The Global Bioequivalence Harmonisation Initiative (GBHI): Report of the fifth international EUFEPS/AAPS conference.

The series of conferences of the Global Bioequivalence Harmonisation Initiative (GBHI) was started in 2015 by the European Federation for Pharmaceutical Sciences (EUFEPS). All GBHI meetings so far were co-organised together with the American Association of Pharmaceutical Scientists (AAPS). Beginning with the 3rd workshop US-FDA joined as co-sponsor - to support global harmonisation of regulatory recommendations for bioequivalence (BE) assessment. At the 5th GBHI conference, the following BE topics were intensively discussed, and the following main conclusions were drawn: (1) Statistical considerations for BE assessment in specific situations covering scaling approaches for highly variable drug (HVD) products, two-stage adaptive design and opportunities of modelling and simulation to support BE: even though special BE study concepts like adaptive designs are not often used in practise so far, a majority of the workshop participants were in favour of a more frequent application of such approaches. The regulatory conditions relevant in this context need further concretisation and harmonisation between the regions. Moreover, modelling and simulation were considered as a promising and evolving approach, also for BE development programmes. (2) Fed versus fasting conditions in BE trials: Findings that BE between generic products could be confirmed only after fasted administration but failed under fed conditions seem more an exception than the rule. Obviously, BCS class IV compounds are most problematic in this context. Differences in critical excipients such as surfactants or pH-modifiers may be relevant reasons for different sensitivity for interactions in fasted versus fed conditions. Consequently, such deviations in composition of generic preparations should be avoided. Moreover, confirmation of BE may be generally difficult comparing different dosage forms, such like capsules versus tablets, especially in fed state. (3) BE assessment of locally acting drug products applied topically to the skin: Appropriateness and potential benefit of in-vitro tests as alternatives to clinical efficacy studies have been comprehensively discussed. In addition to the already well-established in-vitro release and permeation tests, other techniques were suggested, e.g., Raman spectroscopy or dermal open flow microperfusion. Validation of those methods is challenging and, despite significant progress already achieved during previous years, more research is needed before they may be fully accepted for regulatory purposes. (4) BE evaluation of narrow therapeutic index (NTI) drugs: The discrepancies amongst regulatory agencies in necessity of tighter BE acceptance ranges, the recommendations for inclusion of peak and total drug exposure into BE assessment with more restrictive criteria and the importance of comparison of the product-related within-subject variability for NTI drugs were debated. Arguments in favour and against the different approaches were presented and discussed but need further consideration before harmonisation can be achieved. The highly interactive meeting and extensive exchange between regulators and scientists from industry and academia resulted in useful progress in open BE issues and supported the goal of science-driven harmonisation.

Natural compounds boldine and menthol are antagonists of human 5-HT3 receptors: implications for treating gastrointestinal disorders.

BACKGROUND: Impaired 5-HT3 receptor function is likely involved in the pathogenesis of functional gastrointestinal disorders (FGID) and 5-HT3 receptor antagonists are effective treatments for chemotherapy-induced nausea and vomiting (CINV) and irritable bowel syndrome (IBS). The monoterpene alcohol menthol and the aporphine alkaloid boldine combat symptoms of gastrointestinal diseases; both interact with other members of the Cys-loop ligand-gated ion channel family and may therefore also act on 5-HT3 receptors. METHODS: The impact of boldine and menthol on human recombinant homomeric 5-HT3 A- and heteromeric 5-HT3 AB receptors in HEK293 cells was determined by radioligand binding, a luminescence-based Ca(2+) assay, and a membrane potential assay. 5-HT3 protein and mRNA expression was assessed in human colon tissue. KEY RESULTS: Boldine and menthol inhibited the 5-HT-induced activation of 5-HT3 receptors in the low and middle micromolar range, respectively. Boldine was a competitive antagonist of both receptors being 6.5- to 10-fold more potent at 5-HT3 A- vs 5-HT3 AB receptors. Menthol non-competitively and stereoselectively inhibited both receptors: In contrast to (+)-menthol, (-)-menthol was significantly more potent toward 5-HT3 A- vs 5-HT3 AB receptors. We show co-expression of 5-HT3A and 5-HT3B subunits in the human gut epithelium, the lamina propria, the myenteric plexus, and the muscular cell layer. CONCLUSIONS & INFERENCES: The demonstrated 5-HT3 inhibitory effects may be relevant for boldine's and menthol's alleviating properties on FGID and may encourage clinical studies with the compounds or the plant extracts for CINV and IBS treatment. The found receptor-discriminative properties make boldine and (-)-menthol to potentially useful tools for analyzing structural differences between these receptor subtypes.

