LETTERS
Early growth and clotting factors in adult life
about the effects of growth retardation on different organs and systems and hence understand the early processes that "programme" adult disease. D J P BARKER C OSMOND
SIR,-We disagree with Richard de CourcyWheeler and Charles Wolfe,' who seem unclear that plasma fibrinogen and factor VII concentrations in adult men are related to the combination of placental weight and birth weight2; overlook the fact that these relations are independent of gestation; and wrongly state that a raised ratio of placental weight to birth weight is associated with a decreased ratio of head circumference to length. George Davey Smith and Yoar Ben-Shlomo raise the question of whether the strong relations between early growth and adult cardiovascular disease and risk factors result from confounding variables.3 In our recent study men who had had lower weight at 1 year included more cigarette smokers (the smoking history being known for all except three men, not nine as they suggest). The trends in lower fibrinogen concentration with increasing weight at 1 year were independent of smoking. Davey Smith and Ben-Shlomo argue, however, that men who had had different weights at 1 year could also differ in leisure activities, psychosocial characteristics, and other possible confounding variables, known and unknown, measured and unmeasurable. Such arguments can easily be made about any non-randomised study and cannot formally be refuted. The relations of fibrinogen concentration with weight at 1 year and the ratio of placental weight to birth weight, however, were found within each social class. Furthermore, whereas more short men smoked cigarettes, irrespective of their weight as infants, more men who were light during infancy had high plasma fibrinogen and factor VII concentrations irrespective of their adult height. Davey Smith and Ben-Shlomo also suggest that the relation of raised plasma factor VII concentrations with lower weight at 1 year may have arisen because the men who had low weights at 1 year smoke more and eat more saturated fat and consequently have a raised factor VII concentration. The table shows that this suggestion is incorrect. Men who had low weight at 1 year and now smoke had below average factor VII concentrations. The relations between early growth and adult cardiovascular risk factors, including haemostatic factors,2 blood pressure,4 plasma glucose, insulin,5 and apolipoprotein B, are not only strong and graded but specific. Different risk factors are associated with different patterns of reduced fetal or infant growth. We now need to know more
MRC EnvironmentalEpidemiologv Unit, University of Southampton, Southampton General Hospital, Southampton S09 4XY T W MEADE
MRC Epidemiology and Medical Care Uniit, Northwick Park Hospital, Harrow, Middlesex HAI 3UJ 1 De Courcy-Wheeler R, Wolfe C. Fetal growth and ratio of placental weight to birth weight. BMJ7 1992;304:638. (7 March.) 2 Barker DJP, Meade TW, Fall CHD, Lee A, Osmond C, Phipps K, et al. Relation of fetal and infant growth to plasma fibrinogen and factor VII concentrations in adult life. BA4MJ 1992;304:148-52. (18 Januarv.) 3 Davey Smith G, Ben-Shlomo Y. Early growth and clotting factors in-adult life. BMJ 1992;304:638-9. (7 March.' 4 Barker DJP, Bull AR, Osmond C, Simmonds SJ. Fetal and placental size and risk of hypertension in adult life. BMJ_ 1990;301:259-62. 5 Hales CN, Barker DJP, Clark PMS, Cox LJ, Fall C, Osmond C, et al. Fetal and infant growth and impaired glucose tolerance at age 64. BAJ 1991;303:1019-22.
