Collaborative survey of perinatal loss in planned and unplanned home births. Northern Region Perinatal Mortality Survey Coordinating Group.

OBJECTIVE: To document the outcome of planned and unplanned births outside hospital. DESIGN: Confidential review of every pregnancy ending in stillbirth or neonatal death in which plans had been made for home delivery, irrespective of where delivery eventually occurred. The review was part of a sustained collaborative survey of all perinatal deaths. SETTING: Northern Regional Health Authority area. SUBJECTS: All 558,691 registered births to women normally resident in the former Northern Regional Health Authority area during 1981-94. MAIN OUTCOME MEASURE: Perinatal death. RESULTS: The estimated perinatal mortality during 1981-94 among women booked for a home birth was 14 deaths in 2888 births. This was less than half that among all women in the region. Only three of the 14 women delivered outside hospital. Independent review suggested that two of the 14 deaths might have been averted by different management. Both births occurred in hospital, and in only one was management before admission of the mother judged inappropriate. Perinatal loss to the 64 women who booked for hospital delivery but delivered outside and to the 67 women who delivered outside hospital without ever making arrangements to receive professional care during labour accounted for the high perinatal mortality (134 deaths in 3466 deliveries) among all births outside hospital. CONCLUSIONS: The perinatal hazard associated with planned home birth in the few women who exercised this option (< 1%) was low and mostly unavoidable. Health authorities purchasing maternity care need to address the much greater hazard associated with unplanned delivery outside hospital.     

Decline in the prevalence of neural tube defects following folic acid fortification and its cost-benefit in South Africa

BACKGROUND: In October 2003 South Africa embarked on a program of folic acid fortification of staple foods. We measured the change in prevalence of NTDs before and after fortification and assessed the cost benefit of this primary health care intervention. METHODS: Since the beginning of 2002 an ecological study was conducted among 12 public hospitals in four provinces of South Africa. NTDs as well as other birth defect rates were reported before and after fortification. Mortality data were also collected from two independent sources. RESULTS: This study shows a significant decline in the prevalence of NTDs following folic acid fortification in South Africa. A decline of 30.5% was observed, from 1.41 to 0.98 per 1,000 births (RR = 0.69; 95% CI: 0.49–0.98; p = .0379). The cost benefit ratio in averting NTDs was 46 to 1. Spina bifida showed a significant decline of 41.6% compared to 10.9% for anencephaly. Additionally, oro‐facial clefts showed no significant decline (5.7%). An independent perinatal mortality surveillance system also shows a significant decline (65.9%) in NTD perinatal deaths, and in NTD infant mortality (38.8%). CONCLUSIONS: The decrease in NTD rates postfortification is consistent with decreases observed in other countries that have fortified their food supplies. This is the first time this has been observed in a predominantly African population. The economic benefit flowing from the prevention of NTDs greatly exceeds the costs of implementing folic acid fortification. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

Quality of obstetric care provided for Asian immigrants in Leicestershire.

Between 1976 and 1981 some 939 perinatal deaths occurred to women living in Leicestershire, of which 128 (14%) were to Asian women. The qualifications of the general practitioners, the gestation at which women start antenatal care, and perinatal death were used as structural, process, and outcome measures for evaluating the services provided to Asian immigrants within this population. Perinatal deaths were divided into four groups: congenital malformation, macerated stillbirth, asphyxia in labour, and immaturity. Asian mothers had one and a half times the risk of perinatal mortality when social class, parity, height, legitimacy, and the general practitioner''s qualifications were taken into account. Asian and non-Asian mothers with general practitioners who were not on the obstetric list had more than twice the risk of a perinatal death when a similar adjustment was made. Recommendations include priority allocation of community midwives to practitioners not on the obstetric list, the establishment of postgraduate courses for such doctors, and the continued evaluation of the effect of such proposals on perinatal mortality.     

