- Email: [email protected]
Neurological sequelae in in-vitro fertilisation babies
CORRESPONDENCE
was higher than for spontaneous singletons. This result may be misinterpreted as suggesting that twinning reduces the risk of cerebral palsy from IVF. A plausible explanation comes from knowledge that the returning of multiple embryos during IVF results in a high ratio of dizygotic to monozygotic twins.3 Dizygotic twin pregnancies have lower rates of pregnancy complications, pregnancy loss, and perinatal mortality than do monozygotic pregnancies.4 Although data specific to cerebral palsy and zygosity are scarce, we may expect monozygotic twins to have a higher rate of cerebral palsy than dizygotic twins. Adjustment for the crude mortality rate for twin type may reveal an additional risk associated with twin pregnancies from IVF. Evidence shows that dizygotic twins born after IVF have shorter gestations, lower birthweights, and lower APGAR scores than do spontaneously conceived dizygotic twins—all factors associated with cerebral palsy.5 Therefore, although Strömberg and colleagues’ findings are important, there is a continued need to explore factors related to patients and treatment for sources of risk associated with IVF in singleton and multiple pregnancies. *Michael Davies, Robert Norman Reproductive Medicine Unit, Department of Obstetrics and Gynaecology, University of Adelaide, Queen Elizabeth Hospital, Woodville, South Australia 5011 (e-mail: [email protected]) 1
2
3
4 5
Strömberg B, Dahlquist G, Ericson A, Finnström O, Köster M, Stjernqvist K. Neurological sequelae in children born after in-vitro fertilisation: a population-based study. Lancet 2002; 359: 461–65. Grether JK, Nelson KB, Emery ES, Cummins SK. Prenatal and perinatal factors and cerebral palsy in very low birth weight infants. J Pediatr 1996; 128: 407–14. 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. Pharoah PO. Twins and cerebral palsy. Acta Paediatr Suppl 2001; 90: 6–10. 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: 731–36.
Authors’ reply Sir—Valentine Akande and Dierdre Murphy’s view that delivery without labour may decrease the risk of cerebral palsy among very preterm infants is not universally accepted; however, the rate of caesarean section was increased in our study.1 Thus, adjustment for delivery method would only strengthen our results.
Akande and Murphy also ask about the effect of differing rates of intrauterine and early neonatal death between cases and controls. The rate of perinatal death was only slightly higher among IVF singletons than among all singletons (8·2 vs 6·6 per 1000).1 Adjustment for maternal age and gestational age among twins or singletons, showed no significant difference between IVF and control children.1,2 Alan Leviton and co-workers emphasise the raised risk of cerebral palsy with shorter gestation. The causes are not clear, but in extremely preterm and very preterm infants a perinatal or neonatal cause is most probable.3 The absolute number of children with cerebral palsy was small (n=31) even in our large group. Thus, stratification into more than two strata of gestational age would not be statistically sound. As in most large register studies, we could not adjust for all possible confounders. Michael Davies and Robert Norman suggest that adjustment for gravidity or short intervals between births could have increased the effects of IVF on cerebral palsy, but that information was not available. They suggest also that monozygotic twins might have a higher rate of cerebral palsy than dizygotic twins. Around 28% of our control twins were monozygotic compared with 6% of IVF twins.2 This difference might partly explain the similar risk we noted for cerebral palsy in IVF and control twins, whereas among singletons the IVF children were at higher risk. We have no information on zygosity for individual twin pairs, but if we exclude all same-sex twins, the risk of cerebral palsy is slightly but not significantly higher in IVF than in control twins (odds ratio 1·7 [95% CI 0·6–4·7]). 6·8 per 1000 control twins had cerebral palsy compared with 1·4 per 1000 control singletons. Therefore, twin pregnancy is a strong risk factor for cerebral palsy and might hide the additional effect of IVF detectable in singletons. Our regression analysis showed the greatest cause of the excess risk for cerebral palsy in singletons and twins to be prematurity and low birthweight. Overall, single embryo transfer would lower the number of very preterm IVF infants (<32 weeks) by 60%. Even if more treatments are needed to achieve similar take-home baby rates, overall costs will be reduced because costs of neonatal intensive care and disability care will be lower.4 Although, parents might find these risks small, the excess cost of human suffering if transfer of more than one embryo is continued as routine is not
THE LANCET • Vol 360 • August 31, 2002 • www.thelancet.com
acceptable given the absolute number of children born worldwide after IVF every year. Clearly more studies are needed to try to explain the excess risk of singleton IVF children. Gisela Dahlquist, Orvar Finnström, Max Köster, *Bo Strömberg Department of Paediatrics, Umeå University, Umeå; Department of Paediatrics, University Hospital, Linköping; Centre for Epidemiology, National Board of Health and Welfare, Stockholm; and *Department of Women and Child Health, University Children’s Hospital, S-751 85 Uppsala, Sweden (e-mail: [email protected]) 1
2
3
4
Bergh T, Ericson A, Hillensjö T, Nygren K-G, Wennerholm U-B. Deliveries and children born after in-vitro fertilisation in Sweden 1982-95: a retrospective cohort study. Lancet 1999; 354: 1579–85. Children born in Sweden after in-vitro fertilisation 1982–1997. Stockholm: National Board of Health and Welfare, 2000: 1. Hagberg B, Hagberg G, Beckung E, Uvebrant P. Changing panorama of cerebral palsy in Sweden, VIII: prevalence and origin in the birth year period 1991–94. Acta Paediatr 2001; 90: 271–77. Wolner-Hanssen P, Rydstroem H. Costeffectiveness analysis of in-vitro fertilization: estimated costs per successful pregnancy after transfer of one or two embryos. Hum Reprod 1998; 13: 88–94.
