ARTICLES
Folic acid supplements during early pregnancy and likelihood of multiple births: a population-based cohort study
Zhu Li, Jacqueline Gindler, Hong Wang, R J Berry, Song Li, Adolfo Correa, Jun-chi Zheng, J David Erickson, Yu Wang
Summary
Background Folic acid supplements are recommended for women of childbearing age to prevent neural tube defects in their offspring. Results of some studies, however, suggest an increase in multiple births associated with use of vitamin supplements that contain folic acid during pregnancy. Our aim was to assess this association. Methods We used data from a population-based cohort study from which we assessed the occurrence of multiple births in women (n=242 015) who had participated in a campaign to prevent neural tube defects with folic acid supplements (400 g per day) in China. Folic acid use was ascertained before pregnancy outcome was known. We studied the relation between multiple births and any use of folic acid pills before or during early pregnancy; additionally, we investigated mechanisms by which folic acid could potentially affect the occurrence of multiple births by examining pilltaking at three time periods: before ovulation, around the time of fertilisation, and after conception. Findings 1496 (0·62%) multiple births occurred in a cohort of 242 015 women who had registered with the study between October, 1993, and September, 1995, and who had a pregnancy not affected by a birth defect; the rate of multiple births in women who did and did not take folic acid before or during early pregnancy was 0·59% and 0·65%, respectively (rate ratio 0·91; 95% CI 0·82–1·00). Interpretation Our findings suggest that consumption of folic acid supplements during pregnancy is not associated with an increased occurrence of multiple births. Lancet 2003; 361: 380–84
Introduction
Folic acid use is recommended throughout the world for women of childbearing age.1 Periconceptional consumption of folic acid, or multivitamins that contain folic acid, reduces the risk for neural tube defects2–4 and could reduce the risk for other birth defects.5–9 Although the beneficial effect of folic acid is well established, recent reports10–12 have suggested the possibility of an increase in the occurrence of multiple births among women who used vitamin supplements during pregnancy. However, results of one randomised trial13 of folic acid to prevent neural tube defects indicated no such increase. Most of these reports have focused on the use of folic acid as the purported cause of the increase in twinning, despite the fact that most women took folic acid combined with multivitamins; not folic acid alone. Our aim was to ascertain whether a woman’s use of folic acid supplements before and during early pregnancy is associated with an increased likelihood of multiple birth.
Methods
Identification of cohort We assessed the occurrence of multiple birth in a large cohort of women in China who consumed a daily supplement of folic acid before and during early pregnancy as part of a large population-based community intervention programme of folic acid supplementation to prevent neural tube defects.4 The folic acid community intervention programme was done in selected counties in three provinces in China.4 All pregnant women and women who were preparing for marriage registered with a pregnancy monitoring system that served as the principal record of prenatal care; and the source of demographic information, and dates of last menstrual period and delivery. We identified women who registered with this monitoring system between October, 1993, and September, 1995, and who delivered by December 31, 1996. Because the intervention was designed to measure the effect of folic acid consumption on the occurrence of neural tube defects, the cohort included all women whose fetuses or infants could be confirmed as either having or not having a neural tube defect, whether liveborn or stillborn or electively terminated because of prenatal diagnosis of any birth defect. Miscarriages and other elective terminations that took place before 20 weeks’ gestation were not included in our cohort. The study was approved by the institutional review boards of the Centers for Disease Control and Prevention and Peking University. Use of folic acid Women in the community intervention programme were advised to begin taking pills, containing 400 g of folic acid, every day, starting at the time of registration with the pregnancy monitoring system and continuing until completion of the first trimester of pregnancy. Village health workers distributed pills and submitted monthly reports for each woman, from which we obtained the number of pills taken each month and the dates that folic
