1213 sponse and augment the proposed "adaptive the late stages of pre-eclamptic pregnancy. Division of Internal Medicine, University of Calgary, Calgary, Alberta, Canada
process" during
R. M. LEWKONIA
HUMAN PLACENTAL LACTOGEN IN LATE PREGNANCY
SIR,-Dr Letchworth and his colleagues (May 6, p. 955) suggest that human placental lactogen (H.P.L.) in serum be routinely screened in late pregnancy. We have been doing this but occasionally have met problems. One such case was that of a 26-year-old primigravida who, after stopping oral contraceptives 2 years before conception, had had normal 28-day menstrual cycles. The early pregnancy was uneventful and fetal movements were felt at the 21st week. Between the 20th and 33rd week the patient put on 5.55 kg. A routine serum-H.P.L. in the 33rd week was less than 2.0 mg/1 (H.P.L. immunoassay kit, Radiochemical Centre, Amersham). Clinically the size of the uterus and the fetus appeared normal for the gestation; the blood-pressure was normal. H.P.L. values at weeks 34 and 35 were 1.1 and 1.0 mg/1, respectively. Because of these low H.P.L. levels the patient was admitted for observation. During the 34th week the 24 h urinary excretion of oestrogens was 129 mol. Twice-weekly 24 h urinary oestrogen determinations from then on showed a progressive rise, and by the 38th week reached a peak of 240 mol. Oestrogen excretion fell to 198 tmol/24 h at the 39th week. A repeat H.P.L. at 39 weeks was again below 2.0 mg/1. The fetal biparietal diameter at that time was normal for the gestational age. The placenta had some calcification from the 36th week onwards but was of normal size. The patient was induced empirically at term and after a labour lasting 15 h she had a forceps delivery of a male infant weighing 3.42 kg. The only sign of fetal distress was a rapid fall in the fetal heart-rate to 80 beats/min at the beginning of the second stage of labour. The Apgar score was 2 at 1 min and 8 at 5 min. The placenta weighed 550 g and had scattered areas of calcification but no definite infarcts. The subsequent progress of both mother and baby was uneventful. Serum-H.p.L. rises progressively with gestation, and failure to reach the expected concentrations in the 3rd trimester of pregnancy has been found to be an index of placental insufficiency. In this patient’s serum H.P.L. was almost undetectable. We do not know why. The conventional assay kit is one we have used in many pregnancies without encountering this problem. H.P.L. has a dimeric form,’ but the dimer is more active than the monomer in the radioimmunoassay. The H.P.L. produced by our patient may have had altered immunological determinants in the molecule. Another possibility is that H.P.L. production was defective. Saxena et al.2 suggested that low H.P.L./H.C.G. ratios are helpful in distinguishing neoplasms from normal trophoblasts during early pregnancy because of the impaired production of H.P.L. by trophoblastic neoplasms. In our patient there was no evidence that the placenta was abnormal, the pregnancy was uneventful, and follow-up has been unremarkable. Another possible explanation may be that destruction of H.p.L. was more rapid than normal. This case shows that very low H.P.L. values may be found in the last trimester of normal pregnancy. This biochemical finding prompted close monitoring of the patient although the pregnancy and birth were normal.
Maternity
Unit and Department of Chemical Pathology, North Devon District Hospital, Barnstaple, Devon EX31 4JB
1.
W. P. BRADFORD T. HARGREAVES
Schneider, A. B., Kowalski, K., Buchman, G., Sherwood, L. M. Biochim. biophys. Acta, 1977, 493, 69. 2. Saxena, B. N., Goldstein, D. P., Emerson, Jr. K., Selenkow, H. A. Am. J. Obstet. Gynec. 1968, 102, 115.
