891
in quality of preservation, seen discernible. Nonetheless the incidence of experimentally,’ rejection was unexpectedly low, being 50% at 1 year in the cardiosol series and 78% in all other heart transplantation recipients followed up for at least 6 months at our centre. For the last 22 patients operated on before the cardiosol protocol was introduced the 1 year rejection rate was 73%. Historically rejection rates at our centre have not been atypical. 3-5 There are at least two possible explanations for the apparently lower incidence of rejection in this series. One is a greater risk of injury during preservation with standard cardioplegic solutions. This possibility was raised by Howard et al6 in the context of liver preservation but it has not been described in cardiac transplantation, and severe preservation injury is unusual in donor hearts. An alternative explanation is a direct effect of the solution itself on the immune process. Reduced immunogenicity of and the induction of tolerance by antigens covalently linked to PEG have been described7-9 but we know of no evidence for an immunosuppressive effect of PEG in the absence of chemical combination with antigen. PEG can form reversible complexes with lipids such as are found in cell membranes,lo and this process might lead to masking of or alterations in membrane-bound transplantation antigens. We have lately found that this solution delays rejection in a rat liver transplant model and have shown that PEG is the active ingredient (unpublished). Randomised clinical trials of cardiosol and further animal studies on PEG solutions seem warranted.
objective improvement was not
Pacific Transplant Institute, California Pacific Medical Center, San Francisco, California 94115, USA Union and South South
Carbide Chemicals Plastics Co Inc, Charleston Technical Center, Charleston, West Virginia
Pacific Transplant Institute
G. M. COLLINS W. N. WICOMB B. S. LEVIN
Anphar-Rolland SA). We report here a case of liver transplantation secondary to tienilic-acid-induced fulminant hepatitis. A non-alcoholic, previously healthy 49-year-old man was put on tienilic acid 250 mg daily because of mild hypertension, in place of an amiloride/hydrochlorothiazide combination. Allopurinol, fenofibrate, and benfluorex had been prescribed for metabolic disorders. 6 weeks later, jaundice developed. The patient was admitted to Hopital Saint-Antoine on May 25, 1991, with transaminases 88 and 63 times the upper limits of normal. Prothrombin time and factor V were 20% and 23% of normal, respectively. Serological tests for viral hepatitis (A, B, C, cytomegalovirus, herpesvirus) and HIV were negative. All immunological tests gave negative results, except for high titres (500) of liver/kidney microsomal type 2 autoantibodies, which are considered specific for tienilic acid hepatotoxicity.6 The patient rapidly worsened and would have died had liver transplantation 8 days later not been possible. According to our information 52 000 packs of ’Diflurex’ (tienilic acid) were sold in France in March, 1991, this corresponding to about 25 000 patients, all at risk of severe acute or chronic hepatitis. This drug has no advantages over other diuretics; it certainly has the worst risk/benefit ratio of any antihypertensive drug.
Regional Pharmacovigilance Centre and Hepatology Unit, Hôpital Saint-Antoine, 755571 Paris, France
M. BIOUR A. POUJOL O. CHAZOUILLERES C. HOUSSET P. GIRAL R. POUPON
Simpson FO, Wall-Manning HJ. Total ban on tienilic acid. Lancet 1980; i: 978-79. Jean-Pastor M-J, Jouglard J. Bilan des accidents hépatiques médicamenteux recueillis par la pharmacovigilance française. Thérapie 1984; 39: 493-500. 3. Pariente EA, André C, Zafrani ES, et al. Hépatite aigue, hépatite chronique et cirrhose à l’acide tiénilique. Gastrooentérol Clin Biol 1981; 5: 567-71. 4. Lafay J-P, Poupon R, Legendre C, et al. Atteintes hépatiques associées aux anticorps antimicrosomes de foie et de rein (type 2) et à la prise d’acide tiénilique: une étude de 37 observations. Gasteroentérol Clin Biol 1983; 7: 523-28. 5. Lechevalier L, Lebrec D, Lam X, et al. Hépatite fulminante due à l’acide tiénilique. 1.
2.