Mammographic screening: no reliable supporting evidence? Sir—In their report, Olli Miettinen and colleagues (Feb 2, p 404)1 add a new analysis to the vital discussion about the role of mammography screening. This role has been challenged by Olsen and Gøtzsche.2 Miettinen and colleagues use the Malmö trial data3 to assess a new endpoint, the so-called case-fatality rate, for which they note a 55% reduction. They conclude that this fall translates to a reduction of cause-specific (ie, breast cancer) mortality. However, their hypothesis is built on the assumption that breast cancer, whenever it occurs, leads inevitably to death (100% mortality) unless it is detected by mammography screening and cured. This hypothesis bears some pitfalls. Not every breast cancer is an immediate killer. In particular, elderly women with breast cancer have a raised chance of dying from natural causes first, especially if the cancer is in an early stage. These cases are known as victims of more sensitive diagnostic techniques—they are classified as breast cancer patients, but would not otherwise have been identified. In a necropsy study from Denmark to investigate the prevalence of invasive and non-invasive breast cancer in women not known to have the disease, a
719
For personal use. Only reproduce with permission from The Lancet Publishing Group.
was higher than for spontaneous singletons. This result may be misinterpreted as suggesting that twinning reduces the risk of cerebral palsy from IVF. A plausible explanation comes from knowledge that the returning of multiple embryos during IVF results in a high ratio of dizygotic to monozygotic twins.3 Dizygotic twin pregnancies have lower rates of pregnancy complications, pregnancy loss, and perinatal mortality than do monozygotic pregnancies.4 Although data specific to cerebral palsy and zygosity are scarce, we may expect monozygotic twins to have a higher rate of cerebral palsy than dizygotic twins. Adjustment for the crude mortality rate for twin type may reveal an additional risk associated with twin pregnancies from IVF. Evidence shows that dizygotic twins born after IVF have shorter gestations, lower birthweights, and lower APGAR scores than do spontaneously conceived dizygotic twins—all factors associated with cerebral palsy.5 Therefore, although Strömberg and colleagues’ findings are important, there is a continued need to explore factors related to patients and treatment for sources of risk associated with IVF in singleton and multiple pregnancies. *Michael Davies, Robert Norman Reproductive Medicine Unit, Department of Obstetrics and Gynaecology, University of Adelaide, Queen Elizabeth Hospital, Woodville, South Australia 5011 (e-mail: [email protected]) 1
2
3
4 5
Strömberg B, Dahlquist G, Ericson A, Finnström O, Köster M, Stjernqvist K. Neurological sequelae in children born after in-vitro fertilisation: a population-based study. Lancet 2002; 359: 461–65. Grether JK, Nelson KB, Emery ES, Cummins SK. Prenatal and perinatal factors and cerebral palsy in very low birth weight infants. J Pediatr 1996; 128: 407–14. 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. Pharoah PO. Twins and cerebral palsy. Acta Paediatr Suppl 2001; 90: 6–10. 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: 731–36.
Authors’ reply Sir—Valentine Akande and Dierdre Murphy’s view that delivery without labour may decrease the risk of cerebral palsy among very preterm infants is not universally accepted; however, the rate of caesarean section was increased in our study.1 Thus, adjustment for delivery method would only strengthen our results.
