- Email: [email protected]
Outcomes in pregnancy
Proportion patients free from event (%)
CORRESPONDENCE
Outcomes in pregnancy
Atenolol Losartan
100 97 94 91 88 85 82 79 76 73 70 0
Events (%) Rate Losartan 123 (21·0) 46·8 Atenolol 170 (27·9) 65·6 p=0·009
0
12
24
36
48
60
484 472
237 204
Study month Losartan 586 Atenolol 609
558 562
532 540
513 507
Rate expressed per 1000 patient-years of follow-up Adjusted relative risk=27%. Adjusted for degree of left-ventricular hypertrophy and Framingham risk score at randomisation.
reassure Jeffrey Bloom that the difference in outcome between losartan-treated and atenolol-treated patients was present after adjustment for the minor differences at baseline. As we stated, there was a drop in the relative risk reduction of the primary composite endpoint from 26·7% (p=0·017) for unadjusted values to 24·5% (p=0·031) for adjusted. Bloom also states that the patients’ diabetes care was suboptimum, and we agree. That care was, however, at the discretion of the physicians, and did not differ between treatment groups. The change in weight during the study was essentially the same in the losartan-treated and atenolol-treated patients, from 84·3 kg to 82·5 kg and from 84·3 to 82·6 kg, respectively. Michael Bursztyn points out a difference in relative risk reduction of stroke in all patients compared with patients with diabetes. To us, the reductions were similar, 24·9% (p=0·001) versus 21·2% (p=0·204). The difference in the numbers of patients (9193 versus 1195) probably explains the difference in the statistical outcome. Explanatory factors for the difference in new-onset diabetes are sought by Jøran Hjelmesæth and Per-Ola Carlsson. Within-study explanatory factors for new-onset diabetes, and insulin sensitivity will be communicated in future reports.1 *Lars H Lindholm, Björn Dahlöf *Department of Public Health and Clinical Medicine, Umeå University Hospital, SE 901 85 Umeå, Sweden; and Göteborg University, Department of Medicine, Sahlgrenska University Hospital, Göteborg (e-mail: [email protected]) 1
Lindholm LH, Ibsen H, Borch-Johnsen K, et al. New-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE). J Hypertens (in press).
2204
Sir—The hypothesis proposed by Luc Smits and Gerard Essed (Dec 15, p 2074)1 on the role of folate depletion and unfavourable pregnancy outcomes after short interpregnancy intervals contributes substantially to the governing folate paradigm. They report that the teratogenic effects of folate depletion and folate supplementation on the risk of spontaneous abortion and other reproductive casualties are less clear. Folic acid has been suggested as a prerequisite for optimum maturation of the oocyte and inherent favourable outcome, since deficiency is reported to depress the concentrations of oestradiol and progestagen in Rhesus monkeys and to slow down the replication of the granulosa cells, the principal cells in the ovarian follicle. This action results in a reduction of the growth of the follicle and in delayed ovulation, as markers for retardation of embryonic growth and malformations.2 The oocyte and the hormonal conditions that guarantee its optimum maturation play an important part in the causation of unfavourable pregnancy outcomes, as proven in animal experiments and circumstantially shown in human beings.3 The hormonal indications for the first postpartum ovulation are characterised, if not by anovulation, then by lengthened follicular (preovulatory) phases and decreased pregnanediol excretion during the luteal (postovulatory) phases. Folate thus helps to explain the continuum of reproductive wastage in the conditions under which its reserve is depleted— eg, short interpregnancy intervals. Under conditions in which folate is not expected to be depleted, or rather is replenished, however—eg, in advanced maternal age or after long interpregnancy intervals—this theory does not hold, and over-ripeness of ova may cause difficulties. In older women, the reproductive hormone concentrations and ovulatory pattern are liable, and in long interpregnancy intervals they remain in a phase of restoration after a transient anovulatory period. The prevalence of spina bifida is higher after a long interval,4 as is that of other reproductive wastage, whereas optimum intervals of about 2–3 years are advised by Smits and Essed. Both the downward and upward trends of this U-shaped curve related to interval duration are, therefore, caused by restoration of the ovulatory pattern, the former after parturition, the latter after transient anovulation because of endocrinological disturbances, chrono-