S. VERMA
J. AVERY J. D. HILL
Gastroentérol Clin Biol 1987; 11: 262-63. 1. Wicomb WN, Hill JD, Avery J, Collins GM. Optimal cardioplegia and 24-hour heart storage with simplified UW solution containing polyethylene glycol. Transplantation 1990; 49: 261-64. 2. Kriett JM, Kaye MP. The registry of the International Society for Heart Transplantation: seventh official report—1990. J Heart Transplant 1990; 9:
323-30. 3. Starnes VA, Oyer PE, Stinson EB, Dein JR, Shumway NE. Prophylactic OKT3 used as induction therapy for heart transplantation. Circulation 1989; 80: 79-83. 4. Griffith BP, Kormos RL, Armitage JM, Dummer J S, Hardesty RL. Comparative trial of immunoprophylaxis with RATG versus OKT3. J Heart Transplant 1990; 9: 301-05. 5. Renlund DG, O’Connell JB, Gilbert EM, et al. A prospective comparison of murine monoclonal CD3 (OKT3) antibody-based and equine antilymphocyte globulinbased rejection prophylaxis in cardiac transplantation: decreased rejection and less corticosteroid use with OKT3. Transplantation 1989; 47: 599-605. 6. Howard TK, Klintmalm GB, Cofer JB, Husberg BS, Goldstein RM, Gonwa TA. The influence of preservation injury on rejection in the hepatic transplant recipient. Transplantation 1990; 49: 103-07. 7 Savoca KV, Davis FF, Palczuk NC. Induction of tolerance in mice by uricase and monomethoxypolyethylene glycol-modified uricase. Int Arch Allergy Appl Immunol 1984; 75: 58-67. 8. Katre NV. Immunogenicity of recombinant IL-2 modified by covalent attachment of polyethylene glycol. J Immunol 1990; 144: 209-13. 9. Wie SI, Wie WY, Lee WY, Filion LG, Sehon AH, Akerblom E. Suppression of reagin antibodies with modified allergens, III: preparation of tolerogenic conjugates of common allergens with monomethoxypolyethylene glycols of different molecular weights by the mixed anhydride method. Int Arch Allergy Appl Immunol 1981; 64: 84-89. 10. Boni LT, Hah JS, Hui SW, Mukerjee JT, Jung CY. Aggregation and fusion of unilamellar vesicles by poly(ethylene glycol). Biochim Biophys Acta 1984; 775: 409-18.
Fulminant hepatitis due to tienilic acid SiR,—Tienilic acid (ticrynafen) was removed from the US market by the Food and Drug Administration in January, 1980, its US manufacturer (Smith Kline & French) having received 363 reports of hepatotoxicity, 24 fatal. 71 possible or definite cases were notified to French regional centres of pharmacovigilance by June, 1983;1 128 cases, including 4 fatal, have been published in French journals (see refs 2-5, for example); and the French National System of Pharmacovigilance has received almost 500 cases of liver injury since March, 1976. Yet the drug is still marketed in France (by
6.
Homberg J-C, Abuaf N, Helmy-Khaul S, et al. Drug-induced hepatitis associated with anticytoplasmic organelle autoantibodies. Hepatology 1985; 5: 722-27.
Fundal
height—can we trust the umbilicus?
