Impact of misclassification of in vitro fertilisation in studies of fo
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《英国医生杂志》
1 National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Department of Health and Human Services, 1600 Clifton Road, MS E-86, Atlanta, GA 30333, USA, 2 Riddarv?gen 37B, 184 51, ?stersk?r, Stockholm, Sweden
Correspondence to: R J Berry RJBerry@cdc.gov
Objective To determine whether failure to adequately adjust for a reported 40% misclassification of use of in vitro fertilisation (IVF) as reported in a Swedish study could have led to a false finding that folic acid increases dizygotic twinning.
Design Modelling with population based data.
Setting Swedish vital records for 1995-9.
Main outcome measures Rates of twinning calculated according to whether women used IVF to become pregnant. Estimated unadjusted and adjusted odds ratios of the association between use of folic acid and twinning by use of IVF.
Results In 1995-9, Swedish women who used IVF had an almost 20 times the chance of having twins than women who did not use IVF (rate ratio 19.7, 95% confidence interval 18.7 to 20.6). In the absence of a true effect of folic acid, the use of a 40% misclassified surrogate variable to adjust for use of IVF would have resulted in a false finding that folic acid was associated with a more than twofold increase in twinning.
Conclusion Use of IVF is a strong confounder because it is associated with both use of folic acid and twinning. Even when misclassification of IVF was reduced to 5%, this bias persisted in the adjusted model. Using a 40% misclassified surrogate to adjust for IVF, as reported in the Swedish study, probably led to a false finding that folic acid increased dizygotic twinning.
Folic acid is recommended throughout most of the world for women of childbearing age to prevent neural tube defects.1 No European country, however, has implemented mandatory fortification of food, partly because of concerns that use of folic acid is associated with an increased risk of twinning.2 3 A Swedish study found that use of folic acid was associated with a more than twofold increase in dizygotic twinning,2 but the analysis included 40% of the women who had used in vitro fertilisation (IVF) but were not identified as having done so in the Swedish medical birth registry.4 The strong association of IVF with both twinning5 and the use of vitamins make it a potentially strong confounder. Adjustment for a confounder using a misclassified surrogate variable can lead to substantial bias.6 The authors of the Swedish paper claimed they had adjusted for all confounding but did not provide numbers and rates of twinning for women who used IVF by their use of folic acid, which we have previously discussed.7 8 Recently available reports on Swedish vital records have enabled us to calculate background rates of twinning by women's use of IVF.9 10 We used these rates along with data and assumptions based on findings reported in the original Swedish study to model the conditions in which that study was conducted. We used probabilistic simulations to assess bias caused by misclassification of the use of IVF.
Method
Definitions—IVF does not include use of ovarian-stimulating drugs alone, but does include all other assisted reproductive technologies as defined in Swedish reports.9 11
Rates from database—We used numbers of births and twin pregnancies for the years 1995-9 from Swedish vital records9 10 to calculate rates of twinning for women who did and did not use IVF. We defined twinning as the number of pregnancies resulting in a twin birth. The Swedish study reported that 8% of women used folic acid during pregnancy; however, only 0.6% of the women in their analysis actually reported using folic acid.2
Assumptions—In all models we assumed that folic acid does not cause twinning. Our assumption that 50% of women who used IVF took folic acid was supported by a statement in the original study: "folic acid supplementation is often given, notably at IVF."2
Unadjusted analysis—We used rates of use of folic acid to estimate the number of women who did and did not use folic acid and used the total numbers to calculate the unadjusted rate ratio and 95% confidence intervals for the observed association between folic acid and twinning. We then used different estimates of use of folic acid in Sweden to assess how the unadjusted rate ratio would change.
Adjusted analysis—We used a probabilistic simulation model to examine the effect on the Mantel-Haenszel odds ratio of adjustment with a misclassified surrogate variable for use of IVF and an under-reported measure of the use of folic acid (see details of analysis on bmj.com).
Results
During the five year period 1995-9, the rate of twinning in Sweden was 1.5% (6960/450 697). During this period 1.8% (7958/450 697) of all deliveries and 26.1% (1814/6960) of all twin deliveries occurred among women who used IVF. The rates of twinning were 22.8% (1814/7958) among women who used IVF and 1.2% (5146/442 739) among women who did not. Women who used IVF were almost 20 times more likely than those who did not use IVF to have a twin pregnancy (rate ratio 19.7, 95% confidence interval 18.7 to 20.6). We have excluded triplets and higher order births from all tables (n = 138).