Fetal growth and ratio of placental weight to birth weight SIR,-Richard de Courcy-Wheeler and Charles Wolfe argue against using the ratio of placental weight to birth weight as a marker of fetal growth because the regression line does not pass through the origin.' This is not a valid argument. The regression line is not expected to pass through the origin even when there is a true proportional relation unless the two variables are perfectly correlated. The regression line is the best line for predicting birth weight from placental weight. It is not the best line for describing the true relation between these variables. The data of de Courcy-Wheeler and Wolfe may be misleading. Inspection of their figure shows two suspicious points: one for a placental weight of about 30 g and birth weight of 2800 g and another for a placental weight of about 100 g and birth weight of 2100 g. These points may exert considerable influence on the regression line and correlation coefficient. Using data from the St George's birth weight study, for 1492 births we had a minimum placental weight of 190 g, and no subject with a placental weight above 950 g had a birth weight below 3500 g. The correlation between
Mean plasma factor VII concentration (percentage of standard) in men aged 59 to 70 according to weight at I year and smoking habit Smoking habit Never smoked
Weight at 1 year Factor VII No of men (%) (lb)
1052
Ex-smoker
Current smoker
All
Factor VII (%) No of men
Factor VII No of men (%)
Factor VII No of men (%)
7
122 112 108 106 106 103
37 89 175 165 80 33
154
108
579
618 -20 -22 -24 -26 >26
122 101 104 105 102 96
6 11 30 32 17 4
130 122 105 104 105 104
19 48 97 93 46 22
109 101 115 112 114 102
12 30 48 40 17
AU
105
100
109
325
110
birth weight and placental weight was r=-O619. (This is much greater than the value of r=0 385 reported in the text by de Courcy-Wheeler and Wolfe, but in their figure they give r=0O385, which corresponds to r-0620.) rhe regression of birth weight-on placental weight gave the equation birth weight=1784+2-553 placental weight, which is similar to the line reported by de CourcyWheeler and Wolfe. But there are two regression lines. We can also calculate the regression of placental weight on birth weight, giving placental weight=104 5+01503 birth weight. If we rearrange this equation to put birth weight on the left we get birth weight= 695+6 653 placental weight, with a negative intercept. Thus the two regression lines pass either side of the origin. The true, functional relation between birth weight and placental weight will lie somewhere between them. Taking the ratio of placental weight to birth weight implies that one is approximately proportional to the other and so the line describing the true relation should go near the origin. Both sets of data seem consistent with this possibility. There may be other grounds to question the appropriateness of looking at placental weight as a proportion of birth weight, but the ratio should not be rejected because of the findings of de Courcy-Wheeler and Wolfe's regression analysis. The same misconception is common when regression is used in studies comparing methods. Here the two methods measure the same quantity and so the true ratio is around 1 for all subjects. The expected slope and intercept of the regression line, however, are not 1 and O.' DOUGLAS G ALTMAN Medical Statistics Laboratory, Imperial Cancer Research Fund, PO Box 123, London WC2A 3PX
-
MARTIN BILAND LESLEY MEYER
Department of Public Health Sciences, St George's Hospital Medical School, London SW17 ORE 1 De Courcy-Wheeler R, Wolfe C. Fetal growth and ratio of placental weight to birth weight. BMJ 1992;304:638.
(7 March.) 2 Brooke OG, Anderson HR, Bland JM, Peacock JL, Stewart CM. Effects on birth weight of smoking, alcohol, caffeine, socioeconomic factors, and psvchosocial stress. BMJ 1989;298: -795-801. 3 Altman DG, Bland JM. Measurement in medicine: the analysis of method comparison studies. Statistician 1983;32:307-17.
SIR,-Richard de Courcy-Wheeler and Charles Wolfe's letter' arguing that D J P Barker and colleagues' paper2 failed to prove an association between reduced fetal growth and high concentrations of fibrinogen and factor VII raises several interesting issues. Their argument is based on Barker and colleagues' use of the ratio of placental weight to birth weight as a marker of reduced fetal growth. A regression of birth weight on placental weight for 163 male infants is used as evidence of the difficulties of interpreting such a ratio: the (presumably significant) failure of the fitted line to pass through the origin would mean that the ratio would take different values despite birth weight being appropriate to placental weight. No attempt is made to interpret the intercept-that is, to explain why infants with a placental weight of zero should have a birth weight of about 1750 g. In an attempt to derive a more feasible model of
BMJ VOLUME 304
18 APRIL 1992
Numbers of infants categorised according to quintiles of ratio ofplacental weight to birth weight and by gestational age and birth weight (figures in parentheses are column percentages) Weeks of gestation
No of
Birth weight (g)
Placental weight:birth weight
infants
40
4000
-0-164 -0-177 -0-191 -0-209 >0 209
57(20) 57 (20) 60 (21) 60(21) 55(19)
2 (17) 0 1 (8) 2 (17) 7(58)
37 (18) 45 (22) 42(21) 43(21) 34(17)
18 (24) 12 (16) 17(22) 15(20) 14 (18)
1 (9) 2 (18) 0 1 (9) 7(64)
48 (21) 45 (19)
8 (17) 10 (22) 15 (33) 6 (13) 7 (15)
All
289
12
201 0 044
p Value