SiR,—Your Aug 17 editorial (p 415) stresses the importance of monitoring weight gain during pregnancy and suggests that assessment of weight changes together with other clinical risk factors can aid in detecting impaired fetal growth. We would like to discuss another simple physical examination in antenatal care and follow-up. Determination of gestational age is essential in pregnancy management-but in the absence of a reliable menstrual history, this may be based solely on physical findings. Thus, estimation of uterine size is an integral part of any antenatal check-up. The umbilicus is used by most obstetricians as a reference point for fundal height. It is widely assumed that the uterine fundus reaches the umbilicus at about 20 weeks’ gestation. However, perusal of nine textbooks of obstetrics reveals a confusing variety of estimates for the gestational age that is indicated by the level of umbilicus-three books note that the uterine fundus reaches the umbilicus at 20 weeks, three others say 20-24 weeks, and three more at 24 weeks. This variation may reflect the anatomical truth that the location of the umbilicus is inconstant, as are the thickness of the abdominal wall, the amount of amniotic fluid, and the size of the fetus. Uterine leiomyomas and/or multiple pregnancy may compound the obstacles to accurate clinical evaluation. Jimenez and colleagues’ research, based on precise measurements of gestational age after ovulation, further complicated this issue by demonstrating that the fundus reached the umbilicus between 15 and 19 weeks in patients seen weekly.1 Thus gestational age may be overestimated by several weeks or more if it is assumed that the fundus reaches the umbilicus at 20 or 24 weeks. Indeed obstetric estimates based on this often do disagree with estimates based on the paediatrician’s findings on the newborn baby. An accurate date for the last menstrual period provides the most reliable estimate of delivery date. Fairly good estimates can be
892
achieved by averaging the dates of delivery predicted by careful examination of fundal height and fetal heart tones.2 Serial examinations during pregnancy are also useful in assessing normal development of the fetus.3 Because deviations from the expected rate of growth can alert the clinician to abnormalities of pregnancy, some measurement of fundal height should be recorded at every antenatal visit. Thus, measurement of the symphysis-fundus height may provide an easy and inexpensive screening test for intrauterine growth retardation, especially if done by the same investigator.4,5 Whether clinical estimates can approach the reliability of ultrasonography is unclear. Chaim Sheba Medical Centre, Tel Hashomer 52621, Israel
M. ROYBURT D. S. SEIDMAN
Jimenez JM, Tyson JE, Reisch JS. Clinical measures of gestational age in normal pregnancies. Obstet Gynecol 1983; 61: 438-43. 2. Andersen HF, Johnson TRB, Flora J, Barclay ML. Gestational age assessment II: prediction from combined clinical observation. Am J Obstet Gynecol 1981; 140: 1.
770-74. 3. Greenhill JP, Friedman EA. Biological principles and modem practice of obstetrics. Philadelphia: Saunders, 1974: 127. 4. Calvert JP, Crean EE, Newcombe RG, Pearson JF. Antenatal screening by measurement of symphysis-fundus height. Br Med J 1982; 285: 846-49. 5. Reece EA, Gabrielli S, Degennaro N, Hobbins JC. Dating through pregnancy: a measure of growing up. Obstet Gynecol Surv 1989; 44: 544-55.
validated. In the absence of a simple and reliable marker of risk for pre-eclampsia, the indications for use of aspirin in nulliparous women certainly remain few. It is difficult to believe that Davies and colleagues’ data do not favour the efficacy of aspirin, for two reasons. The first is the sample size. To have a 95 % chance of detecting a reduction from 25 to 10% in the frequency of hypertension, 256 cases would be needed. To detect a reduction from 25 to 5%, 122 women would be needed. Furthermore, the confidence interval of the difference in frequency of hypertension is — 0 02, + 0 32, which means that the data are compatible with a 2% increase as well as a 32% decrease in the frequency of hypertension in the treated group. The second reason is that the difference in birthweight that Davies et al observed is very similar to that in our study. We agree that the aim of aspirin treatment is not to increase birthweight per se, but rather to decrease the frequency of low birthweight, In this respect, it would be interesting to know if the observed difference in median birthweight was due to a decrease in low birthweight or an increase in high birthweight. Inserm U-149, 123 Bd de Port-Royal, 75014 Paris, France
Hôpital Tenon, Paris
Congenital heart block and maternal SLE SIR,-In your July 13 editorial about systemic lupus erythematosus (SLE) in pregnancy you report that the frequency of
congenital heart block (CHB) is 1 in 60 for all SLE pregnancies and 1 in 20 in mothers with anti-Ro antibodies, citing RamseyGoldman et al,l This estimation seems too pessimistic. RamseyGoldman and colleagues’ study was retrospective, and 3 of the 7 mothers of infants with CHB were diagnosed only because of their infant’s cardiac problem. In the sole prospective study published2 of 91 infants born to women with SLE who were followed up for 4 years had CHB, and 23% of the mothers were anti-Ro positive. During the same period 2 additional babies with CHB were born to mothers not previously known to have SLE. It is now generally agreed that as many as 70% of mothers of infants with neonatal SLE are symptom-free at the time of delivery3 and are identified only by the birth of an affected child,2,4 and for this reason cannot be prospectively identified.2 On the other hand, the estimated risk of having an infant with CHB is not established in women who are known to have SLE, but it should be very low even in women who are anti-Ro positive.2 none
Divisione Medica "Brera" and "De Gasperis",
Department of Cardiology, Niguarda Hospital, 20123 Milan, Italy
A. BRUCATO G. FERRARO M. GASPARINI
1. Ramsey-Goldman R, Hom D, Deng J, et al. Anti SS-A antibodies and fetal outcome in maternal systemic lupus erythematosus. Arthritis Rheum 1986; 29: 1269-73. 2. Lockshin MD, Bonfa E, Elkon K, Druzin ML. Neonatal lupus risk to newboms of mothers with systemic lupus erythematosus. Arthritis Rheum 1988; 31: 697-701. 3. Olson NY, Lindsley CB. Neonatal lupus syndrome. Am J Dis Chest 1987; 141: 908-10. 4.
