Overview and future perspectives.
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Biomedical subjects
Publications and source records attributed to G M Stirrat.
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OBJECTIVE: To determine the current management of severe pre-eclampsia and eclampsia in the United Kingdom. DESIGN: One-page postal survey to all (1007) UK consultant obstetricians with questions about use of antihypertensive and anticonvulsant drugs in severe pre-eclampsia and eclampsia, other management strategies, definition of factors determining severity, protocol development and regional review. RESULTS: 688 replies (69.6% response rate). The antihypertensive drugs used were mainly oral labetalol (35%), oral methyl dopa (23%) and parenteral hydralazine (29%); diuretics were not used. Diazepam was the preferred drug in eclampsia. Very few consultants used magnesium sulphate (2%). Anticonvulsants were also prescribed by 85% of consultants to prevent fits; the drugs then preferred were diazepam (41%), phenytoin (30%) and chlormethiazole (24%). Two-thirds of consultants felt there was a need for trials to study the effectiveness of antihypertensive and anticonvulsant drugs. In a woman with proteinuric hypertension, 15% of consultants did not regard the development of headache as indicating severe pre-eclampsia. Consistent management practices were not associated with agreement about protocols. Regional review does not appear to have occurred. CONCLUSION: Antihypertensive and anticonvulsant therapies are widely used but trials are considered necessary. Improvements in the management of women with severe pre-eclampsia or eclampsia might occur if UK obstetricians sought more collective opinion and undertook regional audit of protocols.
All new interventions and procedures must be properly assessed in comparison to the currently accepted method(s). It is unethical not to do so. The optimum method is by Randomised Controlled Trial (RCT). This is ideally suited to the testing of drugs because the trial can usually be double blind and placebo controlled. RCTs are less commonly used for the evaluation of new surgical techniques. There are valid and invalid reasons for this and these are discussed.
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Raised levels (greater than or equal to 4.5 munits/ml) of acetylcholinesterase (AChE) activity in amniotic fluid at 14--23 weeks of pregnancy were significantly associated with open fetal neural-tube defects. Out of 72 pregnancies correctly classified by the amniotic-fluid alpha-fetoprotein (A.F.P.) test, 2 of 56 without neural-tube defects and all 16 with open neural-tube defects (8 with anencephaly and 8awith open spina bifida) had raised levels of AChE. Out of 5 pregnancies misclassified by the A.F.P. test (4 without neural-tube defects and 1 with open spina bifida), only 1 was misclassified by the AChE test--namely, one of those without a neural-tube defect. Thus, only 3 of the 77 pregnancies tested were misclassified by the quantitative AChE test. A qualitative test for an isoenzyme of AChE found in cerebrospinal fluid correctly classified these 3 pregnancies. These findings suggest that the analysis of AChE in amniotic fluid may be a useful test in the diagnosis of open neural-tube defects.
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Between May 1975 and the end of 1977, 6443 antenatal patients were screened mainly between 16 and 22 weeks of pregnancy for neural tube defects (NTDs) at the John Radcliffe Hospital, Oxford, by maternal serum alpha-fetoprotein (AFP) measurement; a take-up of 72 per cent. Seventeen out of 18 (94 per cent) patients with open NTD pregnancies (9 out of 9 with anencephaly and 8 out of 9 with open spina bifida) had positive screening tests, and all except one were offered and accepted a termination of pregnancy. Two hundred and forty-five (3.8 per cent) patients with unaffected pregnancies also had positive screening tests, although only 1.4 per cent had an amniocentesis. Following ultrasonography, about 50 per cent of patients with unaffected pregnancies with positive screening tests were not offered an amniocentesis because they had a multiple pregnancy or their gestational age had been underestimated. The odds of having a fetus with an NTD among the women who had an amniocentesis was about 1 to 6 (1 to 11 for open spina bifida alone). Two apparently normal pregnancies were terminated. A survey of the acceptability of the screening programme among a consecutive sample of 73 patients who knew that they had a positive screening test revealed that all except one had no objection to screening in general, and 68 (93 per cent) wanted to be tested again in a future pregnancy. The approximate direct cost of the programme was 2 pounds to 3 pounds per patient screened, or about 1000 pounds per NTD detected (about 2200 pounds per open spina bifida detected).
Maternal serum alpha-fetoprotein (AFP) levels were measured from 12 to 24 weeks gestation in 27 singleton pregnancies in women with insulin-dependent diabetes mellitus and 90 controls without diabetes who were matched for gestational age. The geometric mean AFP level among the diabetic pregnancies was 60 per cent of that in the controls, a difference which was statistically significant (P less than 0.01). The difference in AFP level between diabetic patients and controls was most marked in sera taken before 21 weeks gestation.
