- Email: [email protected]
Propofol-infusion syndrome in children
CORRESPONDENCE
subsequent worsening of the fetalplacental condition. Nuno Montenegro Investigation and Cardiovascular Development Unit, Medicine Faculty of Porto, 4200 Porto, Portugal 1
Wallace EM, Baker LS. Effect of antenatal betamethasone administration on placental vascular resistance. Lancet 1999; 3 5 3 : 1404–07. 2 Derks JB, Mulder EJH, Visser GH. The effects of maternal betamethasone administration on the fetus. Br J Obstet Gynaecol 1995; 102: 40–46. 3 Montenegro N, Santos F, Tavares E, et al. Outcome of 88 pregnancies with absent or reversed end-diastolic blood flow (ARED flow) in the umbilical arteries. Eur J Obstet Gynecol Reprod Med 1998: 7 9 : 43–46. 4 Montenegro N, Laurini R, Brandão O, et al. Placental findings in fetuses with absent or reversed end-diastolic flow in the umbilical arteries (ARED flow): a reappraisal. J Matern Fetal Invest 1997; 7 : 175–59. 5 Caforio L, Caruso A, Testa AC, et al. Short-term maternal oxygen administration in fetuses with absence or reversal of enddiastolic velocity in umbilical artery: pathophysiological and clinical considerations. Acta Obstet Gynecol Scand 1998; 77: 707–11.
Jhum-jhum is a symptom Sir—In their zeal to capture a colourful sounding malady lurking yeti-like in the mountains and valleys of Shangrila, Brandon Kohrt and Steven Schreiber (March 27, p 1070)1 have confused a symptom for a syndrome. “J h u m - j h u m” in English means parasthesia. No more or less. It is one of the most common symptoms encountered in medical clinics throughout the country. Some of our colleagues have postulated that the complaint increases in areas where rice is milled (thus eliminating some B vitamins). We see jhum-jhum regularly with isoniazid ingestion, leprosy, diabetes, vasculitis, and hyperventilation in our practice. A syndrome is an aggregate of symptoms and signs that form one condition. Although jhum-jhum may cluster with certain neurotic complaints like ringata lagcha (feel dizzy), jiu galcha (my body is melting), its long-standing meaning in Nepal does not denote a syndrome of some mystical, undiscovered neuropsychiatric malady. *Buddha Basnyat, Mark Zimmerman, John Sleggs, Himansu Vaidhya Nepal International Clinic, Patan Hospital, Lal Durbar, GPO Box 3595, Kathmandu, Nepal (e-mail: [email protected]) 1
Kohrt BA, Schreiber SS. Jhum-jhum: neuropsychiatric symptoms in a Nepali village. Lancet 1999; 353: 1070.
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Author’s reply Sir—Although j h u m - j h u m may be “one of the most common symptoms encountered in medical clinics throughout the country”, as Buddha Basnyat and colleagues claim, it is rather surprising that there is so little information about it in medical publications. Epidemiological data about prevalence and demographics, as well as reports describing the clinical features of jhum-jhum have, until now, been unavailable. Whether symptom or syndrome, only through the application of rigorous scientific scrutiny can relevant conclusions about potential aetiological factors be drawn and the pathophysiology of jhum-jhum understood. Steven S Schreiber Department of Neurology, University of South California, Los Angeles, CA 90033, USA (e-mail: [email protected])
Propofol-infus ion syndrome in children Sir—I would like to respond to David Hatch’s April 3 commentary1 on my report in Paediatric Anaesthesia on propofol-infusion syndrome in children. 2 The three Newcastle children who developed the syndrome and died were not treated in the intensive-care unit in which I work. I have some ethical concerns about a prospective trial of propofol infusions in children. There are well-tried ways to sedate children in intensive-care units, such as morphine and benzodiazepine infusions. The main disadvantages of such sedatives is that they are sometimes slow to wear off, but this effect can usually be dealt with b y some forethought. The main advantage of propofol is that it wears off quickly, but I wonder whether this effect would justify the possible risk of a child developing this syndrome in the course of the trial. Another difficulty is whether such a trial would be valid. Of the nine children that I reported who received long-term (>48 h) high-dose (>4 mg kg–1 h–1) propofol infusions, six did not develop the syndrome; indeed the child who received the greatest dose was unaffected. This finding indicates that there might be something different about the children who develop the syndrome. Cray and coworkers3 reported a child in Canada who developed the syndrome but survived after haemodialysis. This child was investigated extensively and Cray and colleagues postulated that
the syndrome might be produced by an abnormal, water-soluble metabolite which was removed by the dialysis. If this hypothesis is true then a controlled trial would have to contain some of these susceptible children and it is hard to see how this approach could be managed with the present state of knowledge and in an ethical way. R J Bray Department of Anaesthesia, Royal Victoria Infirmary, Newcasle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne NE1 4LP, UK 1
Hatch DJ. Propofol-infusion syndrome in children. Lancet 1999; 3 5 3 : 1117–18. 2 Bray RJ. Propofol infusion syndrome in children. Paediatr Anaesth 1998; 8 : 491–99. 3 Cray SH, Robinson BH, Cox PN. Lactic academia and bradyarrythmia in a child sedated with propofol. Crit Care Med 1998; 2 6 : 2087–92.