The National Centre for Maternal and Infant Health, and the Department of Health Care Epidemiology, Peking University Health Science Centre, Beijing, China (Prof Z Li MD, H Wang MD, Prof S Li MD, J Zheng MD, Y Wang BS); and the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA (J Gindler MD, R J Berry MD, A Correa MD, J D Erickson PhD) Correspondence to: Dr Robert J Berry, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, 4770 Buford Highway, MS F-45, Atlanta, GA 30341, USA (e-mail: rjberry@cdc.gov)
380
THE LANCET • Vol 361 • February 1, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
ARTICLES
acid pill-taking started and stopped, providing a complete record of each woman’s pill taking. We have previously reported14 that the median pill-taking compliance (the total number of pills taken divided by the total number of days between starting and stopping pill taking) was greater than 80%, with more than 90% of women taking pills through to the end of the first trimester. Women who never took folic acid were considered not to have used folic acid. Among women who took folic acid, we used the monthly record of folic acid use to study the relation between multiple births and any use of folic acid before or during early pregnancy. In addition, we assessed folic acid pill-taking at three time periods to investigate the mechanisms by which folic acid could potentially affect the occurrence of multiple births. The first time period was before ovulation, when the likelihood of both dizygotic and monozygotic multiple pregnancies could be affected by folic acid; either the ovary could be stimulated to release more than one egg or a single egg could be programmed to divide and develop into two or more embryos after fertilisation, producing a dizygotic or a monozygotic multiple birth, respectively. The second time period was around the time of fertilisation, when a fertilised egg could be stimulated to divide and develop into two or more embryos, thus resulting in a monozygotic multiple birth. The third time period was after conception, when a multiple pregnancy that might otherwise have ended in miscarriage or loss of one fetus is preserved, and carried to term; a previous analysis of a subgroup of these women showed no difference in the occurrence of miscarriage among supplemented and nonsupplemented women.15 Identification of multiple births We defined a multiple birth as any pregnancy outcome that resulted in the delivery of two or more infants or fetuses, either liveborn or stillborn, at or after a pregnancy of 20 weeks’ gestation. At delivery, the number of infants or fetuses delivered was noted, and a separate delivery form was completed for each. The date and time of birth, sex, and birthweight were recorded, as was the presence of any external structural congenital anomalies. No attempt was made to identify, in the instance of multiple birth, whether same-sex infants or fetuses were monochorionic or dichorionic. To estimate the rate of dizygotic and monozygotic twinning, we used the method described by Weinberg,16 which uses twice the number of unlike-sex twin pairs to estimate the number of dizygotic twins. We used a birth defects surveillance system established for the community intervention programme, which ascertained external structural birth defects identifiable by 6 weeks of age.4 Birth defects arise more frequently among twins, particularly among monozygotic twins,17,18 and evidence exists that folic acid could reduce the occurrence of birth defects other than neural tube defects.5–9 Therefore, folic acid could indirectly affect the occurrence of twinning through the reduction of the occurrence of birth defects. Since we wanted to assess the direct effect of folic acid alone on the occurrence of twinning, we excluded women whose pregnancy ended in the delivery of one or more infants or fetuses with a birth defect. Statistical analysis We compared the numbers of women who had or had not taken folic acid, according to their age at the date of their last menstrual period, body-mass index, parity, ethnic origin, education, and occupation. We calculated the rates and 95% CIs for multiple births among women who had and had not taken any folic acid and among women who
had taken folic acid as defined by the three time periods. We calculated rate ratios by dividing the rate of multiple gestations among women who had taken folic acid by the rate among those who had not, adjusting separately for age, education, and occupation, using stratified analysis. For all rate ratios, we calculated 95% CIs with the Mantel-Haenszel test. Role of the funding source US government employees and Peking University scientists had joint responsibility for study design and analysis, and for interpretation of data. This report received approval for publication from other employees of the US Government.