logical ageing, or seasonal factors.3 In addition, folate concentration, as mentioned by Smits and Essed, decreases from month 5 of pregnancy onwards in maternal serum, plasma, and erythrocytes and, thus, entrains a cumulative drain in advanced pregnancy. However, an inverse relation between interval length and fetal deaths is surprisingly more apparent in the second than in the third trimester,5 in which folate depletion would be more severe. Finally, the shift in sex ratios and the increase in occurrence of (particularly monozygotic) twins or meiotic (or early mitotic) nondisjunctions after very short interpregnancy intervals and inadequate folate supplementation can be understood only by the involvement of the oocyte. These epidemiological enigmata show the paramount effect of oocyte maturation and support the suggestion of its key role in the folate paradigm. *P H Jongbloet, S A Zielhuis, P C M Pasker-de Jong Department of Epidemiology and Biostatistics, University Medical Centre, PB 9101 Nijmegen, Netherlands 1
2
3
4
5
Smits LJM, Essed GGM. Short interpregnancy intervals and unfavourable pregnancy outcome: role of folate depletion. Lancet 2001; 358: 2074–77. Wynn M, Wynn A. No nation can rise above the level of its women: new thoughts on maternal nutrition—the Caroline Walker lecture 1993. London: Caroline Walker Trust: 1–39. Jongbloet PH, Zielhuis GA, Groenewoud HMM, Pasker-de Jong PCM. The secular trends in male:female ratio at birth in postwar industrialized countries. Environ Health Perspect 2001; 109: 749–52. Doherty M, Watkins M, Khoury MJ. Pregnancy interval and risk for neural tube defects: a population-based study. Am J Epidemiol 1996; 143: S47,186 (abstr). Swenson I, Harper PA. The relation between fetal wastage and pregnancy spacing in Bangladesh. Soc Biol 1978; 25: 251–56.
Sir—In response to Luc Smits and discussion of Gerard Essed’s1 unfavourable pregnancy outcomes, I have presented some data for liveborn babies with no congenital abnormalities in Hungary, 1980–96.2 We assessed birthweight and gestational age in babies born to women taking multivitamins (including folic acid 0·1–1·0 mg) and folic acid (3–6 mg), only multivitamins, only folic acid, or no supplementation during the third trimester of pregnancy. Previously we had shown no difference in the mean birthweight and gestational age between women taking periconceptional supplementation of multivitamins, including folic acid, and placebo-like trace elements.3 In the new analysis we aimed to test the
THE LANCET • Vol 359 • June 22, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
Outcomes in pregnancy
Atenolol Losartan
100 97 94 91 88 85 82 79 76 73 70 0
Events (%) Rate Losartan 123 (21·0) 46·8 Atenolol 170 (27·9) 65·6 p=0·009
0
12
24
36
48
60
484 472
237 204
Study month Losartan 586 Atenolol 609
558 562
532 540
513 507
Rate expressed per 1000 patient-years of follow-up Adjusted relative risk=27%. Adjusted for degree of left-ventricular hypertrophy and Framingham risk score at randomisation.
reassure Jeffrey Bloom that the difference in outcome between losartan-treated and atenolol-treated patients was present after adjustment for the minor differences at baseline. As we stated, there was a drop in the relative risk reduction of the primary composite endpoint from 26·7% (p=0·017) for unadjusted values to 24·5% (p=0·031) for adjusted. Bloom also states that the patients’ diabetes care was suboptimum, and we agree. That care was, however, at the discretion of the physicians, and did not differ between treatment groups. The change in weight during the study was essentially the same in the losartan-treated and atenolol-treated patients, from 84·3 kg to 82·5 kg and from 84·3 to 82·6 kg, respectively. Michael Bursztyn points out a difference in relative risk reduction of stroke in all patients compared with patients with diabetes. To us, the reductions were similar, 24·9% (p=0·001) versus 21·2% (p=0·204). The difference in the numbers of patients (9193 versus 1195) probably explains the difference in the statistical outcome. Explanatory factors for the difference in new-onset diabetes are sought by Jøran Hjelmesæth and Per-Ola Carlsson. Within-study explanatory factors for new-onset diabetes, and insulin sensitivity will be communicated in future reports.1 *Lars H Lindholm, Björn Dahlöf *Department of Public Health and Clinical Medicine, Umeå University Hospital, SE 901 85 Umeå, Sweden; and Göteborg University, Department of Medicine, Sahlgrenska University Hospital, Göteborg (e-mail: [email protected]) 1
Lindholm LH, Ibsen H, Borch-Johnsen K, et al. New-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE). J Hypertens (in press).