SIR,-Dr Letchworth and his colleagues recommend H.P.L. assay as a routine screening test to identify at-risk pregnancies. The prediction of danger to the life of the fetus would be the most important feature of such a test, but Letchworth et al. give no data on this aspect of pregnancy outcome. Spellacy et al.’ in a large study, showed that of 71 pregnancies which ended with intrauterine death only 36 (51%) had low H.P.L. levels at or before fetal death. H.P.L. levels were low in most pregnancies with severe toxaemia, but 18 out of 19 normotensive patients had normal H.P.L. levels. Toxocmia is a major threat and affected patients receive intensive antenatal care as a matter of course. Identification of patients who will have a poor outcome of their pregnancy in the absence of clinical features associated with high risk is very important. In this respect H.P.L. was ineffective and misled the obstetrician. Our experience with H.P.L. assays in late pregnancy, with the same kit method as Letchworth et al., is similar to that of Spellacy et al. We have measured H.P.L. more than 4000 times in some 2300 patients. We have H.P.L. data on 22 pregnancies which resulted in intrauterine death. Only 6 of these patients had abnormally low H.P.L. levels (less than 4-0 mg/1). In 7 patients the blood-sample was obtained after intrauterine death and non-detection of fetal heart sounds; H.P.L. levels were normal or higher. Clearly, maternal serum-H.P.L. values do not reflect fetal health, and it is doubtful if H.P.L. levels bear a quantitative relationship to placental function. We have found many pregnancies with abnormally low H.P.L. levels (less than 2.0 mg/1) and a satisfactory outcome whereas intrauterine death could occur in the presence of normal H.P.L. We have recently measured oestriol in all plasma samples submitted for H.P.L. assay and have to date comparable results in10 pregnancies which resulted in intrauterine death. Oestriol was found to be abnormally low in all cases, but H.P.L. was abnormally low in only 2. In 1 case oestriol fell progressively over three weeks before death of the fetus whereas H.P.L. actually increased slightly over the same period. Measurement of urinary cestrogens is a well-established procedure for screening large numbers of patients in late pregnancy ; serum (or plasma) oestriol assay seems the obvious choice if a further test is required. If H.P.L. assay is used as a screening test an early warning of intrauterine death may be missed in at least 50% of cases. Bellshill Maternity Hospital, Bellshill, Lanarkshire ML4 3JN
L. G. S. RAO W. PLENDERLEITH
CONTROLLED TRIALS IN SURGERY
SIR,-In theory, reviewers of scientific papers impose standards for acceptance based on the aim of all scientists-to report a true result. For therapeutic trials a true result depends on the design-i.e., the results should reveal real treatment effects by measures which avoid bias in selecting patients and administering therapy. Acceptance of the results for publication implies merit, and without publication it is very difficult to establish a new treatment in practice. Medical journals thus become the filter through which properly studied treatments can go on to application but through which badly designed trials should not be able to pass. While this has been increasingly true for drugs it has not been the case for new surgical procedures and new applications of established procedures. Most journal reviewers, abstract referees for scientific meetings, and hospital research committees maintain high standards for the design of medical therapeutic trials. Yet they do not impose equal standards for surgical trials. This is not because such trials cannot be done. Prospective, controlled trials of surgical therapy, including random allocation of patients, are feasible though perhaps 1.
Spellacy, 835.
W. N.,
Buhi, W. C., Birk, S. A. Am. J. Obstet. Gynec. 1975, 121,
1214 difficult than comparably designed trials of non-surgical therapy. Relatively few, however, have been done, and these have followed rather than preceded the widespread introduction of new operations. Yet, to establish as early as possible that a treatment is truly effective and to find out exactly for whom it is indicated, the same principles must apply to all therapies. Unless this is recognised, uncertainty will continue to provoke controversies, as in the protracted arguments over operations for common diseases like peptic ulcer, breast carmore
cinoma, and coronary-artery obstruction. The years consumed and the heat
generated by disputants whose skill and intellect to the persistent problem of getting valid evidence-to the detriment of our patients. We believe that this is the result of the absence of standards of proof for new surgical treatments and new applications of existing surgiare
undoubted, testify
cal treatments. There is no scientific or humanistic reason why standards for acceptance should not be equal for all treatments. On the contrary, science and ethics demand our best efforts for equal standards. Moreover, there is every reason for their application from the very first clinical trial of each treatment. It is true that reduction of operative mortality improves with experience, yet proof of current benefit to patients necessarily applies to current experience. Our point is related to the quality of such proof. We believe that the publication "filter" is the place to maintain equally high standards for all treatments. We would ask you Sir, to consider an explicit policy of equal standards for therapeutic trials of all therapies. -
DAVID H. SPODICK, Cardiology Division, Saint Vincent Hospital, Worcester, Massachusetts 01604, U.S.A.; and University of Massachusetts Medical School WILBERT ARONOW University of California BERNARD Columbia
BARBER, University
BERNARD LOWN University
Harvard
VIRENDRA S. MATHUR, Baylor University
HENRY BLACKBURN, University of Minnesota
HENRY D.