Sir—David Hatch1 comments on the controversy surrounding the use of propofol for the sedation of children in intensive care. Although we agree that further study is needed to look into the use of propofol in this setting, many clinicians believe it is appropriate to continue propofol use in paediatric intensive care. We surveyed all intensive-care units in the UK that were identified in the directory of emergency and specialist care units. We received replies from 18 paediatric units, 31 adult and paediatric units, and 169 adult units. We asked the director of each unit if they would use propofol for sedation in children and what was the lower age limit. 11 (61%) paediatric units (youngest age 3 years), nine (29%) adult and paediatric units (youngest age 1 year), and 30 (18%) nonpaediatric units replied that they would use propofol in children. These units stated that propofol was used in combination with other drugs at about 1–4 mg/kg per h, which is lower than the dose that led to difficulties in the original case series. 2 The use of propofol is indicated for sedation of patients for short-term ventilation and as an aid to weaning. Our survey gives no indication of the absolute number of paediatric patients receiving propofol for sedation in intensive care, but the number of units reporting its use implies it is administered regularly to children. The reasons clinicians in the UK continue to sedate children in intensive care with propofol despite concerns about its use must be the perceived benefits of the agent, but probably include doubts about the importance of the original case reports. A randomised controlled trial
THE LANCET • Vol 353 • June 12, 1999
CORRESPONDENCE
to assess the safety of propofol in paediatric care will be difficult with the rarity of propofol-infusion syndrome in most units. *S D Murdoch, A T Cohen Adult and Paediatric Intensive Care Unit, St James’ University Hospital, Leeds LS9 7TF, UK 1 2
Hatch DJ. Propofol-infusion syndrome in children. Lancet 1999; 353: 1117–18. Parke TJ, Stevens JE, Rice ASC, et al. Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports. BMJ 1992; 305: 613–16.
New formula to calculate mean aor tic pres s ure? Sir—D Chemia and colleagues (March 27, p 1069)1 p r o v i d e additional evidence of the inaccuracy of the commonly used formula to calculate mean arterial pressure: MAP=DAP+(PP)/3, where MAP is mean arterial pressure, DAP is diastolic pressure, PP is pulse pressure, and PP=SAP–DAP (SAP is systolic pressure). The basis of this equation is an approximation of the true mean blood pressure in healthy individuals, and is known to be inaccurate in patients with left-ventricular dysfunction, rhythm disturbances, valvular heart disease, and also in old and young people.2 Since Chemia and colleagues excluded all patients with these conditions, their new formula is invalid in just the patients in whom accurate recording of the blood pressure is needed. The true mean blood pressure corresponds to the DC (constant or zero frequency) component following Fourier analysis of the arterial waveform, which is equal to the arithmetic mean of the blood pressure waveform if equal time interval samples are taken. Thus, Chemia’s formula is mathematically flawed since it does not represent the arithmetic mean. The accuracy of the arithmetic mean calculation increases, the greater the number of samples taken and the shorter the sample interval.3 The isolated use of diastolic pressure and systolic pressure for the calculation of the mean arterial pressure takes no account of the arterial pressure waveform morphology, since it is immediately obvious that two patients with the same diastolic and systolic pressures, but with different arterial pressure waveform morphologies, will not have the same mean arterial pressure. Thus, any formula that involves only the diastolic
THE LANCET • Vol 353 • June 12, 1999
pressure or systolic pressure will by inference have errors. Perhaps analysis of a non-selected population with a true mean blood pressure would have produced a different result that is valid in all patients, as opposed to a select healthy subpopulation. Michael Poullis Department of Cardiothoracic Surgery, Hammersmith Hospital, London, W12 0NN, UK (e-mail: [email protected]) 1
Chemia D, Herbert JL, Coirault C, LeCarpentier Y. A new formula for estimating mean aortic pressure. Lancet 1999; 353: 1069–70. 2 Gevers M, Hack WW, Ree EF, Lafeber HN, Westerhof N. Calculated mean arterial blood pressure in critically ill neonates. Basic Res Cardiol 1993; 88: 80–85. 3 Whittaker E, Robinson G. Practical Fourier analysis. In: the calculus of observations. London: Blackie & Son Limited, 1966: 260–84.