Results
Of the 247 831 women who had registered within the specified time points, we excluded 5816 (2·3%) whose pregnancy ended in the delivery of one or more infants or fetuses with a birth defect. Among the 242 015 women who had a pregnancy not affected by a birth defect, 127 018 (52·5%) had taken folic acid at some time during pregnancy, and 114 997 (47·5%) had not (table 1). Women who took folic acid were on average 16 months younger than those who did not take folic acid when they became pregnant and were more likely to be having their first baby (table 1). 96·8% of women were of Han ethnicity, the largest ethnic group in China. More than 99% of women delivered a singleton infant or fetus. Of the 1496 (0·62%) multiple births, 1488 (99·5% of multiple births) were twins. Among twins, 1181 (79·4%) were same-sex twins, and 304 (20·4%) were opposite-sex twins. For three sets of twins (0·2%) the sex of at least one infant or fetus was not known. The estimated rate of dizygotic twinning was 2·5/1000 pregnancies, and of monozygotic twinning, 3·6/1000. Overall, the rate of multiple birth was 0·59% among women who took any folic acid and 0·65% among women who did not take folic acid (rate ratio 0·91; 95% CI 0·82–1·00). Rate ratios and 95% CIs were similar for multiple births among women with any folic acid use
Any use of folic acid No use of folic acid (n=127 018) (n=114 997)† Age at pregnancy (mean, SD) (years) Body-mass index (mean, SD) (kg/m2) Primiparous Occupation Farmer Factory worker Other or unknown Amount of education High school or college Junior high school Primary school or less, or unknown Plurality Singleton Multiple Twin Triplet Quadruplet 24·0 (2·4) 20·54 (2·31) 117 210 (92·3%) 72 512 (57·1%) 45 863 (36·1%) 8643 (6·8%) 13 916 (11·0%) 80 896 (63·7%) 32 206 (25·4%) 25·3 (3·7) 20·99 (2·46) 83 048 (72·2%) 76 799 (66·8%) 29 168 (25·4%) 9030 (7·9%) 10 901 (9·5%) 64 262 (55·9%) 39 834 (34·6%)
126 270 (99·41%) 748 (0·59%) 745 (0·59%) 2 (0·002%) 1 (0·001%)
114 249 (99·35%) 748 (0·65%) 743 (0·65%) 5 (0·004%) 0
*Excludes those pregnancies from which any infant or fetus had a birth defect. †Includes 288 women who indicated they intended to take pills but who had taken no pills.
Table 1: Characteristics and pregnancy outcomes of women enrolled in the pregnancy monitoring system who had a pregnancy outcome before January, 1997*
THE LANCET • Vol 361 • February 1, 2003 • www.thelancet.com
381
For personal use. Only reproduce with permission from The Lancet Publishing Group.
ARTICLES
Multiple births Rate of multiple (n=1496) birth (95% CI)
Rate ratio (95% CI) Crude Adjusted for age at last menstrual period 1·00 0·90 (0·82–1·00) Adjusted for occupation 1·00 0·89 (0·81–0·99) Adjusted for education 1·00 0·98 (0·8–1·09)
Use of folic acid pills during pregnancy None (n=114 997) 748 0·65 (0·60–0·70) Any (n=127 018) 748 0·59 (0·55–0·63)
1·00 0·91 (0·82–1·00)
Table 2: Rates of multiple birth and crude and adjusted rate ratios for multiple birth, according to folic acid pill-taking status
overall and for women who used folic acid before ovulation (0·91; 0·82–1·01), around the time of fertilisation (0·90; 0·81–1·00), and after conception (0·91; 0·82–1·00), compared with women who did not use folic acid. Adjustment of the overall rate ratio for maternal age, education, and occupation did not change these results (table 2), nor did the occurrence of samesex twins (0·90; 0·80–1·01) or opposite-sex twins (0·95; 0·76–1·19) differ among women who did and did not take folic acid during pregnancy. Among women who used folic acid supplements, the estimated rates of dizygotic and monozygotic twinning were 2·5/1000 and 3·4/1000 pregnancies, respectively. Among women who did not use folic acid, these rates were 2·6/1000 and 3·9/1000 pregnancies, respectively.