In the absence of a true effect of folic acid, a 50% use of folic acid among women who used IVF and an 8% use among those who did not use IVF produces a unadjusted rate ratio of 2.44 (P < 0.0001) for the false association between folic acid and increased twinning (table 1). Table 2 shows how varying the rates of use of folic acid among women who used IVF from 25% to 90% and among women who did not use IVF from 4% to 12% produced highly significant unadjusted rate ratios that varied from 1.31 to 6.15.
Table 1 Numbers of singleton and twin births by use of in vitro fertilisation (IVF) and unadjusted rate ratio and 95% confidence intervals for observed association between estimated use of folic acid and twinning (based on Swedish vital records 1995-9*)
Table 2 Estimated unadjusted rate ratios for observed association between estimated use of folic acid during pregnancy and twinning according to estimated use of folic acid among women who did and did not use in vitro fertilisation (IVF) (based on Swedish vital records, 1995-9*)
In the absence of a true effect of folic acid, the use of a 40% misclassified surrogate variable to adjust for use of IVF in the adjusted analysis would have resulted in a finding that folic acid was associated with a more than twofold increase in twinning (see table A on bmj.com).
Discussion
Cornell MC, Erickson JD. Comparison of national policies on periconceptional use of folic acid to prevent spina bifida and anencephaly. Teratology 1997;55: 134-7.
Ericson A, K?llén B, áberg A. Use of multivitamins and folic acid in early pregnancy and multiple births in Sweden. Twin Res 2001;4: 63-6.
Czeizel AE, Metneki J, Dudas I. The higher rate of multiple births after periconceptional multivitamin supplementation: an analysis of causes. Acta Genet Med Gemellol (Roma) 1994;43: 175-84.
EpC Research Report. The Swedish medical birth registry—a summary of content and quality. Stockholm, Sweden: National Board of Health and Welfare, 2003 (article 2003-112-3).
Bergh T, Ericson A, Hillensj? T, Nygren K-G, Wennerholm U-B. Deliveries and children born after in-vitro fertilization in Sweden 1982-95: a retrospective cohort study. Lancet 1999;354: 1579-85.
Marshall J. Methodologic and statistical considerations regarding use of biomarkers of nutritional exposure in epidemiology. J Nutr 2003;133: 881-7S.
Li Z, Gindler J, Wang H, Berry RJ, Li S, Correa A, et al. Folic acid supplements during early pregnancy and likelihood of multiple births: a population based cohort study. Lancet 2003;361: 380-84.
Kihlberg R, Bui T-H, Nielsen T, S?derhjelm L. Studien visar inte att folsyra ?kar risk f?r tvillingf?dsel. . Dagens Medicin 2002;41: 38.
EpC Report. Assisterad befruktning 2001. . Stockholm, Sweden: National Board of Health and Welfare, 2004 (article 2004-42-4).
EpC Report. Fakta om mammor, f?rlossningar och nyf?dda barn-Medicinska f?delseregistret 1973 till 2000. Stockholm, Sweden: National Board of Health and Welfare; 2002 (article 2002-125-12). (Tables updated to 2002 on 9 August 2004.)
EpC Report. Barn f?dda i Sverige efter provr?rsbefruktning 1982-1997. Stockholm, Sweden: National Board of Health and Welfare, 2000 (article 2000-18-001).
K?llén B. Use of folic acid supplements and risk for dizygotic twinning. Early Hum Dev 2004;80: 143-51.
Czeizel AE, Vargha P. Periconceptional folic acid/multivitamin supplementation and twin pregnancy. Am J Obstet Gynecol 2004;191: 790-4.
K?llén B, Olausson P-O, Nygren K-G. Neonatal outcome in pregnancies from ovarian stimulation. Obstet Gynecol 2002;100: 414-9.
Ericson A, Nygren KG, Olausson PO, K?llén B. Hospital care utilization of infants born after IVF. Hum Reprod 2002;17: 929-32.
George L, Mills JL, Johansson ALV, Nordmark A, Olander B, Granath F, et al. Plasma folate levels and risk of spontaneous abortion. JAMA 2002;288: 1867-73.
Kinzler Wl, Ananth CV, Vintzileos AM. Medical and economic effects of twin gestations. J Soc Gynecol Investig 2000;7: 321-7.
Lumley J, Watson L, Watson M, Bower C. Modelling the potential impact of population-wide periconceptional folate/multivitamin supplementation on multiple births. BJOG 2001;108: 937-42.
Waller DK, Tita ATN, Annegers JF. Rates of twinning before and after fortification of foods in the US with folic acid, Texas, 1996 to 1998. Paediatr Perinat Epidemiol 2003;17: 378-83.
Shaw GM, Carmichael SL, Nelson V, Selvin S, Schaffer DM. Food fortification with folic acid and twinning among California infants. Am J Med Genet 2003;119A: 137-40.