the relation between birth weight and placental weight we analysed data on 289 second born male infants collected as part of a study of psychosocial factors in pregnancy. Whereas the association between birth weight and gestation could be modelled by the familiar logistic growth curve, passing through the origin, the relation between placental weight and gestation was linear (again passing through the origin). If placental weight is fitted to the difference between observed birth weight and that expected according to the growth curve model then the intercept is indeed significant; if, however, gestation and placental weight are fitted simultaneously then the expected values again pass through the origin. This difference means that the effects of gestation and placental weight on birth weight are not independent. A slight improvement on the use of placental weight is the square of this value, which implies that the relative contribution of placental weight to birth weight is greater for larger placental weights (and hence for longer gestations). This model, which implies different, or at least differently timed, fetal and placental growth, also has consequences for the interpretation of Barker and colleagues' finding of a relation between the ratio of placental weight to birth weight and fibrinogen concentration. As would be expected given the relations described, this ratio tends to decrease with increasing gestational age or birth weight (table). This systematic decrease does not reflect the appropriateness of birth weight to gestation but is, rather, explained by the different patterns of fetal and placental growth. While the groups with high ratios of placental weight to birth weight do include infants born at term, infants born at lower gestations are overrepresented. The association between ratios of placental weight to birth weight and haemostatic factors in later life might be explained by poor fetal growth or as one of the sequelae of immaturity at birth (or a more subtle combination of the two). Our understanding of the relation between early development and health in later life would be enhanced if we knew which explanation was the most likely. ALASTAIR LEYLAND COLIN PRITCHARD Public Health Research Unit,
Glasgow University, Glasgow G12 8RZ 1 De Courcy-Wheeler R, Wolfe C. Fetal growth and ratio of placental weight to birth weight. BM7 1992;304:638. (7 March.) 2 Barker DJP, Meade TW, Fall CDH, Osmond C, Phipps K, Stirling Y. Relation of fetal and infant growth to plasma fibrinogen and factor VII concentrations in adult life. BMJ 1992;304:148-52. (18 January.)
Low dose oxybutynin for the unstable bladder SIR,-Oxybutynin was licensed by the Committee on Safety of Medicines at the beginning of last year. Since the withdrawal of terodiline oxybutynin has been used increasingly to treat urinary incontinence secondary to detrusor instability or detrusor hyperreflexia.
BMJ
76
VOLUME
304
18
APRIL
1992
11
45(19) 53(23) 41(18) 232
46
0-007
The datasheet for oxybutynin recommends a dose of 5 mg three times a day. This reflects published reports on the efficacy and safety of the drug at the time the licence was issued.' The drug is a powerful anticholinergic and has side effects. Although oxybutynin has a short plasma half life (about three hours),2 our clinical experience leads us to believe that a lower dose given less frequently -2-5 mg twice daily-may be effective and associated with fewer side effects. We acknowledge that this should be submitted to a double blind controlled trial. Fifty patients have been recruited into such a study in our department, but this has yet to finish. We thought, however, that our clinical experiences may be helpful to those using the drug for the first time. We have analysed the records of 271 patients (210 female, 61 male) treated in our incontinence clinic who were established on oxybutynin as part of their treatment for detrusor instability or detrusor hyperreflexia. Our patients included young and old patients (mean (SD) age 52-8 (19 9) years, median 52, range 6-89). Patients initially take 2-5 mg twice daily, and they are encouraged to titrate this dose in response to efficacy and side effects. We always use a bladder retraining regimen. We found that the optimum dose with regard to clinical effect and side effects was 2-5 mg twice daily in 119 of the 271 patients, 5 mg twice daily in 84, 5 mg three times a day in 27, 5 mg once daily in 19, 2-5 mg three times a day in 11, and various other schedules in 11. The condition of 11 patients deteriorated and of 24 remained unchanged; 92 patients improved but continued to experience some symptoms, and 144 became asymptomatic. There were no relations between age, dose, diagnosis, and outcome. We have probably underestimated the frequency of side effects that were not mentioned by the patients. We recorded a dry mouth in half the patients, constipation in 41, and dry skin and oesophageal reflux in 14. At the doses that we used the drug was well tolerated and clinically helpful. We suggest starting treatment in all patients, regardless of age, at a dose of 2-5 mg twice daily and then titrating this accordingly. JAMES MALONE-LEE DAVID LUBEL GEORGE SZONYI
Division of Geriatric Medicine, Department of Medicine, University College and Middlesex School of Medicine, St Pancras Hospital, London NW 1 OPE 1 Koyanagi T, Maru A, Taniguchi K, Shinno Y, Takamatsu T, Morita H, et al. Clinical evaluation of oxybutynin hydrochloride tablets for the treatment of neurogenic bladder and unstable bladder. A parallel double-blind controlled study with placebo. NishinihonJournal of Urology 1986;48:1052-72. 2 Douchamps J, Derenne F, Stockis A, Gangji D, Juvent M, Herchuelz A. The pharmacokinetics of oxybutynin in man. EurJ Clin Pharmacol 1988;35:515-20.