Buyon JP, Winchester R. Congenital complete heart block. Arthritis Rheum 1990; 33: 609-14.
Low-dose aspirin and nulliparae SIR,-Dr Davies and colleagues (Aug 3, p 324) disagree with the in our report (June 15, p 1427) that "it now seems justifiable to propose aspirin treatment for any patient considered at high risk, even if in her first pregnancy". Their disagreement is based on the results of a trial, which they summarise. We have never proposed an extension of the indications for such treatment, and our clear message is that it is not justifiable to propose aspirin for any patient, unless she is at high risk. Thus, the dispute is about definition of high risk, and not parity. Two studies we discussed1,2 showed prevention of pre-eclampsia with the use of aspirin in nulliparous women. However, the researchers used screening tests that are either not applicable in routine use or not yet statement
1.
2
G. BREART M. BEAUFILS S. UZAN
Wallenburg HCS, Dekker GA, Makowitz JW, Rotmans P. Low-dose aspirin prevents pregnancy-induced hypertension and pre-eclampsia in angiotension-sensitive primigravidae. Lancet 1986; i: 1-3. McParland P, Pearce JM, Chamberlain GVP. Doppler ultrasound and aspirin in recognition and prevention of pregnancy-induced hypertension. Lancet 1990; 335: 1552-55.
Phytophotodermatitis, a botanical view SIR,-Increased awareness of phytophotodermatitis (PPD) has resulted in alarming and sometimes sensational coverage in the press. The front page of the Independent on Sunday on Sept 8 described a controversial case concerning a young child in whom hyperpigmentation had apparently developed after alleged contact with "cow parsley". When PPD is suspected, it is prudent to obtain the opinion of a botanist who has local field experience and can identify plants that might be responsible. The following points may help in the British Isles. Plant contact apart, PPD requires exposure to ultraviolet A in the wavelength range 320-380 nm.1 Many incidents occur in late summer, when high doses of UVA may be available. However, many plants that grow in spring and fruit in early summer have died back by then (eg, cow parsley). The plants responsible contain furocoumarins with a linear, tricyclic structure. Many belong to the Apiaceae (Umbelliferae), a family which contains several vegetables and herbs that have been implicated in contact dermatitis’ (eg, angelica, carrot, celery, fennel, and parsnip). This family also contains giant hogweed (Heradeum mantegazzianum), an enormous plant found on river banks and waste ground in some parts of Britain. PPD from giant hogweed is well known.2 Giant hogweed has spread in Britain but it is still uncommon in many areas. At least two other Apiaceae (hogweed and wild parsnip) could be involved in PPD in Britain. Both grow on roadside verges and in grassy, recreational areas. Hogweed (Hsphondylium) is widespread in Britain but wild parsnip (Pastinaca sativa) is common only in southern Britain, notably the south-east. Both species contain linear furocoumarins and should be suspected if found at the site of a possible PPD incident. Unfortunately, hogweed (H spJwndylium) is sometimes called cow parsnip, an unofficial name that can be confused with cow parsley, a separate species (Anthriscus sylvestris) that may not exhibit a strong phototoxic effect,1 Several Rutaceae, which are grown in parks and gardens, have been implicated in PPD-for example, rue (Ruta graveolens), burning bush (Dictamnus albus), skimmias (Skimmia spp), and citrus species (orange, lemon, lime).3 People who travel to southern Europe or North America may encounter others. During a field course to southern Spain (April, 1981) a student from Swansea had an alarming bullous reaction on the leg after contact with wild rue
