are the main reason for the overall poorer neonatal outcome in pregnancies after assisted conception.2-5
In population based studies on naturally conceived children, twins have four times the risk of cerebral palsy as singletons.6 However, the literature specifically addressing long term morbidity in twins after assisted conception is limited. A Swedish register study has found an increased risk of cerebral palsy in children after assisted conception, mainly because of the high rate of twins.7 Our recent Danish questionnaire study showed similar morbidity in twins after assisted conception and naturally conceived twins, but compared with singletons after assisted conception twins were more likely to have surgical interventions, special needs, and delayed speech development, whereas the prevalence of neurological sequelae was equal.8
To study the long term effects of IVF techniques on twins we established a database with all singletons and twins born after assisted conception between 1995 and 2000. Perinatal outcomes including prevalence rates of malformations, malignancies, mortality, and data on the use of treatments for special needs, including speech therapy, in these children have been published recently.8-10
We assessed prevalence rates of neurological sequelae in Denmark in a nationwide cohort of twins after IVF techniques and in two population based control groups of naturally conceived twins and of singletons conceived by IVF techniques. We also compared the roles of ICSI and conventional IVF in neurological sequelae in these children.
Methods
Demographic data
We included 3393 twins conceived by IVF or ICSI, 10 239 naturally conceived twins, and 5130 IVF or ICSI singletons in the study. Table 1 shows mothers' and infants' characteristics. Since 41 IVF twins and 95 control twins were survivors of a stillborn co-twin, the number of children in both twin cohorts was odd. As expected, mothers of IVF or ICSI twins were older than control twin mothers but younger than mothers of IVF or ICSI singletons. For 1676 IVF-ICSI twin pairs and for 5103 control twin pairs the sex of both twins was known. In contrast to 65.3% (3330/5103) control twin pairs with the same sex, only 50.8% (851/1676) of the IVF or ICSI twins were same sex (P < 0.001; table 1). The zygosity of twins can be determined by Weinberg's differential method.15 In our study, this estimation results in 1.6% (26/1676) monozygotic IVF or ICSI and 31% (1557/5103) monozygotic control twin pairs. We adjusted all analyses for year of birth to account for the differences in average child age at time of follow up.
Table 1 Mothers' and infants' characteristics in the three cohorts
Neurological sequelae
We observed similar prevalence rates of neurological sequelae in IVF or ICSI twins and the two control groups. The crude prevalence of children with neurological sequelae was 8.8/1000 in IVF or ICSI twins, 9.6/1000 in control twins, and 8.2/1000 in IVF or ICSI singletons. The prevalence rates of the specific diagnoses cerebral palsy and mental retardation were also similar (table 2). Odds ratios of neurological sequelae, cerebral palsy, and mental retardation with and without adjustment for a child's sex and year of birth were the same in IVF or ICSI twins and both control groups (table 3). The odds ratios of neurological sequelae in ICSI compared with IVF children were 1.3 (95% confidence interval 0.6 to 3.0) for twins and 0.5 (0.2 to 1.2) singletons.
Table 2 Numbers of children in the three cohorts with neurological sequelae. Diagnoses were counted per child. The primary diagnoses were classified according to severity in the ranking order system. Diagnoses were recorded from 1 January 1995 to 31 December 2002
Table 3 Odds ratio of neurological sequelae, cerebral palsy and mental retardation in IVF-ICSI twins versus control twins and IVF-ICSI singletons. Results are presented as odds ratios and adjusted odds ratios for child sex and year of birth with 95% confidence intervals
We identified one twin pair with neurological sequelae in 30 IVF or ICSI twins and six in 98 control twins, all of the same sex. The concordance rates were therefore 3.3% and 6.1%, respectively.
The role of zygosity
To account for the higher monozygotic rate among naturally conceived twins, we computed odds ratios of neurological sequelae in IVF or ICSI twins of the opposite sex compared with twins of the same sex (0.7, 0.3 to 1.4) and in control twins (1.0, 0.8 to 1.4). To exclude the monozygotic twins we restricted our analyses to twins of the opposite sex. The odds ratios for neurological sequelae were 1.1 (0.6 to 2.3), mental retardation 1.1 (0.4 to 2.6), and cerebral palsy 1.3 (0.4 to 4.0) in twins of the opposite sex conceived by IVF or ICSI compared with control twins of the opposite sex.
Factors influencing the risk of neurological sequelae
We performed multiple logistic regression analyses for all children in the three cohorts and for twins alone to explore the effect of relevant confounders on the risk of neurological sequelae. In each of the analyses we tested separately the risk of the two outcomes, neurological sequelae and cerebral palsy. Table 4 shows that low birth weight or prematurity and male sex were strong risk factors for both outcome measures. After adjustment for low birth weight or prematurity, we observed that IVF and maternal age > 35 years had no independent effect on the risk of neurological sequelae, and neither had being a twin. In the analyses restricted to twins, IVF or ICSI twins had no greater risk of neurological sequelae than naturally conceived twins (table 4). We adjusted all data in the logistic regression analysis for children's year of birth.