Exploding microwaved eggs SIR,-Recently, three cases of ocular injury due to exploding microwaved eggs have been reported."2 In one case seven eggs were microwaved in their
shells and six exploded spontaneously on removal from the oven.2 In the two other cases eggs without their shells were cooked in the microwave oven without the yolk sac having been pierced.' In all three cases return to normal visual acuity occurred. We report a more severe case, in which vision was still reduced four months after the injury. A 22 year old woman cracked an egg into a bowl of water and heated it in a microwave oven. Immediately after she removed the dish from the oven the egg exploded in her face. She sustained first degree burns to the skin on the malar areas and the lower lids. There was epithelial loss affecting the conjunctiva and cornea in both eyes: all corneal epithelium was lost in the left eye. It took two weeks for the left cornea to re-epithelialise. The peripheral cornea became vascularised and inflamed, and the epithelium remained unstable. The patient required treatment in a special corneal clinic and also by the burns team. The right eye and skin of the lid rapidly healed within 10 days of the injury. Four months later the left malar skin remained erythematous and had to be camouflaged with cosmetics. The left cornea remained inflamed and vascularised at the periphery. The eye was still partially closed, and the vision remained reduced to 6/12 owing to abnormal corneal epithelium. Topical steroid treatment was continued. Microwaved eggs explode owing to rapid expansion of gas within closed compartments formed by the chorioallantoic and shell membranes and the yolk sac. Eggs can be safely cooked in a microwave oven if the shell is cracked open and the yolk sac is punctured before heating. Alternatively, eggs can be scrambled. Up to now reported eye injuries due to this cause have not been serious and have resolved fully. The case we describe shows that more serious eye injuries may also occur. Eggs should not be cooked in a microwave oven unless the yolk sac has been pierced, and we additionally suggest that they should not be cooked in water as the combination ofhot water and egg yolk seems to have caused a more severe injury. P CORRIDAN J HSUAN N J PRICE P J McDONNELL
Birmingham and Midland Eye Hospital, Birmingham B3 2NS 1 Singh J, Shah P, Sutton GA. Exploding eggs. N Engl. Med 1991;325: 1749. 2 Bradford GE, Bumstine RA. Exploding eggs. N Engl I Med 1991;325: 1749.