Discussion
Multiple pregnancies result in more complications and poorer outcomes than do singleton pregnancies.19–21 If folic acid consumption before or during pregnancy, or both, were to increase the likelihood of multiple birth, this would likely raise concern among parents and health-care providers. In this large population-based prospective study of a cohort of young women, we noted no increase in the occurrence of multiple births among women who had taken folic acid supplements compared with those who had not taken folic acid. We sought to examine whether rates of multiple births differed among women who did and did not take folic acid during three time periods, during which it is biologically plausible that an exogenous agent could affect the occurrence of multiple birth, and again noted no difference. This finding, though not significant, had 99·9% power at an of 0·05 to detect an increase of 40% over the unexposed rate of 0·65% for all multiple births, and even when restricted to dizygotic multiple births still had 99·6% power at an of 0·05 to detect an increase of 40% over the unexposed rate of 0·26%. Three groups of investigators10–12 have reported that consumption of vitamins or folic acid during pregnancy is associated with an almost 40% increase in multiple birth, raising questions about the safety of vitamin supplementation during pregnancy. In 1994, Czeizel and colleagues10 analysed data from a randomised trial of multivitamins to prevent neural tube defects and reported an increase in the occurrence of infants resulting from multiple births among women who received multivitamins containing 800 g folic acid, compared with women who received only trace elements. The appropriate comparison—the rates of multiple pregnancies in these two groups—was not significantly different (risk ratio 1·49; 0·94–2·38). In 1997, Werler and colleagues11 analysed retrospectively collected data on multiple and singleton births from three separate studies and reported a non-significant 30–60% greater prevalence of periconceptional vitamin supplementation among mothers of multiple rather than singleton births. However, information about supplement use in these studies was obtained retrospectively by interview and did not differentiate among types of vitamin supplements
used. In one of the studies analysed, the increased rate of multiple births was observed only among the malformed infants; the occurrence of multiple birth among nonmalformed infants was lower among women who reported taking vitamin supplements during pregnancy than among those who did not. Finally, Ericson and co-workers12 described an increase in the occurrence of dizygotic twins among women who reported the use of folic acid during early pregnancy in Sweden, compared with the rate of twin births in the entire Swedish population. By contrast with the USA, where about 30% of women of childbearing age take folic acid supplements,22 the overall rate of reported folic acid consumption in this study was less than 1%, and the researchers state that their result was highly confounded by increasing maternal age and the length of involuntary childlessness, raising questions about the representativeness of the women who reported use of folic acid. In a randomised trial of folic acid to prevent neural tube defects, Kirke and colleagues13 reported the occurrence of seven twin pairs. Three were born to women who took folic acid with or without multivitamins, and four were born to women who took multivitamins only or to nonrandomised controls (risk ratio 0·84; 95% CI 0·19–3·69). If the analysis is confined to randomised participants only, the risk ratio is 1·55 (0·16–14·71). If the occurrence of multiple births were affected by consumption of folic acid, the effect might be expected to be greater with increasing folic acid dose; however, this pattern has not been observed. In 1999, Mathews and co-workers23 analysed data from the UK Medical Research Council (MRC) Vitamin study2 in which women took a pill, containing 4000 g folic acid, per day, and from a second, observational study, in which the mean intake of folic acid was 400 g; there was no significant difference in the rates of multiple births reported between supplemented and unsupplemented women.24 Women in our study had equal access to a single community-based maternal and child health-care system, and they received their care at county maternal and child health institutes or at township maternal and child health stations, where sophisticated and expensive health-care procedures, such as assisted reproductive technology, are not available. The lifestyle of the women is very uniform; most were farmers or factory workers and had limited income (
382
THE LANCET • Vol 361 • February 1, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
ARTICLES