Cholesterol-multilipid interactions in bilayers

To extend our knowledge of model membrane systems based upon one lipid component, multi-lamellar bilayers were made of cholesterol with two phospholipids in equimolar ratio, and the enthalpy change delta H of the main phase transition of the temary mixture was measured by differential scanning calorimetry (DSC) as a function of increasing cholesterol concentration c. The lipids were saturated phosphatidylcholines CnPC of acyl chain length n, and as the n of the two lipids became more different (from C13PC/C14PC to C14PC/C15PC to C14PC/C18PC to C14PC/C19PC) distinct breaks in the delta H versus c plots were observed. These mixtures displayed only one broad DSC endotherm. Mixtures of an unsaturated lipid C18: 1PC (dioleoyl) with C16PC or with C18PC showed two peaks, with each peak being associated with its parent lipid. However, the delta H versus c plots for each of these peaks showed an initial independence of cholesterol concentration followed by a dependence on cholesterol concentration. These results indicate that, in lipid mixtures, the type of interaction of cholesterol with each lipid component depends on the concentration of cholesterol present.     

Prevalence of, and risk factors associated with, perinatal calf mortality in pasture-based Holstein-Friesian cows

Recent publications indicate that the prevalence of perinatal mortality has increased in some dairy industries and an increased proportion of this loss is not associated with the traditional risk factors for perinatal mortality. The objectives of this study were to establish the prevalence of perinatal mortality (calf death within 24 h of calving) in Irish dairy herds and to determine the current significance of putative risk factors in pasture-based management systems. A total of 182 026 records of full-term calvings from Holstein-Friesian dams served by artificial insemination (AI) sires of seven breeds in herds of 20 calvings or more per year were available from the Irish national breeding database over 4 years (2002 to 2005). The prevalence of perinatal mortality was 4.29% (7.7% in primiparae and 3.5% in pluriparae). The likelihood of perinatal mortality increased between 2002 and 2005 and was greatest in June and in winter. There was an interaction (P < 0.001) between the effect of calving assistance and parity with the effect of dystocia on perinatal mortality being greater in primiparae. The odds of perinatal mortality were greater in male (OR = 1.12; P < 0.001) and in twin calves (OR = 5.70-13.36; P < 0.001) and in dams that had perinatal mortality at the previous calving (OR = 4.21; P < 0.001). The logit of the probability of perinatal mortality increased by 0.099 per unit increase in sire predicted transmitting ability (PTA) for direct perinatal mortality. The probability of perinatal mortality increased at an increasing rate in primiparae as animals calved at a younger age relative to the median age at first calving. The only herd-level factor examined, herd size did not affect the odds of perinatal mortality. These data indicate that the prevalence of perinatal mortality in this cattle population is similar to that in other pasture-based dairy systems worldwide. The putative exposures and attributes traditionally associated with perinatal mortality were associated with perinatal mortality in this pasture-based dairy cow population. The practical implication of these results is that as many of the significant risk factors are largely not under management control (year of calving, month of calving, twin calving, primiparity, previous perinatal mortality and foetal gender), herd owners must focus on the significant determinants under their control (age at first calving, sire genetic merit for direct perinatal mortality and both the extent of calving supervision and the degree of assistance), in order to reduce the prevalence of perinatal mortality and improve perinatal welfare.     

Quantitative analysis of free fatty acids in rat plasma using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry with meso-tetrakis porphyrin as matrix

Quantitative analysis of free fatty acids was achieved using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with a meso-tetrakis porphyrin matrix. Cesium acetate was employed as a cationizing agent. The MALDI signal was reproducible and dominated by cesiated cesium carboxylates [RCOOCs + Cs]+. The addition of two Cs ions resulted in a mass shift of 264.8 Da for each fatty acid and greatly reduced background peaks. A linear relationship between fatty acid concentration and corresponding fatty acid to internal standard peak intensity ratio was observed for three representative fatty acids analyzed across a concentration range from 4.40 to 150 microM, with correlation coefficients between 0.986 and 0.987. The application of this method was demonstrated with the analysis of free fatty acids in nonfasted and fasted rat plasmas. A total of eight free fatty acids (14:0, 16:0, 16:1, 17:0, 18:0, 18:1, 18:2, and 20:4) were detected. The relative peak height ratios of the fatty acids to the internal standard allow quantitative measurements of the free fatty acids. It was shown that the levels of free fatty acids were higher in fasted rats than in rats in a nonfasted state. This method is simple, sensitive, and fast. Thus, it provides an appealing tool for the analysis of free fatty acids or other low-molecular weight compounds during drug discovery and/or development.     