Eight case histories are presented which demonstrate clinical problems associated with the antenatal screening for and diagnosis of neural tube defects. It is suggested how some of these problems might be avoided in future.
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Sixteen patients with severe pre-eclampsia had more IgG-containing and C1q-binding circulating soluble immune complexes than did 16 matched women with normal pregnancies. The clinical features of preeclampsia may be explained by damage due to such complexes, although raised complex levels were also present in a few women with normal pregnancies. As immune complexes are so heterogenous in terms of the type of antigen, class and subclass of immunoglobulin, size, and complement-binding capacity, further investigations are needed to determine their role in normal and pre-eclamptic pregnancies.
A retrospective study is presented of the effect of propranolol on fetal outcome in pregnancies complicated by maternal hypertension. In nine pregnancies in which propranolol was given to markedly hypertensive women (diastolic blood pressure over 105 mm Hg) the fetal outcome was worse than in 15 patients using other hypotensive agents. The probability of fetal or neonatal death was related to the amount of proteinuria and the presence of parenchymal renal disease but was also significantly higher when the mother had been treated with propranolol. Experimental evidence suggests that beta-adrenergic blockade is harmful to the hypoxic fetus, for these reasons the use of propranolol in hypertensive pregnancies complicated by placental insufficiency may be contraindicated unless there is no satisfactory alternative.
In 50 women with high-risk pregnancies, increased factor-VII consumption, as estimated by the difference between the levels of factor-VIII-related antigen and factor-VIII clotting activity, correlated with the severity of pre-eclampsia, particularly when measured by increases in plasma-urate. Longitudinal studies of the evolution of pre-eclampsia demonstrated that increased factor-VIII consumption usually but not always developed before hyperuricaemia. The earliest time that abnormal factor-VIII consumption was demonstrated was at 18 weeks' gestation in a woman who had had two previous stillbirths. Subcutaneous heparin and oral dipyridamole failed to reverse the coagulation abnormality, and the fetus died in utero at 28 weeks' gestation. The renal and coagulation changes characteristic of pre-eclampsia were also seen in a patient without hypertension. This suggests that the concept of pre-eclampsia may need to be widened to include a non-hypertensive syndrome characterised by these changes in clotting and renal function.
High maternal serum-alpha-fetoprotein (A.F.P.) concentrations in the first half of pregnancy were associated with prematurity and high perinatal mortality. 94 singleton pregnancies without neural-tube defects but with A.F.P. levels equal to or greater than three times the normal median resulted in the birth of infants weighing, on average, 357 g less than controls (P less than 0-001). The mean head circumference of the infants was also smaller than that of the controls. The 1 stillbirth and 3 neonatal deaths yielded a mortality-rate more than three and a half times that for singleton births without neural-tube defects at the same hospital in the years 1974-76. The results suggest that some pregnant women who will deliver low-birth-weight infants at high risk of perinatal death may be identified by means of serum-A.F.P. measurement early in pregnancy.
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The relationship between spontaneous abortion and maternal serum alpha-fetoprotein (AFP) levels was investigated between 9 and 25 weeks of pregnancy. Seven out of 126 (5-6 per cent) women who had spontaneous abortions had raised maternal serum AFP levels at their antenatal booking visit compared to 4 out of 247 (1-6 per cent) control patients who were delivered of single liveborn infants, a statistically significant differences. The raised AFP concentrations were, however, associated with spontaneous abortion only if the serum samples had been taken immediately before, or at sometime after the abortion was first clinically suspected. This suggests that high levels do not predict the development of abortion in women who have not already threatened to abort. It is therefore unlikely that women who have not already threatened to abort. Therefore, when maternal serum AFP levels are used to screen for fetal neural tube defects, women referred for a diagnostic amniocentesis on account of a high level are unlikely to have been selected on the basis of a tendency to abort.
The development of a terminal-labelling microcytotoxicity assay is described in which target cells (fetal fibroblasts) were labelled with 125I-iododeoxyuridine after effector (lymphoid) cells had been incubated with them for 24 h. The time-course for the development of cell-mediated cytotoxicity was assessed following allogeneic skin grafting. 'Non-specific' cytotoxicity detracts from the sensitivity of all microcytotoxicity assays and the terminal-labelling assay using 125I is no exception. The non-specific effects can be reduced but not eliminated by the removal of adherent cells. The optimum target cell/effector cell ratio would seem to be between 1:100 and 1:250. Residual lymph node cells did not appear to incorporate enough label to affect the test results. In vivo correlates of in vitro findings are still not easy to determine.
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