Duration of pregnancy and risk of breast cancer Sir—Women who have had a pregnancy interruption might be at increased risk of breast cancer, compared with women who have delivered at term, because they never attain the protective effect of mammary-gland differentiation. 1 However, epidemiological studies of the relation between abortions that occur during the first trimester of pregnancy and risk of breast cancer have yielded conflicting results. 2 One might propose that the protective effects lie at other periods of pregnancy. The case-control study by C-c Hsieh and colleagues (April 10, p 1239)3 shows a possible link between delivery during the third trimester of pregnancy and breast-cancer risk. They report a significantly increased risk of breast cancer among women aged 40 or older who have a premature delivery, compared with women who delivered at term. Citing the example of uniparous women, they emphasise possible dual effects of livebirth on maternal risk of breast cancer, which is opposite to that observed in women who have an infant born at term. Indeed, a transient decrease followed by a long-term increase of cancer risk has been observed in women who have a premature delivery. These findings indicate that interruption of pregnancy during the final phase of breast-cell differentiation (ie, third trimester) would have more significant effects on risk of breast cancer than pregnancy interruption during the first phase of breast-cell proliferation (ie, first trimester). 4
Therefore, one might postulate that term pregnancy prevents the initiation of a neoplastic process through the induction of a complete differentiation of the mammary gland. The regulation of specific proteins involved in breastcell differentiation during both pregnancy and carcinogenesis (such as cyclin D1) might be altered by the abrupt termination of the pregnancy, and in turn would modify the response of the organ to ulterior hormonal changes. A remaining question is whether specific time lags exist during which interruption of pregnancy would significantly increase the risk of breast cancer. This latter hypothesis is supported by Ekbom and colleagues’ comparison of the odds ratio of women who delivered before 33 weeks of gestation,5 and that of women who delivered before 37 weeks of gestation. Indeed, the risk of breast cancer increased two-fold in women whose babies were born before 33 weeks of gestation (odds ratio 3·96), compared with women who delivered before 37 weeks (1·17). Although C-c Hsieh and colleagues proposed this latter hypothesis, they did not report consistent data on any relation between gestational age and maternal risk of breast cancer risk among women who have a premature delivery. Therefore, the importance of time lags in pregnancy interruption on risk of breast cancer remains an open question. Hélène Lapillonne, Roy M Golsteyn, *Alexandre Lapillonne Ecole Normale Supérieure de Lyon, UMR 49 Centre National de la Recherche Scientifique, Laboratoire de Biologie Moléculaire et Cellulaire, Lyon, France; and *Institut CurieUMR 144 Centre National de la Recherche Scientifique, Laboratoire de Morphogenèse et Signalisation Cellulaires, 75248 Paris Cedex 05, France (e-mail: [email protected]) 1
Russo J, Russo IH. Susceptibility of the mammary gland to carcinogenesis. II. Pregnancy interruption as a risk factor in tumor incidence. Am J Pathol 1980; 1 0 0 : 497–512. 2 Melbye M, Wohlfahrt J, Olsen JH, et al. Induced abortion and the risk of breast cancer. N Engl J Med 1997; 3 3 6 : 81–85. 3 Hsieh C-c, Lambe M, Trichopoulos D, Adami HO, Ekbom A. Delivery of premature newborns and maternal breastcancer risk. Lancet 1999; 353: 1239. 4 Ferguson DJ, Anderson TJ. A morphological study of the changes which occur during pregnancy in the human breast. Virchows Arch 1983; 401: 163–75. 5 Ekbom A, Hsieh C-c, Lipworth L, Adami HQ, Trichopoulos D. Intrauterine environment and breast cancer risk in women: a population-based study. J Natl Cancer Inst 1997; 89: 71–76.