DAVID BOYD, Lahey Clinic
THOMAS A. PRESTON,
C. RICHARD CONTI, University of Florida
JAMES P. LOGERFO, University of Washington
MCINTOSH,
Watson Clinic
U.S. P.H.S., Seattle
ARTHUR SELZER, University of California TIMOTHY TAKARO, V.A., Asheville, N. C.
rapidly.
We have confirmed these
findings but also noted a few
patients had very large gains, particularly on days 2-3.
largest single weight gain in a 24 h period was in a 62 who put on 3.1kg (5% of body-weight). Although kg she had not had toxaemia her blood-pressure rose to 200/120 mm Hg after delivery but settled rapidly without treatment on day 1, and she lost her extra fluid over the next few days. A West Indian patient gained 2.2kg on day 2, lost 1 -0kg on day 3, and then gained 1.9kg on day 4, when slight ankle oedema developed. Her net gain was 3-1kg. A second West Indian woman gained 2.75 kg over 48 h. 5 other patients had gains greater than 1 kg, on days 2, 4, or 5. Thus 20% of the sample gained more than 1 kg and 5% had weight gains greater than 3 kg during the early puerperium. Except for the patient with transient hypertension the patients were symptom-free. These large weight gains, which were followed by equally large losses on days 4-7, prompted us to examine urinary sodium excretion, since the changes seemed larger than could be explained by diet alone. We collected sequential 24 h urines from 9 of the patients from day 2 to day 7. No patient had The
woman
heart-disease, toxa:mia, excessive blood-loss,
or anorexia, and the standard hospital diet. They would be expected to excrete 100-300 mmol of sodium per 24 h. During day 4 sodium excretion was 137 (40-416) mmol/24 h (mean and range) and on day 6 it was 140 (38-222); however, excretion and in 3 was reduced on day 2 to 48 mmol (3-142) (P
process" during
R. M. LEWKONIA
HUMAN PLACENTAL LACTOGEN IN LATE PREGNANCY
SIR,-Dr Letchworth and his colleagues (May 6, p. 955) suggest that human placental lactogen (H.P.L.) in serum be routinely screened in late pregnancy. We have been doing this but occasionally have met problems. One such case was that of a 26-year-old primigravida who, after stopping oral contraceptives 2 years before conception, had had normal 28-day menstrual cycles. The early pregnancy was uneventful and fetal movements were felt at the 21st week. Between the 20th and 33rd week the patient put on 5.55 kg. A routine serum-H.P.L. in the 33rd week was less than 2.0 mg/1 (H.P.L. immunoassay kit, Radiochemical Centre, Amersham). Clinically the size of the uterus and the fetus appeared normal for the gestation; the blood-pressure was normal. H.P.L. values at weeks 34 and 35 were 1.1 and 1.0 mg/1, respectively. Because of these low H.P.L. levels the patient was admitted for observation. During the 34th week the 24 h urinary excretion of oestrogens was 129 mol. Twice-weekly 24 h urinary oestrogen determinations from then on showed a progressive rise, and by the 38th week reached a peak of 240 mol. Oestrogen excretion fell to 198 tmol/24 h at the 39th week. A repeat H.P.L. at 39 weeks was again below 2.0 mg/1. The fetal biparietal diameter at that time was normal for the gestational age. The placenta had some calcification from the 36th week onwards but was of normal size. The patient was induced empirically at term and after a labour lasting 15 h she had a forceps delivery of a male infant weighing 3.42 kg. The only sign of fetal distress was a rapid fall in the fetal heart-rate to 80 beats/min at the beginning of the second stage of labour. The Apgar score was 2 at 1 min and 8 at 5 min. The placenta weighed 550 g and had scattered areas of calcification but no definite infarcts. The subsequent progress of both mother and baby was uneventful. Serum-H.p.L. rises progressively with gestation, and failure to reach the expected concentrations in the 3rd trimester of pregnancy has been found to be an index of placental insufficiency. In this patient’s serum H.P.L. was almost undetectable. We do not know why. The conventional assay kit is one we have used in many pregnancies without encountering this problem. H.P.L. has a dimeric form,’ but the dimer is more active than the monomer in the radioimmunoassay. The H.P.L. produced by our patient may have had altered immunological determinants in the molecule. Another possibility is that H.P.L. production was defective. Saxena et al.2 suggested that low H.P.L./H.C.G. ratios are helpful in distinguishing neoplasms from normal trophoblasts during early pregnancy because of the impaired production of H.P.L. by trophoblastic neoplasms. In our patient there was no evidence that the placenta was abnormal, the pregnancy was uneventful, and follow-up has been unremarkable. Another possible explanation may be that destruction of H.p.L. was more rapid than normal. This case shows that very low H.P.L. values may be found in the last trimester of normal pregnancy. This biochemical finding prompted close monitoring of the patient although the pregnancy and birth were normal.