conditions, but local stores did not stock any vitamin products. Additionally, findings of our early surveys and focus groups showed no indication that vitamin supplements were available or used by women in the project areas. When this study began, foreignmanufactured prenatal vitamins were starting to become available in Western-style shops in large cities, at a cost of more than US$10 per month. All women were encouraged to take folic acid. The main difference between the groups of women who did and did not use folic acid was whether they registered for prenatal health care before the end of the first trimester of pregnancy. Among women who took folic acid, overall compliance was high, and did not differ by education or occupation.14 Women who did not take folic acid were more likely to be entering the second trimester of their pregnancy for their second child when they first registered for maternal and child health care, and had no opportunity to take periconceptional folic acid. During the campaign, women stopped taking folic acid pills at the end of their first trimester of pregnancy, which means that no woman took folic acid during the second and third trimesters. This limited our assessment of the possibility that use of folic acid after the first trimester might increase the viability of fetuses during a multiple pregnancy. Although our study was not randomised, the conditions in these counties in rural China limit the potential for confounding. The factors most likely to affect the occurrence of multiple births are maternal age, race, ethnic origin, and availability of assisted reproduction technology. These women were all young, primarily primiparous, and members of one Chinese ethnic group with no access to assisted reproduction technologies. We noted negligible differences in educational level, occupation, and age among women who did and did not take folic acid, and controlling for small differences in age at pregnancy, parity, education, and occupation with stratification and multiple logistic regression (data not shown) did not change our results. Another potential limitation of our study is related to the low rate of dizygotic twinning in China. Whereas the rate of monozygotic twinning is constant, at about 3·0–3·5/1000 pregnancies, irrespective of maternal age, ethnic origin, or parity,26 the rate of dizygotic twinning varies by race and other factors, from a high of more than 45/1000 pregnancies in some areas of Nigeria27 to 2–4/1000 pregnancies among individuals from Asia.28–30 Findings of a German study31 show an inverse association between the common methylenetetrahydrofolate reductase 677C→T mutation and the rate of dichorionic twin pregnancies.31 The high reported rate of this mutation in Chinese people is consistent with the low reported rate of dizygotic twinning. Investigators in Australia who modelled the effect of folic acid or multivitamin supplementation, or both, on the occurrence of multiple birth suggested that the low rate of dizygotic twinning in China could limit the applicability of our findings to other countries.32 However, without a better idea of possible mechanisms by which folic acid could increase twinning, such an increase might, in fact, be more easily detected in China than elsewhere, since the baseline rate of dizygotic twinning is low. Our study has additional important strengths. Other studies of multiple births have been done in populations where the rates of twinning might be affected by increasing maternal age and the use of ovarian stimulation.10,12 Our study population comprised a cohort of young women in whom the use of ovarian stimulation is extremely low. Thus, this population could represent a
good group for the study of the occurrence of multiple birth, since we did not need to control for these factors. Another strength of our study is that precise records of pill-taking were collected prospectively, before the outcome of pregnancy was known, thereby minimising the potential for recall bias. Possibly the most important aspect of our study is that, unlike in other studies,10,11 the women consumed a pill containing only 400 g of folic acid. Finally, we could examine the effect of folic acid on twinning without any potential affect of folic acid preventing birth defects. When we included infants with birth defects in our analyses, the rate of twinning in women who took any folic acid before or during early pregnancy was 0·62%, and in women who did not take folic acid was 0·67% (rate ratio 0·92; 95% CI 0·83–1·01); virtually the same result as that noted in the analysis from which infants born with birth defects were excluded. Our findings suggest that consumption of 400 g of folic acid alone per day, before and during early pregnancy, does not increase a woman’s likelihood of having a multiple birth, whether taken before the estimated date of ovulation, around the estimated time of fertilisation, or after conception. In all instances, the rate of multiple birth was lower in women who took folic acid than in those who did not take folic acid.