in quality of preservation, seen discernible. Nonetheless the incidence of experimentally,’ rejection was unexpectedly low, being 50% at 1 year in the cardiosol series and 78% in all other heart transplantation recipients followed up for at least 6 months at our centre. For the last 22 patients operated on before the cardiosol protocol was introduced the 1 year rejection rate was 73%. Historically rejection rates at our centre have not been atypical. 3-5 There are at least two possible explanations for the apparently lower incidence of rejection in this series. One is a greater risk of injury during preservation with standard cardioplegic solutions. This possibility was raised by Howard et al6 in the context of liver preservation but it has not been described in cardiac transplantation, and severe preservation injury is unusual in donor hearts. An alternative explanation is a direct effect of the solution itself on the immune process. Reduced immunogenicity of and the induction of tolerance by antigens covalently linked to PEG have been described7-9 but we know of no evidence for an immunosuppressive effect of PEG in the absence of chemical combination with antigen. PEG can form reversible complexes with lipids such as are found in cell membranes,lo and this process might lead to masking of or alterations in membrane-bound transplantation antigens. We have lately found that this solution delays rejection in a rat liver transplant model and have shown that PEG is the active ingredient (unpublished). Randomised clinical trials of cardiosol and further animal studies on PEG solutions seem warranted.
objective improvement was not
Pacific Transplant Institute, California Pacific Medical Center, San Francisco, California 94115, USA Union and South South
Carbide Chemicals Plastics Co Inc, Charleston Technical Center, Charleston, West Virginia
Pacific Transplant Institute
G. M. COLLINS W. N. WICOMB B. S. LEVIN
Anphar-Rolland SA). We report here a case of liver transplantation secondary to tienilic-acid-induced fulminant hepatitis. A non-alcoholic, previously healthy 49-year-old man was put on tienilic acid 250 mg daily because of mild hypertension, in place of an amiloride/hydrochlorothiazide combination. Allopurinol, fenofibrate, and benfluorex had been prescribed for metabolic disorders. 6 weeks later, jaundice developed. The patient was admitted to Hopital Saint-Antoine on May 25, 1991, with transaminases 88 and 63 times the upper limits of normal. Prothrombin time and factor V were 20% and 23% of normal, respectively. Serological tests for viral hepatitis (A, B, C, cytomegalovirus, herpesvirus) and HIV were negative. All immunological tests gave negative results, except for high titres (500) of liver/kidney microsomal type 2 autoantibodies, which are considered specific for tienilic acid hepatotoxicity.6 The patient rapidly worsened and would have died had liver transplantation 8 days later not been possible. According to our information 52 000 packs of ’Diflurex’ (tienilic acid) were sold in France in March, 1991, this corresponding to about 25 000 patients, all at risk of severe acute or chronic hepatitis. This drug has no advantages over other diuretics; it certainly has the worst risk/benefit ratio of any antihypertensive drug.
Regional Pharmacovigilance Centre and Hepatology Unit, Hôpital Saint-Antoine, 755571 Paris, France
M. BIOUR A. POUJOL O. CHAZOUILLERES C. HOUSSET P. GIRAL R. POUPON
Simpson FO, Wall-Manning HJ. Total ban on tienilic acid. Lancet 1980; i: 978-79. Jean-Pastor M-J, Jouglard J. Bilan des accidents hépatiques médicamenteux recueillis par la pharmacovigilance française. Thérapie 1984; 39: 493-500. 3. Pariente EA, André C, Zafrani ES, et al. Hépatite aigue, hépatite chronique et cirrhose à l’acide tiénilique. Gastrooentérol Clin Biol 1981; 5: 567-71. 4. Lafay J-P, Poupon R, Legendre C, et al. Atteintes hépatiques associées aux anticorps antimicrosomes de foie et de rein (type 2) et à la prise d’acide tiénilique: une étude de 37 observations. Gasteroentérol Clin Biol 1983; 7: 523-28. 5. Lechevalier L, Lebrec D, Lam X, et al. Hépatite fulminante due à l’acide tiénilique. 1.
2.