Maternity
Unit and Department of Chemical Pathology, North Devon District Hospital, Barnstaple, Devon EX31 4JB
1.
W. P. BRADFORD T. HARGREAVES
Schneider, A. B., Kowalski, K., Buchman, G., Sherwood, L. M. Biochim. biophys. Acta, 1977, 493, 69. 2. Saxena, B. N., Goldstein, D. P., Emerson, Jr. K., Selenkow, H. A. Am. J. Obstet. Gynec. 1968, 102, 115.
SIR,-Dr Letchworth and his colleagues recommend H.P.L. assay as a routine screening test to identify at-risk pregnancies. The prediction of danger to the life of the fetus would be the most important feature of such a test, but Letchworth et al. give no data on this aspect of pregnancy outcome. Spellacy et al.’ in a large study, showed that of 71 pregnancies which ended with intrauterine death only 36 (51%) had low H.P.L. levels at or before fetal death. H.P.L. levels were low in most pregnancies with severe toxaemia, but 18 out of 19 normotensive patients had normal H.P.L. levels. Toxocmia is a major threat and affected patients receive intensive antenatal care as a matter of course. Identification of patients who will have a poor outcome of their pregnancy in the absence of clinical features associated with high risk is very important. In this respect H.P.L. was ineffective and misled the obstetrician. Our experience with H.P.L. assays in late pregnancy, with the same kit method as Letchworth et al., is similar to that of Spellacy et al. We have measured H.P.L. more than 4000 times in some 2300 patients. We have H.P.L. data on 22 pregnancies which resulted in intrauterine death. Only 6 of these patients had abnormally low H.P.L. levels (less than 4-0 mg/1). In 7 patients the blood-sample was obtained after intrauterine death and non-detection of fetal heart sounds; H.P.L. levels were normal or higher. Clearly, maternal serum-H.P.L. values do not reflect fetal health, and it is doubtful if H.P.L. levels bear a quantitative relationship to placental function. We have found many pregnancies with abnormally low H.P.L. levels (less than 2.0 mg/1) and a satisfactory outcome whereas intrauterine death could occur in the presence of normal H.P.L. We have recently measured oestriol in all plasma samples submitted for H.P.L. assay and have to date comparable results in10 pregnancies which resulted in intrauterine death. Oestriol was found to be abnormally low in all cases, but H.P.L. was abnormally low in only 2. In 1 case oestriol fell progressively over three weeks before death of the fetus whereas H.P.L. actually increased slightly over the same period. Measurement of urinary cestrogens is a well-established procedure for screening large numbers of patients in late pregnancy ; serum (or plasma) oestriol assay seems the obvious choice if a further test is required. If H.P.L. assay is used as a screening test an early warning of intrauterine death may be missed in at least 50% of cases. Bellshill Maternity Hospital, Bellshill, Lanarkshire ML4 3JN
L. G. S. RAO W. PLENDERLEITH
CONTROLLED TRIALS IN SURGERY
SIR,-In theory, reviewers of scientific papers impose standards for acceptance based on the aim of all scientists-to report a true result. For therapeutic trials a true result depends on the design-i.e., the results should reveal real treatment effects by measures which avoid bias in selecting patients and administering therapy. Acceptance of the results for publication implies merit, and without publication it is very difficult to establish a new treatment in practice. Medical journals thus become the filter through which properly studied treatments can go on to application but through which badly designed trials should not be able to pass. While this has been increasingly true for drugs it has not been the case for new surgical procedures and new applications of established procedures. Most journal reviewers, abstract referees for scientific meetings, and hospital research committees maintain high standards for the design of medical therapeutic trials. Yet they do not impose equal standards for surgical trials. This is not because such trials cannot be done. Prospective, controlled trials of surgical therapy, including random allocation of patients, are feasible though perhaps 1.