Survival of peripheral intravenous infusions SIR,-J F Hecker fails to address well established factors that play an important part in the survival of peripheral intravenous infusions-namely, trauma at the site of the infusion, the size of the cannula and the material from which it is made, and the use of topical non-steroidal antiinflammatory gel. ' The skill of the operator inserting the cannula is important: Cosentino found that greater experience in performing venepuncture decreased the incidence of infusion thrombophlebitis.2 In response to this problem, many North American hospitals employ intravenous therapy teams for routine insertion of cannulas.3 Recent advances in polymer technology have resulted in improved materials for cannulas. Polyurethane is less thrombogenic than Teflon, which in turn is less thrombogenic than polyethylene and polypropylene.4'6 Comparison of Teflon and polyurethane cannulas showed that the material from which the cannula was made was the single most important factor in the incidence and severity of infusion thrombophlebitis, polyurethane cannulas being associated with a 46% lower incidence.6
1053
Early growth and clotting factors in adult life
about the effects of growth retardation on different organs and systems and hence understand the early processes that "programme" adult disease. D J P BARKER C OSMOND
SIR,-We disagree with Richard de CourcyWheeler and Charles Wolfe,' who seem unclear that plasma fibrinogen and factor VII concentrations in adult men are related to the combination of placental weight and birth weight2; overlook the fact that these relations are independent of gestation; and wrongly state that a raised ratio of placental weight to birth weight is associated with a decreased ratio of head circumference to length. George Davey Smith and Yoar Ben-Shlomo raise the question of whether the strong relations between early growth and adult cardiovascular disease and risk factors result from confounding variables.3 In our recent study men who had had lower weight at 1 year included more cigarette smokers (the smoking history being known for all except three men, not nine as they suggest). The trends in lower fibrinogen concentration with increasing weight at 1 year were independent of smoking. Davey Smith and Ben-Shlomo argue, however, that men who had had different weights at 1 year could also differ in leisure activities, psychosocial characteristics, and other possible confounding variables, known and unknown, measured and unmeasurable. Such arguments can easily be made about any non-randomised study and cannot formally be refuted. The relations of fibrinogen concentration with weight at 1 year and the ratio of placental weight to birth weight, however, were found within each social class. Furthermore, whereas more short men smoked cigarettes, irrespective of their weight as infants, more men who were light during infancy had high plasma fibrinogen and factor VII concentrations irrespective of their adult height. Davey Smith and Ben-Shlomo also suggest that the relation of raised plasma factor VII concentrations with lower weight at 1 year may have arisen because the men who had low weights at 1 year smoke more and eat more saturated fat and consequently have a raised factor VII concentration. The table shows that this suggestion is incorrect. Men who had low weight at 1 year and now smoke had below average factor VII concentrations. The relations between early growth and adult cardiovascular risk factors, including haemostatic factors,2 blood pressure,4 plasma glucose, insulin,5 and apolipoprotein B, are not only strong and graded but specific. Different risk factors are associated with different patterns of reduced fetal or infant growth. We now need to know more
MRC EnvironmentalEpidemiologv Unit, University of Southampton, Southampton General Hospital, Southampton S09 4XY T W MEADE
MRC Epidemiology and Medical Care Uniit, Northwick Park Hospital, Harrow, Middlesex HAI 3UJ 1 De Courcy-Wheeler R, Wolfe C. Fetal growth and ratio of placental weight to birth weight. BMJ7 1992;304:638. (7 March.) 2 Barker DJP, Meade TW, Fall CHD, Lee A, Osmond C, Phipps K, et al. Relation of fetal and infant growth to plasma fibrinogen and factor VII concentrations in adult life. BA4MJ 1992;304:148-52. (18 Januarv.) 3 Davey Smith G, Ben-Shlomo Y. Early growth and clotting factors in-adult life. BMJ 1992;304:638-9. (7 March.' 4 Barker DJP, Bull AR, Osmond C, Simmonds SJ. Fetal and placental size and risk of hypertension in adult life. BMJ_ 1990;301:259-62. 5 Hales CN, Barker DJP, Clark PMS, Cox LJ, Fall C, Osmond C, et al. Fetal and infant growth and impaired glucose tolerance at age 64. BAJ 1991;303:1019-22.