神农架金丝猴的生态学观察

金丝猴(Rhinopithecus roxellanae)仅产于我国,属国家Ⅰ级保护动物,自然分布于四川、陕西、甘肃的部分地区和湖北省神农架自然保护区。1983年以来,笔者对神农架金丝猴生存环境生态习性等作了长期观察研究,结果报道如下。     

Perinatal mortality in Utrecht, The Netherlands, 1880–1940

The secular trend of perinatal mortality in Utrecht between 1880 and 1940 and its causes are examined in this study, based on patient records of two maternity clinics, those of the city's academic hospital, and of its outpatient clinic. The sample includes 17,111 deliveries. Over the period the proportion of births in the city occurring in the two institutions rose from 3 to 90%. The perinatal mortality rate in the hospital declined and then rose slightly at the end of the 19th century, but remained constant, even if cyclical, thereafter in both the hospital and the outpatient clinic. Rates differed substantially between the two maternity services. Logistic regression analysis reveals a cluster of factors related to perinatal death. Low birth weight had a powerful association with perinatal mortality in both samples. Most of the other factors associated with perinatal mortality were related to the health of the patients, to obstetric problems related to deliveries, and to infant sex and maternal age. Relationships between perinatal mortality and other measures of human welfare in The Netherlands are explored.     

Density of infectious virus and complement-fixing antigens of two rhinovirus strains

Dans, P. E. (National Institute of Allergy and Infectious Diseases, Bethesda, Md.), B. R. Forsyth, and R. M. Chanock. Density of infectious virus and complement-fixing antigens of two rhinovirus strains. J. Bacteriol. 91:1605-1611. 1966.-Two rhinovirus serotypes (echovirus 28 and HGP) and poliovirus type 1 were banded by isopycnic centrifugation in cesium chloride. The rhinovirus virions had a density of 1.41 g/ml, whereas that of poliovirus was 1.34. Since a number of other enteroviruses also have a density of 1.34 g/ml in cesium chloride, a basic difference in density may exist between the rhinovirus and enterovirus subgroups of the picornavirus family. Whether this difference reflects differences in ribonucleic acid content or binding of cesium ions remains to be determined. In tests with echovirus 28 two peaks of CF activity were detected: one in association with the virion (1.41 g/ml), and a larger peak of lower density (1.30 g/ml). With echovirus 28 antiserum, a heterotypically reactive complement-fixing (CF) antigen was detected in the HGP virus suspension at a density less than that of the virion (1.30 g/ml). This antigen corresponded in density to the less dense CF antigen of echovirus 28.     

Perinatal mortality and sex ratios in Hawaii

Retrospective data obtained from a sample of 926 mothers of European ancestry (AEA) and 368 mothers of Japanese ancestry (AJA) living in Hawaii were used to evaluate two hypotheses, the selective male affliction hypothesis and the Trivers-Willard female condition hypothesis, for male-biased perinatal mortality and altered sex ratio at birth. Logit analyses using pregnancy outcome (live-birth versus stillbirth or miscarriage) as the dependent variable and either sex of prior sib, sex of offspring, parity, age of mother, or interval since last pregnacy as independent variables did not support either hypothesis. In contrast to the prediction of the selective male affliction model, sex of previous pregnancy was not related to perinatal mortality. Although each of the other independent variables exerted significant effects on perinatal mortality and, therefore, presumably affected female condition, in no case did natal sex ratios become female-biased. The Trivers-Willard hypothesis predicts that female-biased sex ratios are expected when female condition is reduced. The results are discussed in relation to the possibility that degree of sexual dimorphism may favor male-biased perinatal mortality and explains the observed decline in sex ratio with parity.     

Home births in England and Wales, 1979: perinatal mortality according to intended place of delivery.

A survey was carried out of all 8856 births occurring at home in England and Wales in 1979. Of these births, 67% had been booked for delivery at home, 21% had been booked for delivery in hospital, 3% had not been booked, and for 9% the intended place of delivery was unknown. The perinatal mortality varied almost 50-fold according to the intended place of delivery, ranging from 4.1/1000 births in those booked for delivery at home to 196.6/1000 unbooked births. Deliveries that occurred at home but had been booked for a hospital consultant unit were associated with a perinatal mortality of 67.5/1000. Births that had been booked for delivery at home included the smallest proportion of babies of low birth weight: 2.5% weighed 2500 g or less compared with 18% of those booked for consultant units and 29% of those not booked. Within these low birthweight groups there were noticeable differences in perinatal mortality; births booked to occur at home had the lowest mortality and unbooked births had the highest. Perinatal mortality among babies who weighed more than 2500 g was generally low irrespective of the intended place of delivery; the only exception was in babies whose delivery had not been booked. In all groups perinatal mortality was considerably higher in nulliparous than parous women. Women booking a delivery at home are clearly a selected group, and some may have been transferred to hospital during labour and were thus not included in the survey. Nevertheless, these data suggest that the perinatal mortality among births booked to occur at home is low, especially for parous women.     