Table 4 Multiple logistic regression analysis showing independent effects of being a twin infant, assisted conception (IVF and ICSI), maternal age 35 years, male sex, and low birth weight (<2500 g) (upper panel) or low gestational age (<37 weeks) (lower panel) on the risk of neurological sequelae and cerebral palsy. Results are presented as odds ratios (95% confidence intervals), adjusted for child sex and year of birth
To study the effect of ICSI, we performed regression analyses restricted to IVF or ICSI children. ICSI children had similar odds ratios as IVF children for neurological sequelae (0.9, 0.5 to 1.6) and cerebral palsy (0.8, 0.3 to 2.4). Also in these analyses male sex and low birth weight or prematurity independently affected the risk of both outcomes, and we found no difference between twins and singletons in the risk of any of the outcomes.
Discussion
Nyboe Andersen A, Gianaroli L, Nygren KG. Assisted reproductive technology in Europe, 2000. Results generated from European registers by ESHRE. Hum Reprod 2004;19: 490-03.
Bergh T, Ericson A, Hillensj? T, Nygren KG, Wennerholm UB. Deliveries and children born after in-vitro fertilisation in Sweden 1982-95: a retrospective cohort study. Lancet 1999;354: 1579-85.
Dhont M, Sutter PD, 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.
Westergaard HB, Johansen AMT, Erb K, Nyboe Andersen A. Danish national in-vitro fertilization registry 1994 and 1995: a controlled study of birth, malformations and cytogenetic findings. Hum Reprod 1999;14: 1896-902.
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: 731-37.
Scher AI, Petterson B, Blair E, Ellenberg JH, Grether JK, Haan E, et al. The Risk of mortality or cerebral palsy in twins: a collaborative population-based study. Pediatr Res 2002;52: 671-81.
Str?mberg B, Dahlquist G, Ericson A, Finnstr?m O, K?ster M, Stjernquist, K. Neurological sequelae in children born after in-vitro fertilisation: a population based study. Lancet 2002;359: 461-65.
Pinborg A, Loft A, Schmidt L, Nyboe Andersen A. Morbidity in a Danish national cohort of 472 IVF/ICSI twins, 1132 non-IVF/ICSI twins and 634 IVF/ICSI singletons: health-related and social implications for the children and their families. Hum Reprod 2003;18: 1234-43.
Pinborg A, Loft A, Rasmussen S, Schmidt L, Langhoff-Roos J, Greisen G, Nyboe Andersen A. Neonatal outcome in a Danish national cohort of 3438 IVF/ICSI twins and 10362 non-IVF/ICSI twins born in 1995 to 2000. Hum Reprod 2004;19: 435-41.
Pinborg A, Loft A, Nyboe Andersen A. Neonatal outcome in a Danish national cohort of 8602 children born after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI): the role of twin pregnancy. Acta Gynecol Obstet Scand 2004 (in press).
Knudsen L, Olsen J. The Danish Medical Birth Registry. Dan Med Bull 1998;45: 320-3.
Nyboe Andersen A, Westergaard HB, Olsen J. The Danish in vitro fertilisation (IVF) registry. Dan Med Bull 1999;46: 357-60.
Andersen TF, Madsen M, Jorgensen J, Mellemkjaer L, Olsen J. The Danish hospital register. A valuable source of data for modern health sciences. Dan Med Bull 1999;46: 263-68.
Munk-Jorgensen P, Mortensen PB. The Danish psychiatric central register. Dan Med Bull 1997;44: 82-4.
Weinberg W. Beitr?ge zur Physiologie und Pathologie der Mehrlingsgebuhrten beim Menschen . Archiv Gesamte Physiol Menschen Tiere 1902;88: 346-430.
Daniel Y, Ochshorn Y, Fait G, Geva E, Bar-Am A, Lessing JB. Analysis of 104 twin pregnancies conceived with assisted reproductive technologies and 193 spontaneously conceived twin pregnancies. Fertil Steril 2000;74: 683-89.
K?llen B, Olausson PO, Nygren KG. Neonatal outcome in pregnancies from ovarian stimulation. Obstet Gynecol, 2002;100: 414-9.
Sutcliffe AG, Taylor B, Saunders K, Thornton S, Lieberman BA, Grudzinskas JG. Outcome in the second year of life after in-vitro fertilisation by intracytoplasmic sperm injection: a UK case-control study. Lancet 2001;357: 2080-84.
Leslie GI, Gibson FL, McMahon C, Cohen J, Saunders DM, Tennant C. Children conceived using ICSI do not have an increased risk of delayed mental development at 5 years of age. Hum Reprod 2003;18: 2067-72.
Minakami H, Sayama M, Honma Y, Matsubara S, Koike T, Sato I, et al. Lower risk of adverse outcome in twins conceived by artificial reproductive techniques compared with spontaneously conceived twins. Hum Reprod 1998;13: 2005-8.
Koivurova S, Hartikainen AL, Sovio U, Gissler M, Hemminki E, J?rvelin MR. Growth, psychomotor development and morbidity up to 3 years of age in children born after IVF. Hum Reprod 2003;18: 2328-36.
Hagberg B, Hagberg G, Beckung E, Uvebrandt P. Changing panorama of cerebral palsy in Sweden. VIII. Prevalence and origin in the birth year period 1991-94. Acta Paediatr 2001;90: 271-7.
Topp M, Uldall P, Greisen G. Cerebral palsy births in eastern Denmark, 1987-1990: implications for neonatal care. Pediatr Perinat Epidemiol 2001;15: 271-7.(Anja Pinborg, research fe)