Akande and Murphy also ask about the effect of differing rates of intrauterine and early neonatal death between cases and controls. The rate of perinatal death was only slightly higher among IVF singletons than among all singletons (8·2 vs 6·6 per 1000).1 Adjustment for maternal age and gestational age among twins or singletons, showed no significant difference between IVF and control children.1,2 Alan Leviton and co-workers emphasise the raised risk of cerebral palsy with shorter gestation. The causes are not clear, but in extremely preterm and very preterm infants a perinatal or neonatal cause is most probable.3 The absolute number of children with cerebral palsy was small (n=31) even in our large group. Thus, stratification into more than two strata of gestational age would not be statistically sound. As in most large register studies, we could not adjust for all possible confounders. Michael Davies and Robert Norman suggest that adjustment for gravidity or short intervals between births could have increased the effects of IVF on cerebral palsy, but that information was not available. They suggest also that monozygotic twins might have a higher rate of cerebral palsy than dizygotic twins. Around 28% of our control twins were monozygotic compared with 6% of IVF twins.2 This difference might partly explain the similar risk we noted for cerebral palsy in IVF and control twins, whereas among singletons the IVF children were at higher risk. We have no information on zygosity for individual twin pairs, but if we exclude all same-sex twins, the risk of cerebral palsy is slightly but not significantly higher in IVF than in control twins (odds ratio 1·7 [95% CI 0·6–4·7]). 6·8 per 1000 control twins had cerebral palsy compared with 1·4 per 1000 control singletons. Therefore, twin pregnancy is a strong risk factor for cerebral palsy and might hide the additional effect of IVF detectable in singletons. Our regression analysis showed the greatest cause of the excess risk for cerebral palsy in singletons and twins to be prematurity and low birthweight. Overall, single embryo transfer would lower the number of very preterm IVF infants (<32 weeks) by 60%. Even if more treatments are needed to achieve similar take-home baby rates, overall costs will be reduced because costs of neonatal intensive care and disability care will be lower.4 Although, parents might find these risks small, the excess cost of human suffering if transfer of more than one embryo is continued as routine is not
THE LANCET • Vol 360 • August 31, 2002 • www.thelancet.com
acceptable given the absolute number of children born worldwide after IVF every year. Clearly more studies are needed to try to explain the excess risk of singleton IVF children. Gisela Dahlquist, Orvar Finnström, Max Köster, *Bo Strömberg Department of Paediatrics, Umeå University, Umeå; Department of Paediatrics, University Hospital, Linköping; Centre for Epidemiology, National Board of Health and Welfare, Stockholm; and *Department of Women and Child Health, University Children’s Hospital, S-751 85 Uppsala, Sweden (e-mail: [email protected]) 1
2
3
4
Bergh T, Ericson A, Hillensjö T, Nygren K-G, Wennerholm U-B. Deliveries and children born after in-vitro fertilisation in Sweden 1982-95: a retrospective cohort study. Lancet 1999; 354: 1579–85. Children born in Sweden after in-vitro fertilisation 1982–1997. Stockholm: National Board of Health and Welfare, 2000: 1. Hagberg B, Hagberg G, Beckung E, Uvebrant P. Changing panorama of cerebral palsy in Sweden, VIII: prevalence and origin in the birth year period 1991–94. Acta Paediatr 2001; 90: 271–77. Wolner-Hanssen P, Rydstroem H. Costeffectiveness analysis of in-vitro fertilization: estimated costs per successful pregnancy after transfer of one or two embryos. Hum Reprod 1998; 13: 88–94.
Mammographic screening: no reliable supporting evidence? Sir—In their report, Olli Miettinen and colleagues (Feb 2, p 404)1 add a new analysis to the vital discussion about the role of mammography screening. This role has been challenged by Olsen and Gøtzsche.2 Miettinen and colleagues use the Malmö trial data3 to assess a new endpoint, the so-called case-fatality rate, for which they note a 55% reduction. They conclude that this fall translates to a reduction of cause-specific (ie, breast cancer) mortality. However, their hypothesis is built on the assumption that breast cancer, whenever it occurs, leads inevitably to death (100% mortality) unless it is detected by mammography screening and cured. This hypothesis bears some pitfalls. Not every breast cancer is an immediate killer. In particular, elderly women with breast cancer have a raised chance of dying from natural causes first, especially if the cancer is in an early stage. These cases are known as victims of more sensitive diagnostic techniques—they are classified as breast cancer patients, but would not otherwise have been identified. In a necropsy study from Denmark to investigate the prevalence of invasive and non-invasive breast cancer in women not known to have the disease, a
719
For personal use. Only reproduce with permission from The Lancet Publishing Group.