Fetal growth and ratio of placental weight to birth weight SIR,-Richard de Courcy-Wheeler and Charles Wolfe argue against using the ratio of placental weight to birth weight as a marker of fetal growth because the regression line does not pass through the origin.' This is not a valid argument. The regression line is not expected to pass through the origin even when there is a true proportional relation unless the two variables are perfectly correlated. The regression line is the best line for predicting birth weight from placental weight. It is not the best line for describing the true relation between these variables. The data of de Courcy-Wheeler and Wolfe may be misleading. Inspection of their figure shows two suspicious points: one for a placental weight of about 30 g and birth weight of 2800 g and another for a placental weight of about 100 g and birth weight of 2100 g. These points may exert considerable influence on the regression line and correlation coefficient. Using data from the St George's birth weight study, for 1492 births we had a minimum placental weight of 190 g, and no subject with a placental weight above 950 g had a birth weight below 3500 g. The correlation between
Mean plasma factor VII concentration (percentage of standard) in men aged 59 to 70 according to weight at I year and smoking habit Smoking habit Never smoked
Weight at 1 year Factor VII No of men (%) (lb)
1052
Ex-smoker
Current smoker
All
Factor VII (%) No of men
Factor VII No of men (%)
Factor VII No of men (%)
7
122 112 108 106 106 103
37 89 175 165 80 33
154
108
579
618 -20 -22 -24 -26 >26
122 101 104 105 102 96
6 11 30 32 17 4
130 122 105 104 105 104
19 48 97 93 46 22
109 101 115 112 114 102
12 30 48 40 17
AU
105
100
109
325
110
birth weight and placental weight was r=-O619. (This is much greater than the value of r=0 385 reported in the text by de Courcy-Wheeler and Wolfe, but in their figure they give r=0O385, which corresponds to r-0620.) rhe regression of birth weight-on placental weight gave the equation birth weight=1784+2-553 placental weight, which is similar to the line reported by de CourcyWheeler and Wolfe. But there are two regression lines. We can also calculate the regression of placental weight on birth weight, giving placental weight=104 5+01503 birth weight. If we rearrange this equation to put birth weight on the left we get birth weight= 695+6 653 placental weight, with a negative intercept. Thus the two regression lines pass either side of the origin. The true, functional relation between birth weight and placental weight will lie somewhere between them. Taking the ratio of placental weight to birth weight implies that one is approximately proportional to the other and so the line describing the true relation should go near the origin. Both sets of data seem consistent with this possibility. There may be other grounds to question the appropriateness of looking at placental weight as a proportion of birth weight, but the ratio should not be rejected because of the findings of de Courcy-Wheeler and Wolfe's regression analysis. The same misconception is common when regression is used in studies comparing methods. Here the two methods measure the same quantity and so the true ratio is around 1 for all subjects. The expected slope and intercept of the regression line, however, are not 1 and O.' DOUGLAS G ALTMAN Medical Statistics Laboratory, Imperial Cancer Research Fund, PO Box 123, London WC2A 3PX
-
MARTIN BILAND LESLEY MEYER
Department of Public Health Sciences, St George's Hospital Medical School, London SW17 ORE 1 De Courcy-Wheeler R, Wolfe C. Fetal growth and ratio of placental weight to birth weight. BMJ 1992;304:638.
(7 March.) 2 Brooke OG, Anderson HR, Bland JM, Peacock JL, Stewart CM. Effects on birth weight of smoking, alcohol, caffeine, socioeconomic factors, and psvchosocial stress. BMJ 1989;298: -795-801. 3 Altman DG, Bland JM. Measurement in medicine: the analysis of method comparison studies. Statistician 1983;32:307-17.
SIR,-Richard de Courcy-Wheeler and Charles Wolfe's letter' arguing that D J P Barker and colleagues' paper2 failed to prove an association between reduced fetal growth and high concentrations of fibrinogen and factor VII raises several interesting issues. Their argument is based on Barker and colleagues' use of the ratio of placental weight to birth weight as a marker of reduced fetal growth. A regression of birth weight on placental weight for 163 male infants is used as evidence of the difficulties of interpreting such a ratio: the (presumably significant) failure of the fitted line to pass through the origin would mean that the ratio would take different values despite birth weight being appropriate to placental weight. No attempt is made to interpret the intercept-that is, to explain why infants with a placental weight of zero should have a birth weight of about 1750 g. In an attempt to derive a more feasible model of
BMJ VOLUME 304
18 APRIL 1992
Numbers of infants categorised according to quintiles of ratio ofplacental weight to birth weight and by gestational age and birth weight (figures in parentheses are column percentages) Weeks of gestation
No of
Birth weight (g)
Placental weight:birth weight
infants
40
4000
-0-164 -0-177 -0-191 -0-209 >0 209
57(20) 57 (20) 60 (21) 60(21) 55(19)
2 (17) 0 1 (8) 2 (17) 7(58)
37 (18) 45 (22) 42(21) 43(21) 34(17)
18 (24) 12 (16) 17(22) 15(20) 14 (18)
1 (9) 2 (18) 0 1 (9) 7(64)
48 (21) 45 (19)
8 (17) 10 (22) 15 (33) 6 (13) 7 (15)
All
289
12
201 0 044
p Value