Kucik J, Correa A. Trends in twinning rates in metropolitan Atlanta before and after folic acid fortification. J Reprod Med 2004;49: 707-12.
((R J Berry, medical epidemiologist1, R Ki)
Correspondence to: R J Berry RJBerry@cdc.gov
Objective To determine whether failure to adequately adjust for a reported 40% misclassification of use of in vitro fertilisation (IVF) as reported in a Swedish study could have led to a false finding that folic acid increases dizygotic twinning.
Design Modelling with population based data.
Setting Swedish vital records for 1995-9.
Main outcome measures Rates of twinning calculated according to whether women used IVF to become pregnant. Estimated unadjusted and adjusted odds ratios of the association between use of folic acid and twinning by use of IVF.
Results In 1995-9, Swedish women who used IVF had an almost 20 times the chance of having twins than women who did not use IVF (rate ratio 19.7, 95% confidence interval 18.7 to 20.6). In the absence of a true effect of folic acid, the use of a 40% misclassified surrogate variable to adjust for use of IVF would have resulted in a false finding that folic acid was associated with a more than twofold increase in twinning.
Conclusion Use of IVF is a strong confounder because it is associated with both use of folic acid and twinning. Even when misclassification of IVF was reduced to 5%, this bias persisted in the adjusted model. Using a 40% misclassified surrogate to adjust for IVF, as reported in the Swedish study, probably led to a false finding that folic acid increased dizygotic twinning.
Folic acid is recommended throughout most of the world for women of childbearing age to prevent neural tube defects.1 No European country, however, has implemented mandatory fortification of food, partly because of concerns that use of folic acid is associated with an increased risk of twinning.2 3 A Swedish study found that use of folic acid was associated with a more than twofold increase in dizygotic twinning,2 but the analysis included 40% of the women who had used in vitro fertilisation (IVF) but were not identified as having done so in the Swedish medical birth registry.4 The strong association of IVF with both twinning5 and the use of vitamins make it a potentially strong confounder. Adjustment for a confounder using a misclassified surrogate variable can lead to substantial bias.6 The authors of the Swedish paper claimed they had adjusted for all confounding but did not provide numbers and rates of twinning for women who used IVF by their use of folic acid, which we have previously discussed.7 8 Recently available reports on Swedish vital records have enabled us to calculate background rates of twinning by women's use of IVF.9 10 We used these rates along with data and assumptions based on findings reported in the original Swedish study to model the conditions in which that study was conducted. We used probabilistic simulations to assess bias caused by misclassification of the use of IVF.
Method
Definitions—IVF does not include use of ovarian-stimulating drugs alone, but does include all other assisted reproductive technologies as defined in Swedish reports.9 11
Rates from database—We used numbers of births and twin pregnancies for the years 1995-9 from Swedish vital records9 10 to calculate rates of twinning for women who did and did not use IVF. We defined twinning as the number of pregnancies resulting in a twin birth. The Swedish study reported that 8% of women used folic acid during pregnancy; however, only 0.6% of the women in their analysis actually reported using folic acid.2
Assumptions—In all models we assumed that folic acid does not cause twinning. Our assumption that 50% of women who used IVF took folic acid was supported by a statement in the original study: "folic acid supplementation is often given, notably at IVF."2
Unadjusted analysis—We used rates of use of folic acid to estimate the number of women who did and did not use folic acid and used the total numbers to calculate the unadjusted rate ratio and 95% confidence intervals for the observed association between folic acid and twinning. We then used different estimates of use of folic acid in Sweden to assess how the unadjusted rate ratio would change.
Adjusted analysis—We used a probabilistic simulation model to examine the effect on the Mantel-Haenszel odds ratio of adjustment with a misclassified surrogate variable for use of IVF and an under-reported measure of the use of folic acid (see details of analysis on bmj.com).
Results
During the five year period 1995-9, the rate of twinning in Sweden was 1.5% (6960/450 697). During this period 1.8% (7958/450 697) of all deliveries and 26.1% (1814/6960) of all twin deliveries occurred among women who used IVF. The rates of twinning were 22.8% (1814/7958) among women who used IVF and 1.2% (5146/442 739) among women who did not. Women who used IVF were almost 20 times more likely than those who did not use IVF to have a twin pregnancy (rate ratio 19.7, 95% confidence interval 18.7 to 20.6). We have excluded triplets and higher order births from all tables (n = 138).
In the absence of a true effect of folic acid, a 50% use of folic acid among women who used IVF and an 8% use among those who did not use IVF produces a unadjusted rate ratio of 2.44 (P < 0.0001) for the false association between folic acid and increased twinning (table 1). Table 2 shows how varying the rates of use of folic acid among women who used IVF from 25% to 90% and among women who did not use IVF from 4% to 12% produced highly significant unadjusted rate ratios that varied from 1.31 to 6.15.