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subsequent worsening of the fetalplacental condition. Nuno Montenegro Investigation and Cardiovascular Development Unit, Medicine Faculty of Porto, 4200 Porto, Portugal 1
Wallace EM, Baker LS. Effect of antenatal betamethasone administration on placental vascular resistance. Lancet 1999; 3 5 3 : 1404–07. 2 Derks JB, Mulder EJH, Visser GH. The effects of maternal betamethasone administration on the fetus. Br J Obstet Gynaecol 1995; 102: 40–46. 3 Montenegro N, Santos F, Tavares E, et al. Outcome of 88 pregnancies with absent or reversed end-diastolic blood flow (ARED flow) in the umbilical arteries. Eur J Obstet Gynecol Reprod Med 1998: 7 9 : 43–46. 4 Montenegro N, Laurini R, Brandão O, et al. Placental findings in fetuses with absent or reversed end-diastolic flow in the umbilical arteries (ARED flow): a reappraisal. J Matern Fetal Invest 1997; 7 : 175–59. 5 Caforio L, Caruso A, Testa AC, et al. Short-term maternal oxygen administration in fetuses with absence or reversal of enddiastolic velocity in umbilical artery: pathophysiological and clinical considerations. Acta Obstet Gynecol Scand 1998; 77: 707–11.
Jhum-jhum is a symptom Sir—In their zeal to capture a colourful sounding malady lurking yeti-like in the mountains and valleys of Shangrila, Brandon Kohrt and Steven Schreiber (March 27, p 1070)1 have confused a symptom for a syndrome. “J h u m - j h u m” in English means parasthesia. No more or less. It is one of the most common symptoms encountered in medical clinics throughout the country. Some of our colleagues have postulated that the complaint increases in areas where rice is milled (thus eliminating some B vitamins). We see jhum-jhum regularly with isoniazid ingestion, leprosy, diabetes, vasculitis, and hyperventilation in our practice. A syndrome is an aggregate of symptoms and signs that form one condition. Although jhum-jhum may cluster with certain neurotic complaints like ringata lagcha (feel dizzy), jiu galcha (my body is melting), its long-standing meaning in Nepal does not denote a syndrome of some mystical, undiscovered neuropsychiatric malady. *Buddha Basnyat, Mark Zimmerman, John Sleggs, Himansu Vaidhya Nepal International Clinic, Patan Hospital, Lal Durbar, GPO Box 3595, Kathmandu, Nepal (e-mail: [email protected]) 1
Kohrt BA, Schreiber SS. Jhum-jhum: neuropsychiatric symptoms in a Nepali village. Lancet 1999; 353: 1070.
2074
Author’s reply Sir—Although j h u m - j h u m may be “one of the most common symptoms encountered in medical clinics throughout the country”, as Buddha Basnyat and colleagues claim, it is rather surprising that there is so little information about it in medical publications. Epidemiological data about prevalence and demographics, as well as reports describing the clinical features of jhum-jhum have, until now, been unavailable. Whether symptom or syndrome, only through the application of rigorous scientific scrutiny can relevant conclusions about potential aetiological factors be drawn and the pathophysiology of jhum-jhum understood. Steven S Schreiber Department of Neurology, University of South California, Los Angeles, CA 90033, USA (e-mail: [email protected])
Propofol-infus ion syndrome in children Sir—I would like to respond to David Hatch’s April 3 commentary1 on my report in Paediatric Anaesthesia on propofol-infusion syndrome in children. 2 The three Newcastle children who developed the syndrome and died were not treated in the intensive-care unit in which I work. I have some ethical concerns about a prospective trial of propofol infusions in children. There are well-tried ways to sedate children in intensive-care units, such as morphine and benzodiazepine infusions. The main disadvantages of such sedatives is that they are sometimes slow to wear off, but this effect can usually be dealt with b y some forethought. The main advantage of propofol is that it wears off quickly, but I wonder whether this effect would justify the possible risk of a child developing this syndrome in the course of the trial. Another difficulty is whether such a trial would be valid. Of the nine children that I reported who received long-term (>48 h) high-dose (>4 mg kg–1 h–1) propofol infusions, six did not develop the syndrome; indeed the child who received the greatest dose was unaffected. This finding indicates that there might be something different about the children who develop the syndrome. Cray and coworkers3 reported a child in Canada who developed the syndrome but survived after haemodialysis. This child was investigated extensively and Cray and colleagues postulated that
the syndrome might be produced by an abnormal, water-soluble metabolite which was removed by the dialysis. If this hypothesis is true then a controlled trial would have to contain some of these susceptible children and it is hard to see how this approach could be managed with the present state of knowledge and in an ethical way. R J Bray Department of Anaesthesia, Royal Victoria Infirmary, Newcasle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne NE1 4LP, UK 1
Hatch DJ. Propofol-infusion syndrome in children. Lancet 1999; 3 5 3 : 1117–18. 2 Bray RJ. Propofol infusion syndrome in children. Paediatr Anaesth 1998; 8 : 491–99. 3 Cray SH, Robinson BH, Cox PN. Lactic academia and bradyarrythmia in a child sedated with propofol. Crit Care Med 1998; 2 6 : 2087–92.