Spellacy, 835.
W. N.,
Buhi, W. C., Birk, S. A. Am. J. Obstet. Gynec. 1975, 121,
1214 difficult than comparably designed trials of non-surgical therapy. Relatively few, however, have been done, and these have followed rather than preceded the widespread introduction of new operations. Yet, to establish as early as possible that a treatment is truly effective and to find out exactly for whom it is indicated, the same principles must apply to all therapies. Unless this is recognised, uncertainty will continue to provoke controversies, as in the protracted arguments over operations for common diseases like peptic ulcer, breast carmore
cinoma, and coronary-artery obstruction. The years consumed and the heat
generated by disputants whose skill and intellect to the persistent problem of getting valid evidence-to the detriment of our patients. We believe that this is the result of the absence of standards of proof for new surgical treatments and new applications of existing surgiare
undoubted, testify
cal treatments. There is no scientific or humanistic reason why standards for acceptance should not be equal for all treatments. On the contrary, science and ethics demand our best efforts for equal standards. Moreover, there is every reason for their application from the very first clinical trial of each treatment. It is true that reduction of operative mortality improves with experience, yet proof of current benefit to patients necessarily applies to current experience. Our point is related to the quality of such proof. We believe that the publication "filter" is the place to maintain equally high standards for all treatments. We would ask you Sir, to consider an explicit policy of equal standards for therapeutic trials of all therapies. -
DAVID H. SPODICK, Cardiology Division, Saint Vincent Hospital, Worcester, Massachusetts 01604, U.S.A.; and University of Massachusetts Medical School WILBERT ARONOW University of California BERNARD Columbia
BARBER, University
BERNARD LOWN University
Harvard
VIRENDRA S. MATHUR, Baylor University
HENRY BLACKBURN, University of Minnesota
HENRY D.
DAVID BOYD, Lahey Clinic
THOMAS A. PRESTON,
C. RICHARD CONTI, University of Florida
JAMES P. LOGERFO, University of Washington
MCINTOSH,
Watson Clinic
U.S. P.H.S., Seattle
ARTHUR SELZER, University of California TIMOTHY TAKARO, V.A., Asheville, N. C.
rapidly.
We have confirmed these
findings but also noted a few
patients had very large gains, particularly on days 2-3.
largest single weight gain in a 24 h period was in a 62 who put on 3.1kg (5% of body-weight). Although kg she had not had toxaemia her blood-pressure rose to 200/120 mm Hg after delivery but settled rapidly without treatment on day 1, and she lost her extra fluid over the next few days. A West Indian patient gained 2.2kg on day 2, lost 1 -0kg on day 3, and then gained 1.9kg on day 4, when slight ankle oedema developed. Her net gain was 3-1kg. A second West Indian woman gained 2.75 kg over 48 h. 5 other patients had gains greater than 1 kg, on days 2, 4, or 5. Thus 20% of the sample gained more than 1 kg and 5% had weight gains greater than 3 kg during the early puerperium. Except for the patient with transient hypertension the patients were symptom-free. These large weight gains, which were followed by equally large losses on days 4-7, prompted us to examine urinary sodium excretion, since the changes seemed larger than could be explained by diet alone. We collected sequential 24 h urines from 9 of the patients from day 2 to day 7. No patient had The
woman
heart-disease, toxa:mia, excessive blood-loss,
or anorexia, and the standard hospital diet. They would be expected to excrete 100-300 mmol of sodium per 24 h. During day 4 sodium excretion was 137 (40-416) mmol/24 h (mean and range) and on day 6 it was 140 (38-222); however, excretion and in 3 was reduced on day 2 to 48 mmol (3-142) (P