S. VERMA
J. AVERY J. D. HILL
Gastroentérol Clin Biol 1987; 11: 262-63. 1. Wicomb WN, Hill JD, Avery J, Collins GM. Optimal cardioplegia and 24-hour heart storage with simplified UW solution containing polyethylene glycol. Transplantation 1990; 49: 261-64. 2. Kriett JM, Kaye MP. The registry of the International Society for Heart Transplantation: seventh official report—1990. J Heart Transplant 1990; 9:
323-30. 3. Starnes VA, Oyer PE, Stinson EB, Dein JR, Shumway NE. Prophylactic OKT3 used as induction therapy for heart transplantation. Circulation 1989; 80: 79-83. 4. Griffith BP, Kormos RL, Armitage JM, Dummer J S, Hardesty RL. Comparative trial of immunoprophylaxis with RATG versus OKT3. J Heart Transplant 1990; 9: 301-05. 5. Renlund DG, O’Connell JB, Gilbert EM, et al. A prospective comparison of murine monoclonal CD3 (OKT3) antibody-based and equine antilymphocyte globulinbased rejection prophylaxis in cardiac transplantation: decreased rejection and less corticosteroid use with OKT3. Transplantation 1989; 47: 599-605. 6. Howard TK, Klintmalm GB, Cofer JB, Husberg BS, Goldstein RM, Gonwa TA. The influence of preservation injury on rejection in the hepatic transplant recipient. Transplantation 1990; 49: 103-07. 7 Savoca KV, Davis FF, Palczuk NC. Induction of tolerance in mice by uricase and monomethoxypolyethylene glycol-modified uricase. Int Arch Allergy Appl Immunol 1984; 75: 58-67. 8. Katre NV. Immunogenicity of recombinant IL-2 modified by covalent attachment of polyethylene glycol. J Immunol 1990; 144: 209-13. 9. Wie SI, Wie WY, Lee WY, Filion LG, Sehon AH, Akerblom E. Suppression of reagin antibodies with modified allergens, III: preparation of tolerogenic conjugates of common allergens with monomethoxypolyethylene glycols of different molecular weights by the mixed anhydride method. Int Arch Allergy Appl Immunol 1981; 64: 84-89. 10. Boni LT, Hah JS, Hui SW, Mukerjee JT, Jung CY. Aggregation and fusion of unilamellar vesicles by poly(ethylene glycol). Biochim Biophys Acta 1984; 775: 409-18.
Fulminant hepatitis due to tienilic acid SiR,—Tienilic acid (ticrynafen) was removed from the US market by the Food and Drug Administration in January, 1980, its US manufacturer (Smith Kline & French) having received 363 reports of hepatotoxicity, 24 fatal. 71 possible or definite cases were notified to French regional centres of pharmacovigilance by June, 1983;1 128 cases, including 4 fatal, have been published in French journals (see refs 2-5, for example); and the French National System of Pharmacovigilance has received almost 500 cases of liver injury since March, 1976. Yet the drug is still marketed in France (by
6.
Homberg J-C, Abuaf N, Helmy-Khaul S, et al. Drug-induced hepatitis associated with anticytoplasmic organelle autoantibodies. Hepatology 1985; 5: 722-27.
Fundal
height—can we trust the umbilicus?