2204
Sir—The hypothesis proposed by Luc Smits and Gerard Essed (Dec 15, p 2074)1 on the role of folate depletion and unfavourable pregnancy outcomes after short interpregnancy intervals contributes substantially to the governing folate paradigm. They report that the teratogenic effects of folate depletion and folate supplementation on the risk of spontaneous abortion and other reproductive casualties are less clear. Folic acid has been suggested as a prerequisite for optimum maturation of the oocyte and inherent favourable outcome, since deficiency is reported to depress the concentrations of oestradiol and progestagen in Rhesus monkeys and to slow down the replication of the granulosa cells, the principal cells in the ovarian follicle. This action results in a reduction of the growth of the follicle and in delayed ovulation, as markers for retardation of embryonic growth and malformations.2 The oocyte and the hormonal conditions that guarantee its optimum maturation play an important part in the causation of unfavourable pregnancy outcomes, as proven in animal experiments and circumstantially shown in human beings.3 The hormonal indications for the first postpartum ovulation are characterised, if not by anovulation, then by lengthened follicular (preovulatory) phases and decreased pregnanediol excretion during the luteal (postovulatory) phases. Folate thus helps to explain the continuum of reproductive wastage in the conditions under which its reserve is depleted— eg, short interpregnancy intervals. Under conditions in which folate is not expected to be depleted, or rather is replenished, however—eg, in advanced maternal age or after long interpregnancy intervals—this theory does not hold, and over-ripeness of ova may cause difficulties. In older women, the reproductive hormone concentrations and ovulatory pattern are liable, and in long interpregnancy intervals they remain in a phase of restoration after a transient anovulatory period. The prevalence of spina bifida is higher after a long interval,4 as is that of other reproductive wastage, whereas optimum intervals of about 2–3 years are advised by Smits and Essed. Both the downward and upward trends of this U-shaped curve related to interval duration are, therefore, caused by restoration of the ovulatory pattern, the former after parturition, the latter after transient anovulation because of endocrinological disturbances, chrono-
logical ageing, or seasonal factors.3 In addition, folate concentration, as mentioned by Smits and Essed, decreases from month 5 of pregnancy onwards in maternal serum, plasma, and erythrocytes and, thus, entrains a cumulative drain in advanced pregnancy. However, an inverse relation between interval length and fetal deaths is surprisingly more apparent in the second than in the third trimester,5 in which folate depletion would be more severe. Finally, the shift in sex ratios and the increase in occurrence of (particularly monozygotic) twins or meiotic (or early mitotic) nondisjunctions after very short interpregnancy intervals and inadequate folate supplementation can be understood only by the involvement of the oocyte. These epidemiological enigmata show the paramount effect of oocyte maturation and support the suggestion of its key role in the folate paradigm. *P H Jongbloet, S A Zielhuis, P C M Pasker-de Jong Department of Epidemiology and Biostatistics, University Medical Centre, PB 9101 Nijmegen, Netherlands 1
2
3
4
5
Smits LJM, Essed GGM. Short interpregnancy intervals and unfavourable pregnancy outcome: role of folate depletion. Lancet 2001; 358: 2074–77. Wynn M, Wynn A. No nation can rise above the level of its women: new thoughts on maternal nutrition—the Caroline Walker lecture 1993. London: Caroline Walker Trust: 1–39. Jongbloet PH, Zielhuis GA, Groenewoud HMM, Pasker-de Jong PCM. The secular trends in male:female ratio at birth in postwar industrialized countries. Environ Health Perspect 2001; 109: 749–52. Doherty M, Watkins M, Khoury MJ. Pregnancy interval and risk for neural tube defects: a population-based study. Am J Epidemiol 1996; 143: S47,186 (abstr). Swenson I, Harper PA. The relation between fetal wastage and pregnancy spacing in Bangladesh. Soc Biol 1978; 25: 251–56.
Sir—In response to Luc Smits and discussion of Gerard Essed’s1 unfavourable pregnancy outcomes, I have presented some data for liveborn babies with no congenital abnormalities in Hungary, 1980–96.2 We assessed birthweight and gestational age in babies born to women taking multivitamins (including folic acid 0·1–1·0 mg) and folic acid (3–6 mg), only multivitamins, only folic acid, or no supplementation during the third trimester of pregnancy. Previously we had shown no difference in the mean birthweight and gestational age between women taking periconceptional supplementation of multivitamins, including folic acid, and placebo-like trace elements.3 In the new analysis we aimed to test the
THE LANCET • Vol 359 • June 22, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.