Contributors
J D Erickson conceived the study; R J Berry and Z Li designed the study, and R J Berry and A Correa supervised all aspects of the analysis. J Gindler and J Zheng did the epidemiological analysis, and R J Berry and A Correa did the statistical analysis. H Wang and S Li supervised all aspects of fieldwork, and Y Wang was responsible for the design of the data collection instruments, computer programming, and data management.
Conflict of interest statement
None declared.
Acknowledgments
We are indebted to the leaders of the Chinese Ministry of Health and Peking University (Zhang Wenkang, Qin Xinhua, Peng Ruicong, Wang Debing, and Yan Renying) without whose support and assistance this project could not have been completed successfully. This work was supported by a cooperative agreement between the Centers for Disease Control and Prevention and Peking University.
References
1 Cornell MC, Erickson JD. Comparison of national policies on periconceptional use of folic acid to prevent spina bifida and anencephaly. Teratology 1997; 55: 134–37. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 338: 131–37. Czeizel AE, Dudás I. Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. N Engl J Med 1992; 327: 1832–35. Berry RJ, Li Z, Erickson JD, et al. Preventing neural-tube defects with folic acid in China. N Engl J Med 1999; 341: 1485–90. Myers MF, Li S, Correa-Villaseñor A, et al. Folic acid supplementation and risk for imperforate anus in China. Am J Epidemiol 2001; 154: 1051–56. Botto LD, Khoury MJ, Mulinare J, Erickson JD. Periconceptional multivitamin use and the occurrence of conotruncal heart defects: results from a population-based case-control study. Pediatrics 1996; 98: 911–17. Li D, Daling JR, Mueller BA, Hickok DE, Gantel AG, Weiss NS. Periconceptional multivitamin use in relation to the risk of congenital urinary tract anomalies. Epidemiology 1995; 6: 212–18. Tolarova M, Harris J. Reduced recurrence of orofacial clefts after periconceptional supplementation with high-dose folic acid and multivitamins. Teratology 1995; 51: 71–78. Shaw GM, O’Malley CD, Wasserman CR, Tolarova MM, Lammer EJ. Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Am J Med Genet 1995; 59: 536–45.
2
3
4 5
6
7
8
9
THE LANCET • Vol 361 • February 1, 2003 • www.thelancet.com
383
For personal use. Only reproduce with permission from The Lancet Publishing Group.
ARTICLES
10 Czeizel AE, Métneki J, Dudás I. The higher rate of multiple births after periconceptional multivitamin supplementation: an analysis of causes. Acta Genet Med Gemellol (Roma) 1994; 43: 175–84. 11 Werler MM, Cragan JD, Wasserman CR, Shaw GM, Erickson JD, Mitchell AA. Multivitamin supplementation and multiple births. Am J Med Genet 1997; 71: 93–96. 12 Ericson A, Källén B, Áberg A. Use of multivitamins and folic acid in early pregnancy and multiple births in Sweden. Twin Research 2001; 4: 63–66. 13 Kirke PN, Daly LE, Elwood JH, for the Irish Vitamin Study Group. A randomized trial of low dose folic acid to prevent neural tube defects. Arch Dis Child 1992; 67: 1442–46. 14 Berry RJ, Li Z. Folic acid alone prevents neural tube defects: evidence from the China study. Epidemiology 2002; 13: 114–16. 15 Gindler J, Li Z, Berry RJ, et al. Folic acid supplements during pregnancy and risk of miscarriage. Lancet 2001; 358: 796–800. 16 Vogel F, Motulsky AG, Human genetics: problems and approaches, 3rd edn. Berlin: Springer, 1997: 230. 17 Mastroiacovo P, Botto L. Structural congenital defects in multiple births. Acta Genet Med Gemellol (Roma) 1994; 43: 57–70. 18 Luke B, Keith LG. Monozygotic twinning as a congenital defect and congenital defects in monozygotic twins. Fetal Diagn Ther 1990; 5: 61–69. 19 Sibai BM, Hauth J, Caritis S, et al. Hypertensive disorders in twin versus singleton gestations. Am J Obstet Gynecol 2000; 182: 938–42. 20 Schwartz DB, Daoud Y, Zazula P, et al. Gestational diabetes mellitus: metabolic and blood glucose parameters in singleton versus twin pregnancies. Am J Obstet Gynecol 1999; 181: 912–14. 21 Kinzler Wl, Ananth CV, Vintzileos AM. Medical and economic effects of twin gestations. J Soc Gynecol Investig 2000; 7: 321–27.