Sir—David Hatch1 comments on the controversy surrounding the use of propofol for the sedation of children in intensive care. Although we agree that further study is needed to look into the use of propofol in this setting, many clinicians believe it is appropriate to continue propofol use in paediatric intensive care. We surveyed all intensive-care units in the UK that were identified in the directory of emergency and specialist care units. We received replies from 18 paediatric units, 31 adult and paediatric units, and 169 adult units. We asked the director of each unit if they would use propofol for sedation in children and what was the lower age limit. 11 (61%) paediatric units (youngest age 3 years), nine (29%) adult and paediatric units (youngest age 1 year), and 30 (18%) nonpaediatric units replied that they would use propofol in children. These units stated that propofol was used in combination with other drugs at about 1–4 mg/kg per h, which is lower than the dose that led to difficulties in the original case series. 2 The use of propofol is indicated for sedation of patients for short-term ventilation and as an aid to weaning. Our survey gives no indication of the absolute number of paediatric patients receiving propofol for sedation in intensive care, but the number of units reporting its use implies it is administered regularly to children. The reasons clinicians in the UK continue to sedate children in intensive care with propofol despite concerns about its use must be the perceived benefits of the agent, but probably include doubts about the importance of the original case reports. A randomised controlled trial
THE LANCET • Vol 353 • June 12, 1999
CORRESPONDENCE
to assess the safety of propofol in paediatric care will be difficult with the rarity of propofol-infusion syndrome in most units. *S D Murdoch, A T Cohen Adult and Paediatric Intensive Care Unit, St James’ University Hospital, Leeds LS9 7TF, UK 1 2
Hatch DJ. Propofol-infusion syndrome in children. Lancet 1999; 353: 1117–18. Parke TJ, Stevens JE, Rice ASC, et al. Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports. BMJ 1992; 305: 613–16.
New formula to calculate mean aor tic pres s ure? Sir—D Chemia and colleagues (March 27, p 1069)1 p r o v i d e additional evidence of the inaccuracy of the commonly used formula to calculate mean arterial pressure: MAP=DAP+(PP)/3, where MAP is mean arterial pressure, DAP is diastolic pressure, PP is pulse pressure, and PP=SAP–DAP (SAP is systolic pressure). The basis of this equation is an approximation of the true mean blood pressure in healthy individuals, and is known to be inaccurate in patients with left-ventricular dysfunction, rhythm disturbances, valvular heart disease, and also in old and young people.2 Since Chemia and colleagues excluded all patients with these conditions, their new formula is invalid in just the patients in whom accurate recording of the blood pressure is needed. The true mean blood pressure corresponds to the DC (constant or zero frequency) component following Fourier analysis of the arterial waveform, which is equal to the arithmetic mean of the blood pressure waveform if equal time interval samples are taken. Thus, Chemia’s formula is mathematically flawed since it does not represent the arithmetic mean. The accuracy of the arithmetic mean calculation increases, the greater the number of samples taken and the shorter the sample interval.3 The isolated use of diastolic pressure and systolic pressure for the calculation of the mean arterial pressure takes no account of the arterial pressure waveform morphology, since it is immediately obvious that two patients with the same diastolic and systolic pressures, but with different arterial pressure waveform morphologies, will not have the same mean arterial pressure. Thus, any formula that involves only the diastolic
THE LANCET • Vol 353 • June 12, 1999
pressure or systolic pressure will by inference have errors. Perhaps analysis of a non-selected population with a true mean blood pressure would have produced a different result that is valid in all patients, as opposed to a select healthy subpopulation. Michael Poullis Department of Cardiothoracic Surgery, Hammersmith Hospital, London, W12 0NN, UK (e-mail: [email protected]) 1
Chemia D, Herbert JL, Coirault C, LeCarpentier Y. A new formula for estimating mean aortic pressure. Lancet 1999; 353: 1069–70. 2 Gevers M, Hack WW, Ree EF, Lafeber HN, Westerhof N. Calculated mean arterial blood pressure in critically ill neonates. Basic Res Cardiol 1993; 88: 80–85. 3 Whittaker E, Robinson G. Practical Fourier analysis. In: the calculus of observations. London: Blackie & Son Limited, 1966: 260–84.