Methods and models to determine perinatal status of Florida manatee carcasses

Differences in perinatal mortality can be indicators of differences in physiology, behavior, toxicology, population dynamics, and ecology of species and individuals. Extensive data collected under the Florida Manatee Carcass Recovery Program provide important information about manatee perinatal mortality. However, early age at death can be difficult to determine for often highly decomposed carcasses. Here, I provide quantitative methods to identify perinatal status for manatee carcasses. First, perinatal and nonperinatal mortality were defined based on physiological indicators. After review of necropsy reports, specific length classes became clear indicators of perinatal status: carcasses <82‐cm long were always perinatal, and carcasses >160‐cm long were always nonperinatal. Using data from carcasses 82–160 cm long of known perinatal status, Bayesian models quantify the relationship among age at death, carcass length, and carcass recovery month. The models predict the perinatal status of carcass 82–160 cm long when physiological indicators are unavailable. Overall, perinatal status could be determined for 98.2% of carcasses collected from 1978 to 2005. Initial examination of the fraction of perinatal mortalities within the entire carcass sample reveals interesting spatial and temporal patterns that warrant further analyses.     

Influence of maternal age, parity and social class on perinatal mortality in Scotland: 1960-82

This study examines secular changes in the influence of maternal age, parity and social class on perinatal mortality in Scotland. Using cross-sectional national data on all Scottish legitimate births the effects of these factors are estimated on the risk of stillbirths, neonatal and perinatal deaths, and the extent to which the current pattern of relative risks in the early 1980s has changed over the past 2 decades is investigated. Social class is used as a crude measure of relative as opposed to absolute differences in socioeconomic conditions which may influence reproductive outcomes. The effects of age, parity and social class are estimated using logistic models. The most parsimonious model adequately describing the data is provided by a main effects model without interactions. Despite changes in reproductive behavior, improved access to maternity services and more effective perinatal care, the influence of maternal age and social class on perinatal mortality remained unchanged between 1960 and 1982. Although the absolute risks of stillbirths and neonatal deaths declined in all maternal age groups, this improvement was not accompained by a significant change in the relative risks traditionally associated with age. Despite no significant changes in the traditional J-shaped association between parity and stillbirths, cross-sectional analysis shows that in the early 1980s the risk of both neonatal and perinatal deaths decreased as parity increased. This finding is consistent with the pattern of risks observed in longitudinal studies and retrospective surveys of reproductive histories. In view of the stability of age, parity and social class effects on the risk of perinatal mortality, little if any of the overall decrease in Scottish stillbirth and neonatal death rates can be attributed to a significant narrowing of relative risks. The results suggest that the attributable risk of high maternal age or low social class on perinatal mortality is negligible. Future improvements in perinatal mortality are thus likely to result from a continuation of the uniform decrease in perinatal mortality for women of all ages, parities and social classes and not from a diminishing of differences in relative risks which are now virtually identical for a large and growing % of women in Scotland.     

Perinatal mortality by birth order within cohorts based on sibship size.

Cross-sectional surveys of perinatal mortality show a U-shaped curve when plotted against parity, implying that fourth and subsequent babies are at increased risk. Our study of a large, population-based longitudinal data set shows that this result is an artefact and that perinatal mortality falls with increasing parity. Within cohorts of mothers based on attained sibship size the perinatal mortality decreases with increasing parity and increases with sibship size. These associations, which are not noticeably affected by maternal age, ssem in part to operate through an association between parity, sibship size, and birth weight. This analysis shows the importance of using longitudinal data in analysing such relations.     