Table 1 Numbers of singleton and twin births by use of in vitro fertilisation (IVF) and unadjusted rate ratio and 95% confidence intervals for observed association between estimated use of folic acid and twinning (based on Swedish vital records 1995-9*)
Table 2 Estimated unadjusted rate ratios for observed association between estimated use of folic acid during pregnancy and twinning according to estimated use of folic acid among women who did and did not use in vitro fertilisation (IVF) (based on Swedish vital records, 1995-9*)
In the absence of a true effect of folic acid, the use of a 40% misclassified surrogate variable to adjust for use of IVF in the adjusted analysis would have resulted in a finding that folic acid was associated with a more than twofold increase in twinning (see table A on bmj.com).
Discussion
Cornell MC, Erickson JD. Comparison of national policies on periconceptional use of folic acid to prevent spina bifida and anencephaly. Teratology 1997;55: 134-7.
Ericson A, K?llén B, áberg A. Use of multivitamins and folic acid in early pregnancy and multiple births in Sweden. Twin Res 2001;4: 63-6.
Czeizel AE, Metneki J, Dudas I. The higher rate of multiple births after periconceptional multivitamin supplementation: an analysis of causes. Acta Genet Med Gemellol (Roma) 1994;43: 175-84.
EpC Research Report. The Swedish medical birth registry—a summary of content and quality. Stockholm, Sweden: National Board of Health and Welfare, 2003 (article 2003-112-3).
Bergh T, Ericson A, Hillensj? T, Nygren K-G, Wennerholm U-B. Deliveries and children born after in-vitro fertilization in Sweden 1982-95: a retrospective cohort study. Lancet 1999;354: 1579-85.
Marshall J. Methodologic and statistical considerations regarding use of biomarkers of nutritional exposure in epidemiology. J Nutr 2003;133: 881-7S.
Li Z, Gindler J, Wang H, Berry RJ, Li S, Correa A, et al. Folic acid supplements during early pregnancy and likelihood of multiple births: a population based cohort study. Lancet 2003;361: 380-84.
Kihlberg R, Bui T-H, Nielsen T, S?derhjelm L. Studien visar inte att folsyra ?kar risk f?r tvillingf?dsel. . Dagens Medicin 2002;41: 38.
EpC Report. Assisterad befruktning 2001. . Stockholm, Sweden: National Board of Health and Welfare, 2004 (article 2004-42-4).
EpC Report. Fakta om mammor, f?rlossningar och nyf?dda barn-Medicinska f?delseregistret 1973 till 2000. Stockholm, Sweden: National Board of Health and Welfare; 2002 (article 2002-125-12). (Tables updated to 2002 on 9 August 2004.)
EpC Report. Barn f?dda i Sverige efter provr?rsbefruktning 1982-1997. Stockholm, Sweden: National Board of Health and Welfare, 2000 (article 2000-18-001).
K?llén B. Use of folic acid supplements and risk for dizygotic twinning. Early Hum Dev 2004;80: 143-51.
Czeizel AE, Vargha P. Periconceptional folic acid/multivitamin supplementation and twin pregnancy. Am J Obstet Gynecol 2004;191: 790-4.
K?llén B, Olausson P-O, Nygren K-G. Neonatal outcome in pregnancies from ovarian stimulation. Obstet Gynecol 2002;100: 414-9.
Ericson A, Nygren KG, Olausson PO, K?llén B. Hospital care utilization of infants born after IVF. Hum Reprod 2002;17: 929-32.
George L, Mills JL, Johansson ALV, Nordmark A, Olander B, Granath F, et al. Plasma folate levels and risk of spontaneous abortion. JAMA 2002;288: 1867-73.
Kinzler Wl, Ananth CV, Vintzileos AM. Medical and economic effects of twin gestations. J Soc Gynecol Investig 2000;7: 321-7.
Lumley J, Watson L, Watson M, Bower C. Modelling the potential impact of population-wide periconceptional folate/multivitamin supplementation on multiple births. BJOG 2001;108: 937-42.
Waller DK, Tita ATN, Annegers JF. Rates of twinning before and after fortification of foods in the US with folic acid, Texas, 1996 to 1998. Paediatr Perinat Epidemiol 2003;17: 378-83.
Shaw GM, Carmichael SL, Nelson V, Selvin S, Schaffer DM. Food fortification with folic acid and twinning among California infants. Am J Med Genet 2003;119A: 137-40.
Kucik J, Correa A. Trends in twinning rates in metropolitan Atlanta before and after folic acid fortification. J Reprod Med 2004;49: 707-12.
((R J Berry, medical epidemiologist1, R Ki)