the relation between birth weight and placental weight we analysed data on 289 second born male infants collected as part of a study of psychosocial factors in pregnancy. Whereas the association between birth weight and gestation could be modelled by the familiar logistic growth curve, passing through the origin, the relation between placental weight and gestation was linear (again passing through the origin). If placental weight is fitted to the difference between observed birth weight and that expected according to the growth curve model then the intercept is indeed significant; if, however, gestation and placental weight are fitted simultaneously then the expected values again pass through the origin. This difference means that the effects of gestation and placental weight on birth weight are not independent. A slight improvement on the use of placental weight is the square of this value, which implies that the relative contribution of placental weight to birth weight is greater for larger placental weights (and hence for longer gestations). This model, which implies different, or at least differently timed, fetal and placental growth, also has consequences for the interpretation of Barker and colleagues' finding of a relation between the ratio of placental weight to birth weight and fibrinogen concentration. As would be expected given the relations described, this ratio tends to decrease with increasing gestational age or birth weight (table). This systematic decrease does not reflect the appropriateness of birth weight to gestation but is, rather, explained by the different patterns of fetal and placental growth. While the groups with high ratios of placental weight to birth weight do include infants born at term, infants born at lower gestations are overrepresented. The association between ratios of placental weight to birth weight and haemostatic factors in later life might be explained by poor fetal growth or as one of the sequelae of immaturity at birth (or a more subtle combination of the two). Our understanding of the relation between early development and health in later life would be enhanced if we knew which explanation was the most likely. ALASTAIR LEYLAND COLIN PRITCHARD Public Health Research Unit,
Glasgow University, Glasgow G12 8RZ 1 De Courcy-Wheeler R, Wolfe C. Fetal growth and ratio of placental weight to birth weight. BM7 1992;304:638. (7 March.) 2 Barker DJP, Meade TW, Fall CDH, Osmond C, Phipps K, Stirling Y. Relation of fetal and infant growth to plasma fibrinogen and factor VII concentrations in adult life. BMJ 1992;304:148-52. (18 January.)
Low dose oxybutynin for the unstable bladder SIR,-Oxybutynin was licensed by the Committee on Safety of Medicines at the beginning of last year. Since the withdrawal of terodiline oxybutynin has been used increasingly to treat urinary incontinence secondary to detrusor instability or detrusor hyperreflexia.
BMJ
76
VOLUME
304
18
APRIL
1992
11
45(19) 53(23) 41(18) 232
46
0-007
The datasheet for oxybutynin recommends a dose of 5 mg three times a day. This reflects published reports on the efficacy and safety of the drug at the time the licence was issued.' The drug is a powerful anticholinergic and has side effects. Although oxybutynin has a short plasma half life (about three hours),2 our clinical experience leads us to believe that a lower dose given less frequently -2-5 mg twice daily-may be effective and associated with fewer side effects. We acknowledge that this should be submitted to a double blind controlled trial. Fifty patients have been recruited into such a study in our department, but this has yet to finish. We thought, however, that our clinical experiences may be helpful to those using the drug for the first time. We have analysed the records of 271 patients (210 female, 61 male) treated in our incontinence clinic who were established on oxybutynin as part of their treatment for detrusor instability or detrusor hyperreflexia. Our patients included young and old patients (mean (SD) age 52-8 (19 9) years, median 52, range 6-89). Patients initially take 2-5 mg twice daily, and they are encouraged to titrate this dose in response to efficacy and side effects. We always use a bladder retraining regimen. We found that the optimum dose with regard to clinical effect and side effects was 2-5 mg twice daily in 119 of the 271 patients, 5 mg twice daily in 84, 5 mg three times a day in 27, 5 mg once daily in 19, 2-5 mg three times a day in 11, and various other schedules in 11. The condition of 11 patients deteriorated and of 24 remained unchanged; 92 patients improved but continued to experience some symptoms, and 144 became asymptomatic. There were no relations between age, dose, diagnosis, and outcome. We have probably underestimated the frequency of side effects that were not mentioned by the patients. We recorded a dry mouth in half the patients, constipation in 41, and dry skin and oesophageal reflux in 14. At the doses that we used the drug was well tolerated and clinically helpful. We suggest starting treatment in all patients, regardless of age, at a dose of 2-5 mg twice daily and then titrating this accordingly. JAMES MALONE-LEE DAVID LUBEL GEORGE SZONYI
Division of Geriatric Medicine, Department of Medicine, University College and Middlesex School of Medicine, St Pancras Hospital, London NW 1 OPE 1 Koyanagi T, Maru A, Taniguchi K, Shinno Y, Takamatsu T, Morita H, et al. Clinical evaluation of oxybutynin hydrochloride tablets for the treatment of neurogenic bladder and unstable bladder. A parallel double-blind controlled study with placebo. NishinihonJournal of Urology 1986;48:1052-72. 2 Douchamps J, Derenne F, Stockis A, Gangji D, Juvent M, Herchuelz A. The pharmacokinetics of oxybutynin in man. EurJ Clin Pharmacol 1988;35:515-20.