SiR,—Your Aug 17 editorial (p 415) stresses the importance of monitoring weight gain during pregnancy and suggests that assessment of weight changes together with other clinical risk factors can aid in detecting impaired fetal growth. We would like to discuss another simple physical examination in antenatal care and follow-up. Determination of gestational age is essential in pregnancy management-but in the absence of a reliable menstrual history, this may be based solely on physical findings. Thus, estimation of uterine size is an integral part of any antenatal check-up. The umbilicus is used by most obstetricians as a reference point for fundal height. It is widely assumed that the uterine fundus reaches the umbilicus at about 20 weeks’ gestation. However, perusal of nine textbooks of obstetrics reveals a confusing variety of estimates for the gestational age that is indicated by the level of umbilicus-three books note that the uterine fundus reaches the umbilicus at 20 weeks, three others say 20-24 weeks, and three more at 24 weeks. This variation may reflect the anatomical truth that the location of the umbilicus is inconstant, as are the thickness of the abdominal wall, the amount of amniotic fluid, and the size of the fetus. Uterine leiomyomas and/or multiple pregnancy may compound the obstacles to accurate clinical evaluation. Jimenez and colleagues’ research, based on precise measurements of gestational age after ovulation, further complicated this issue by demonstrating that the fundus reached the umbilicus between 15 and 19 weeks in patients seen weekly.1 Thus gestational age may be overestimated by several weeks or more if it is assumed that the fundus reaches the umbilicus at 20 or 24 weeks. Indeed obstetric estimates based on this often do disagree with estimates based on the paediatrician’s findings on the newborn baby. An accurate date for the last menstrual period provides the most reliable estimate of delivery date. Fairly good estimates can be
892
achieved by averaging the dates of delivery predicted by careful examination of fundal height and fetal heart tones.2 Serial examinations during pregnancy are also useful in assessing normal development of the fetus.3 Because deviations from the expected rate of growth can alert the clinician to abnormalities of pregnancy, some measurement of fundal height should be recorded at every antenatal visit. Thus, measurement of the symphysis-fundus height may provide an easy and inexpensive screening test for intrauterine growth retardation, especially if done by the same investigator.4,5 Whether clinical estimates can approach the reliability of ultrasonography is unclear. Chaim Sheba Medical Centre, Tel Hashomer 52621, Israel
M. ROYBURT D. S. SEIDMAN
Jimenez JM, Tyson JE, Reisch JS. Clinical measures of gestational age in normal pregnancies. Obstet Gynecol 1983; 61: 438-43. 2. Andersen HF, Johnson TRB, Flora J, Barclay ML. Gestational age assessment II: prediction from combined clinical observation. Am J Obstet Gynecol 1981; 140: 1.
770-74. 3. Greenhill JP, Friedman EA. Biological principles and modem practice of obstetrics. Philadelphia: Saunders, 1974: 127. 4. Calvert JP, Crean EE, Newcombe RG, Pearson JF. Antenatal screening by measurement of symphysis-fundus height. Br Med J 1982; 285: 846-49. 5. Reece EA, Gabrielli S, Degennaro N, Hobbins JC. Dating through pregnancy: a measure of growing up. Obstet Gynecol Surv 1989; 44: 544-55.
validated. In the absence of a simple and reliable marker of risk for pre-eclampsia, the indications for use of aspirin in nulliparous women certainly remain few. It is difficult to believe that Davies and colleagues’ data do not favour the efficacy of aspirin, for two reasons. The first is the sample size. To have a 95 % chance of detecting a reduction from 25 to 10% in the frequency of hypertension, 256 cases would be needed. To detect a reduction from 25 to 5%, 122 women would be needed. Furthermore, the confidence interval of the difference in frequency of hypertension is — 0 02, + 0 32, which means that the data are compatible with a 2% increase as well as a 32% decrease in the frequency of hypertension in the treated group. The second reason is that the difference in birthweight that Davies et al observed is very similar to that in our study. We agree that the aim of aspirin treatment is not to increase birthweight per se, but rather to decrease the frequency of low birthweight, In this respect, it would be interesting to know if the observed difference in median birthweight was due to a decrease in low birthweight or an increase in high birthweight. Inserm U-149, 123 Bd de Port-Royal, 75014 Paris, France
Hôpital Tenon, Paris
Congenital heart block and maternal SLE SIR,-In your July 13 editorial about systemic lupus erythematosus (SLE) in pregnancy you report that the frequency of
congenital heart block (CHB) is 1 in 60 for all SLE pregnancies and 1 in 20 in mothers with anti-Ro antibodies, citing RamseyGoldman et al,l This estimation seems too pessimistic. RamseyGoldman and colleagues’ study was retrospective, and 3 of the 7 mothers of infants with CHB were diagnosed only because of their infant’s cardiac problem. In the sole prospective study published2 of 91 infants born to women with SLE who were followed up for 4 years had CHB, and 23% of the mothers were anti-Ro positive. During the same period 2 additional babies with CHB were born to mothers not previously known to have SLE. It is now generally agreed that as many as 70% of mothers of infants with neonatal SLE are symptom-free at the time of delivery3 and are identified only by the birth of an affected child,2,4 and for this reason cannot be prospectively identified.2 On the other hand, the estimated risk of having an infant with CHB is not established in women who are known to have SLE, but it should be very low even in women who are anti-Ro positive.2 none
Divisione Medica "Brera" and "De Gasperis",
Department of Cardiology, Niguarda Hospital, 20123 Milan, Italy
A. BRUCATO G. FERRARO M. GASPARINI
1. Ramsey-Goldman R, Hom D, Deng J, et al. Anti SS-A antibodies and fetal outcome in maternal systemic lupus erythematosus. Arthritis Rheum 1986; 29: 1269-73. 2. Lockshin MD, Bonfa E, Elkon K, Druzin ML. Neonatal lupus risk to newboms of mothers with systemic lupus erythematosus. Arthritis Rheum 1988; 31: 697-701. 3. Olson NY, Lindsley CB. Neonatal lupus syndrome. Am J Dis Chest 1987; 141: 908-10. 4.