Canine perinatal mortality: a cohort study of 224 breeds

Canine perinatal mortality is known to be relatively high. However, the literature on perinatal mortality in dogs is still sparse and often refers to a single or only a few breeds. The aim of this large-scale observational study was to describe the perinatal mortality in purebred dogs of various breeds at both puppy and litter level. In addition, the influence of breed, breed size, litter size, age of the bitch, litter number and season for whelping on the risk of perinatal mortality at litter level was studied and the mean litter size at eight days and eight wks after birth was calculated. A retrospective cohort study was performed by studying 10,810 litters of 224 breeds registered in the Norwegian Kennel Club in 2006 and 2007. Perinatal mortality was defined as the sum of stillborn puppies and puppies that died during the first wk after birth (early neonatal mortality) and was present in 24.6% of the litters. Eight percent of the puppies died before eight days after birth, with 4.3% as stillbirth and 3.7% as early neonatal mortality. For most breeds the perinatal mortality was low, but for some breeds a higher perinatal mortality was found. The mean litter size at eight days and eight wks after birth was 4.97 (±0.02) and 4.92 (±0.02) puppies, respectively. Of all puppies born, only 1% died during the period from eight days to eight wks after birth. Random effects logistic regression analysis indicated that increasing litter size and age of the bitch were associated with an increased risk of stillbirth, early neonatal mortality and total perinatal mortality at the litter level (P < 0.001). The random breed effect was significant for all outcomes. Litter number also had a significant effect on stillbirth, early neonatal mortality and total perinatal mortality at the litter level, with the highest risk of perinatal mortality found in the first litter (P < 0.001). Further, the risk of early neonatal mortality was doubled in litters with stillborn puppies. No significant effect of whelping season on perinatal mortality at litter level was found. An interaction existed between the age of the bitch and litter number and the risk of stillbirth was three times as high (odds ratio = 3.00) in litters from bitches having their first litter after the age of six y. Breed was a more important determinant of perinatal mortality in litters than breed size. However, more than 90% of the variation in perinatal mortality was found at the individual litter level and efforts to minimize puppy mortality should be targeted at the management of the individual litter rather than at the breed level.     

Perinatal mortality: a continuing collaborative regional survey.

A collaborative survey of perinatal mortality in each district of the Northern region set up in July 1980 was able to obtain information on 99% of all the registered perinatal deaths among babies born in 1981-2 to mothers resident in the region. There were 12.4 perinatal deaths/1000 births over this two year period, but 41% of the stillbirths and early neonatal deaths were of babies with a lethal malformation or weighing less than 1000 g at birth (or both). All causes of perinatal mortality had become less common than they had been at the time of the National Birthday Trust survey in 1958, though there had been a relatively small decrease in the number of deaths due to malformation (in the absence of any neural tube defect) and in the number of stillbirths of normally developed fetuses: 36% of the antepartum stillbirths among non-malformed singleton fetuses were associated with poor fetal growth (weight below the fifth centile at birth) and 21% were due to sudden unexplained placental abruption.     

Prospective population based survey of outcome of pregnancy in diabetic women: results of the Northern Diabetic Pregnancy Audit, 1994.

OBJECTIVE: To determine whether the St Vincent declaration (1989) target of diabetic pregnancy outcome approximating non-diabetic pregnancy outcome in near to being achieved. DESIGN: Prospective collection of population based information on pregnancies in women with diabetes from all participating hospitals. SETTING: District general and teaching hospitals of the former Northern region. SUBJECTS: 111 diabetic women booking with pregnancy during 1 January to 31 December 1994. MAIN OUTCOME MEASURES: Diabetic control, perinatal mortality rate, fetal abnormality rate. RESULTS: The perinatal mortality rate was 48/1000 for diabetic pregnancies compared with 8.9/1000 for the background population (odds ratio 5.38; 95% confidence interval 2.27 to 12.70) and the neonatal mortality rate was 59/1000 compared with 3.9/1000 (15.0; 6.77 to 33.10). Two late neonatal deaths were due to congenital heart defects. Six per cent of all fetal losses (6/109 cases) were due to major malformations. The congenital malformation rate was 83/1000 compared with 21.3/1000 (3.76; 2.00 to 7.06) in the background population. CONCLUSIONS: Diabetic pregnancy remains a high risk state with perinatal mortality and fetal malformation rates much higher than in the background population.     