22 Anon. Folic acid and the prevention of birth defects: a national survey of pre-pregnancy awareness and behavior among women of childbearing age, 1995–2001. Conducted by the Gallup Organization. March of Dimes. August, 2001. http://marchofdimes/professionals/ 1689.asp (accessed Nov 25, 2002). 23 Mathews F, Yudkin P, Neil A. Folates in the peri-conceptional period: are women getting enough? Br J Obstet Gynaecol 1998; 105: 954–59. 24 Mathews F, Murphy M, Wald NJ, Hackshaw A. Twinning and folic acid use. Lancet 1999; 353: 291–92. 25 Yang G, Fan L, Tan J, et al. Smoking in China: findings of the 1996 national prevalence survey. JAMA 1999; 282: 1247–53. 26 Little J, Thompson B. Descriptive epidemiology. In: MacGillivray I, Campbell DM, Thompson B, eds. Twinning and twins. New York: Wiley, 1988: 37–66. 27 Nylander PP. The twinning incidence of Nigeria. Acta Genet Med Gemellol (Roma) 1979; 28: 261–63. 28 Whipley PW, Wray JA, Hyman HH, Arellano MG, Borhani NO. Frequency of twinning in California: its relationship to maternal age, parity and race. Am J Epidemiol 1966; 85: 147–56. 29 Pollard R. Ethnic comparison of twinning rates in California. Hum Biol 1995; 67: 921–31. 30 Chen C-J, Lin T-M, Chang C, Cheng Y-J. Epidemiological characteristics of twinning rates in Taiwan. Acta Genet Med Gemellol (Roma) 1987; 36: 335–42. 31 Hasbargen U, Lohse P, Thaler CJ. The number of dichorionic twin pregnancies is reduced by the common MTHFR 677C→T mutation. Hum Reprod 2000; 15: 2659–62. 32 Lumley J, Watson L, Watson M, Bower C. Modelling the potential impact of population-wide periconceptional folate/multivitamin supplementation on multiple births. Br J Obstet Gynaecol 2001; 108: 937–42.
Clinical picture
Purpura fulminans
Keleigh S Culpeper, H Carlos Nousari
A 78-year-old man with history of myeloproliferative syndrome and an uncharacterised circulating anticoagulant had an elective tracheostomy. Immediately after surgery he developed disseminated haemorrhagic skin necrosis (figure, upper) that histologically showed noninflammatory microvascular fibrin deposits (figure, lower). He was afebrile and normotensive. Before surgery he had received vitamin K and -aminocaproic acid. Blood tests showed anti-prothrombin antibodies and prolonged activated partial thromboplastin and prothrombin times which were uncorrected by plasmamixing studies. He had no abnormalities in cryoglobulin, D-dimer, anti-cardiolipin, anti- 2-glycoprotein 1, or antiannexin-5 antibody levels, and blood and urine cultures were sterile. He fully recovered after 6 weeks of supportive care. Catastrophic antiphospholipid syndrome presents with microvascular thrombosis of the skin (purpura fulminans) and other organs, as does disseminated intravascular coagulation. This syndrome, unlike sepsisassociated purpura fulminans, may carry a good prognosis, be triggered by surgery and procoagulants, and be associated with antibodies other than those to cardiolipin.
Division of Immunodermatology (H Carlos Nousari MD, K S Culpeper MD), Johns Hopkins Medical Institutions, Baltimore, MD 20905, USA
384
THE LANCET • Vol 361 • February 1, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.