Duration of pregnancy and risk of breast cancer Sir—Women who have had a pregnancy interruption might be at increased risk of breast cancer, compared with women who have delivered at term, because they never attain the protective effect of mammary-gland differentiation. 1 However, epidemiological studies of the relation between abortions that occur during the first trimester of pregnancy and risk of breast cancer have yielded conflicting results. 2 One might propose that the protective effects lie at other periods of pregnancy. The case-control study by C-c Hsieh and colleagues (April 10, p 1239)3 shows a possible link between delivery during the third trimester of pregnancy and breast-cancer risk. They report a significantly increased risk of breast cancer among women aged 40 or older who have a premature delivery, compared with women who delivered at term. Citing the example of uniparous women, they emphasise possible dual effects of livebirth on maternal risk of breast cancer, which is opposite to that observed in women who have an infant born at term. Indeed, a transient decrease followed by a long-term increase of cancer risk has been observed in women who have a premature delivery. These findings indicate that interruption of pregnancy during the final phase of breast-cell differentiation (ie, third trimester) would have more significant effects on risk of breast cancer than pregnancy interruption during the first phase of breast-cell proliferation (ie, first trimester). 4
Therefore, one might postulate that term pregnancy prevents the initiation of a neoplastic process through the induction of a complete differentiation of the mammary gland. The regulation of specific proteins involved in breastcell differentiation during both pregnancy and carcinogenesis (such as cyclin D1) might be altered by the abrupt termination of the pregnancy, and in turn would modify the response of the organ to ulterior hormonal changes. A remaining question is whether specific time lags exist during which interruption of pregnancy would significantly increase the risk of breast cancer. This latter hypothesis is supported by Ekbom and colleagues’ comparison of the odds ratio of women who delivered before 33 weeks of gestation,5 and that of women who delivered before 37 weeks of gestation. Indeed, the risk of breast cancer increased two-fold in women whose babies were born before 33 weeks of gestation (odds ratio 3·96), compared with women who delivered before 37 weeks (1·17). Although C-c Hsieh and colleagues proposed this latter hypothesis, they did not report consistent data on any relation between gestational age and maternal risk of breast cancer risk among women who have a premature delivery. Therefore, the importance of time lags in pregnancy interruption on risk of breast cancer remains an open question. Hélène Lapillonne, Roy M Golsteyn, *Alexandre Lapillonne Ecole Normale Supérieure de Lyon, UMR 49 Centre National de la Recherche Scientifique, Laboratoire de Biologie Moléculaire et Cellulaire, Lyon, France; and *Institut CurieUMR 144 Centre National de la Recherche Scientifique, Laboratoire de Morphogenèse et Signalisation Cellulaires, 75248 Paris Cedex 05, France (e-mail: [email protected]) 1
Russo J, Russo IH. Susceptibility of the mammary gland to carcinogenesis. II. Pregnancy interruption as a risk factor in tumor incidence. Am J Pathol 1980; 1 0 0 : 497–512. 2 Melbye M, Wohlfahrt J, Olsen JH, et al. Induced abortion and the risk of breast cancer. N Engl J Med 1997; 3 3 6 : 81–85. 3 Hsieh C-c, Lambe M, Trichopoulos D, Adami HO, Ekbom A. Delivery of premature newborns and maternal breastcancer risk. Lancet 1999; 353: 1239. 4 Ferguson DJ, Anderson TJ. A morphological study of the changes which occur during pregnancy in the human breast. Virchows Arch 1983; 401: 163–75. 5 Ekbom A, Hsieh C-c, Lipworth L, Adami HQ, Trichopoulos D. Intrauterine environment and breast cancer risk in women: a population-based study. J Natl Cancer Inst 1997; 89: 71–76.
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