Isolation of the major chondroitin sulfate/dermatan sulfate and heparan sulfate proteoglycans from embryonic chicken retina

A technique is presented for the preparation of three major proteoglycans from 14-day embryonic chicken retinas following their culture overnight with [35S]sulfate and either [3H]glucosamine or [3H]serine. Homogenization of the tissue in saline permitted extraction of heterogeneous soluble proteoglycans separately from most of the heparan sulfate proteoglycans. The latter were extracted from the 140,000g pellet with 0.5% Triton X-100 in 8 M urea. The medium plus the saline and urea-detergent extracts were separated from low-molecular-weight contaminants, and fractionated into two peaks of radioactivity on Sephacryl S-300 in saline with 3 M urea and 0.5% Triton X-100. The proteoglycans were isolated directly from these fractions on DEAE-Sephacel, and subjected to ultrafiltration concentration and then further purification on cesium chloride density gradient centrifugation in 4 M guanidine hydrochloride. A further step involving cetylpyridinium chloride precipitation was examined, but it resulted in essentially no further purification. The fractionations separated a large chondroitin sulfate/dermatan sulfate proteoglycan from the culture medium that was excluded from S-300 and of low buoyant density; a large heparan sulfate proteoglycan from the urea-detergent extract that was also excluded from S-300 and of low buoyant density; and two smaller and possibly related heparan sulfate proteoglycans. One was found in the medium and showed low to intermediate buoyant density; the other was isolated from the urea-detergent extract and showed a significantly higher buoyant density, associated with a lower protein content. The saline extract contained both of the two larger proteoglycans and only minor amounts of the smaller molecules.     

Reproductive pattern,perinatal mortality,and sex preference in rural Tamil Nadu,south India: community based,cross sectional study.

OBJECTIVES: To study reproductive pattern and perinatal mortality in rural Tamil Nadu, South India. DESIGN: Community based, cross sectional questionnaire study of 30 randomly selected areas served by health subcentres. SETTING: Rural parts of Salem District, Tamil Nadu, South India. SUBJECTS: 1321 women and their offspring delivered in the 6 months before the interview. MAIN OUTCOME MEASURES: Number of pregnancies, pregnancy outcome, spacing of pregnancies, sex of offspring, perinatal and neonatal mortality rates. RESULTS: 41% of the women (535) were primiparous; 7 women (0.5%) were grand multiparous (> 6 births). The women had a mean age of 22 years and a mean of 2.3 pregnancies and 1.8 live children. The sex ratio at birth of the index children was 107 boys per 100 girls. The stillbirth rate was 13.5/1000 births, the neonatal mortality rate was 35.3/1000, and the perinatal mortality rate was 42.0/1000. Girls had an excess neonatal mortality (rate ratio 3.42%; 95% confidence interval 1.68 to 6.98; this was most pronounced among girls born to multiparous women with no living sons (rate ratio 15.48 (2.04 to 177.73) v 1.87 (0.63 to 5.58) in multiparous women with at least one son alive). CONCLUSIONS: In this rural part of Tamil Nadu, women had a controlled reproductive pattern. The excess neonatal mortality among girls constitutes about one third of the perinatal mortality rate. It seems to be linked to a preference for sons and should therefore be addressed through a holistic societal approach rather than through specific healthcare measures.     

Overview of randomised trials of diuretics in pregnancy.

Over the past 20 years at least 11 randomised trials of the prevention with diuretics of pre-eclampsia and its sequelae have been undertaken. Nine of these were reviewed. Reliable data from the remaining two were not available. The nine reviewed had investigated a total of nearly 7000 people. Significant evidence of prevention of "pre-eclampsia" was overwhelming, even when oedema was not included as a diagnostic criterion. But as the definitions of pre-eclampsia that had been used depended heavily on increases in blood pressure this evidence may simply have reflected the well known ability of diuretics to reduce blood pressure. When the data on perinatal death were reviewed a little difference was seen in postnatal survival. The incidence of stillbirths was reduced by about one third with treatment, but, perhaps owing to small numbers (only 37 stillbirths), the difference was not significant. Thus these randomised trials failed to provide reliable evidence of either the presence or the absence of any worthwhile effects of treatment with diuretics on perinatal mortality. The implications of this for current and future trials of beta blockers and other agents in the prevention of pre-eclampsia and its sequelae are that extremely large, ultra simple randomised trials are needed, of a size sufficient to permit direct assessment of the effects of treatment not on pre-eclampsia but on perinatal mortality itself. This may require the study of tens of thousands of pregnancies.