Buyon JP, Winchester R. Congenital complete heart block. Arthritis Rheum 1990; 33: 609-14.
Low-dose aspirin and nulliparae SIR,-Dr Davies and colleagues (Aug 3, p 324) disagree with the in our report (June 15, p 1427) that "it now seems justifiable to propose aspirin treatment for any patient considered at high risk, even if in her first pregnancy". Their disagreement is based on the results of a trial, which they summarise. We have never proposed an extension of the indications for such treatment, and our clear message is that it is not justifiable to propose aspirin for any patient, unless she is at high risk. Thus, the dispute is about definition of high risk, and not parity. Two studies we discussed1,2 showed prevention of pre-eclampsia with the use of aspirin in nulliparous women. However, the researchers used screening tests that are either not applicable in routine use or not yet statement
1.
2
G. BREART M. BEAUFILS S. UZAN
Wallenburg HCS, Dekker GA, Makowitz JW, Rotmans P. Low-dose aspirin prevents pregnancy-induced hypertension and pre-eclampsia in angiotension-sensitive primigravidae. Lancet 1986; i: 1-3. McParland P, Pearce JM, Chamberlain GVP. Doppler ultrasound and aspirin in recognition and prevention of pregnancy-induced hypertension. Lancet 1990; 335: 1552-55.
Phytophotodermatitis, a botanical view SIR,-Increased awareness of phytophotodermatitis (PPD) has resulted in alarming and sometimes sensational coverage in the press. The front page of the Independent on Sunday on Sept 8 described a controversial case concerning a young child in whom hyperpigmentation had apparently developed after alleged contact with "cow parsley". When PPD is suspected, it is prudent to obtain the opinion of a botanist who has local field experience and can identify plants that might be responsible. The following points may help in the British Isles. Plant contact apart, PPD requires exposure to ultraviolet A in the wavelength range 320-380 nm.1 Many incidents occur in late summer, when high doses of UVA may be available. However, many plants that grow in spring and fruit in early summer have died back by then (eg, cow parsley). The plants responsible contain furocoumarins with a linear, tricyclic structure. Many belong to the Apiaceae (Umbelliferae), a family which contains several vegetables and herbs that have been implicated in contact dermatitis’ (eg, angelica, carrot, celery, fennel, and parsnip). This family also contains giant hogweed (Heradeum mantegazzianum), an enormous plant found on river banks and waste ground in some parts of Britain. PPD from giant hogweed is well known.2 Giant hogweed has spread in Britain but it is still uncommon in many areas. At least two other Apiaceae (hogweed and wild parsnip) could be involved in PPD in Britain. Both grow on roadside verges and in grassy, recreational areas. Hogweed (Hsphondylium) is widespread in Britain but wild parsnip (Pastinaca sativa) is common only in southern Britain, notably the south-east. Both species contain linear furocoumarins and should be suspected if found at the site of a possible PPD incident. Unfortunately, hogweed (H spJwndylium) is sometimes called cow parsnip, an unofficial name that can be confused with cow parsley, a separate species (Anthriscus sylvestris) that may not exhibit a strong phototoxic effect,1 Several Rutaceae, which are grown in parks and gardens, have been implicated in PPD-for example, rue (Ruta graveolens), burning bush (Dictamnus albus), skimmias (Skimmia spp), and citrus species (orange, lemon, lime).3 People who travel to southern Europe or North America may encounter others. During a field course to southern Spain (April, 1981) a student from Swansea had an alarming bullous reaction on the leg after contact with wild rue