Exploding microwaved eggs SIR,-Recently, three cases of ocular injury due to exploding microwaved eggs have been reported."2 In one case seven eggs were microwaved in their
shells and six exploded spontaneously on removal from the oven.2 In the two other cases eggs without their shells were cooked in the microwave oven without the yolk sac having been pierced.' In all three cases return to normal visual acuity occurred. We report a more severe case, in which vision was still reduced four months after the injury. A 22 year old woman cracked an egg into a bowl of water and heated it in a microwave oven. Immediately after she removed the dish from the oven the egg exploded in her face. She sustained first degree burns to the skin on the malar areas and the lower lids. There was epithelial loss affecting the conjunctiva and cornea in both eyes: all corneal epithelium was lost in the left eye. It took two weeks for the left cornea to re-epithelialise. The peripheral cornea became vascularised and inflamed, and the epithelium remained unstable. The patient required treatment in a special corneal clinic and also by the burns team. The right eye and skin of the lid rapidly healed within 10 days of the injury. Four months later the left malar skin remained erythematous and had to be camouflaged with cosmetics. The left cornea remained inflamed and vascularised at the periphery. The eye was still partially closed, and the vision remained reduced to 6/12 owing to abnormal corneal epithelium. Topical steroid treatment was continued. Microwaved eggs explode owing to rapid expansion of gas within closed compartments formed by the chorioallantoic and shell membranes and the yolk sac. Eggs can be safely cooked in a microwave oven if the shell is cracked open and the yolk sac is punctured before heating. Alternatively, eggs can be scrambled. Up to now reported eye injuries due to this cause have not been serious and have resolved fully. The case we describe shows that more serious eye injuries may also occur. Eggs should not be cooked in a microwave oven unless the yolk sac has been pierced, and we additionally suggest that they should not be cooked in water as the combination ofhot water and egg yolk seems to have caused a more severe injury. P CORRIDAN J HSUAN N J PRICE P J McDONNELL
Birmingham and Midland Eye Hospital, Birmingham B3 2NS 1 Singh J, Shah P, Sutton GA. Exploding eggs. N Engl. Med 1991;325: 1749. 2 Bradford GE, Bumstine RA. Exploding eggs. N Engl I Med 1991;325: 1749.
Survival of peripheral intravenous infusions SIR,-J F Hecker fails to address well established factors that play an important part in the survival of peripheral intravenous infusions-namely, trauma at the site of the infusion, the size of the cannula and the material from which it is made, and the use of topical non-steroidal antiinflammatory gel. ' The skill of the operator inserting the cannula is important: Cosentino found that greater experience in performing venepuncture decreased the incidence of infusion thrombophlebitis.2 In response to this problem, many North American hospitals employ intravenous therapy teams for routine insertion of cannulas.3 Recent advances in polymer technology have resulted in improved materials for cannulas. Polyurethane is less thrombogenic than Teflon, which in turn is less thrombogenic than polyethylene and polypropylene.4'6 Comparison of Teflon and polyurethane cannulas showed that the material from which the cannula was made was the single most important factor in the incidence and severity of infusion thrombophlebitis, polyurethane cannulas being associated with a 46% lower incidence.6
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