Ginger and its pungent constituents non-competitively inhibit activation of human recombinant and native 5-HT3 receptors of enteric neurons.

BACKGROUND: Beneficial effects of ginger in the treatment of gastrointestinal (GI) problems and chemotherapy-induced nausea and vomiting are well accepted. In rodents, the action of ginger seems to be mediated by the inhibition of 5-HT3 receptors, which are established targets to combat emesis and irritable bowel syndrome. METHODS: Heterologously expressed human 5-HT3 A or 5-HT3 AB receptors were characterized by means of Ca(2+) influx studies using HEK293 cells. Complementing Ca(2+) measurements in Fluo-4-AM-stained whole-mount preparations of the human submucous plexus were carried out. Furthermore, [3H]GR65630 binding assays were performed to reveal the mode of action of ginger and its pungent compounds. KEY RESULTS: We show for the first time that ginger extracts and its pungent arylalkane constituents concentration-dependently inhibit activation of human 5-HT3 receptors. Ginger extracts inhibited both receptors with increasing content of pungent compounds, confirming that these are part of ginger's active principle. Inhibition potencies of the arylalkanes 6-gingerol and 6-shogaol on both receptors were in the low micromolar range. A lipophilic ginger extract and 6-gingerol had no influence on 5-HT potency, but reduced the 5-HT maximum effect, indicating non-competitive inhibition. The non-competitive action was confirmed by [(3) H]GR65630 binding, showing that the ginger extract did not displace the radioligand from 5-HT3 A and 5-HT3 AB receptors. The potential relevance of the inhibitory action of ginger on native 5-HT3 receptors in the gut was confirmed in whole-mount preparations of the human submucous plexus. While a general neurotoxic effect of 6-gingerol was ruled out, it inhibited the 2-methyl-5-HT-mediated activation of 5-HT3 receptors residing on enteric neurons. CONCLUSIONS & INFERENCES: Our findings may encourage the use of ginger extracts to alleviate nausea in cancer patients receiving chemotherapy and to treat functional GI disorders.

One-year follow-up of the outcome of a randomized controlled trial of a home-based intervention programme for children with autism and developmental delay and their families.

INTRODUCTION: There is debate about the type and intensity of early childhood intervention that is most helpful for children with developmental problems. The aim of the study was to determine whether a home-based programme provided over 12 months resulted in sustained improvement in development and behaviour 12 months after the intervention ceased. The characteristics of the children and families who benefited most from the intervention were also studied. METHOD: Randomized controlled trial. Participants A total of 59 children, aged 3-5 years, attending two early childhood intervention centres in Melbourne, Australia. Intervention Half of the subjects received an additional home-based programme consisting of 40 weekly visits. MAIN OUTCOME MEASURES: Bayley Scales of Infant Development and Wechsler Preschool and Primary Scale of Intelligence Revised, Preschool Behaviour Checklist, Bayley Behaviour Rating Scale and Behaviour Screening Questionnaire. All tests administered pre-intervention, following the intervention and 12 months later. Secondary outcome measures Family stress, support and empowerment. RESULTS: Fifty-four children completed the assessments 12 months after conclusion of the intervention. Compared with the control group, improvement in aspects of cognitive development in the children who received the extra intervention was sustained 1 year later (P= 0.007) while significant behavioural differences post intervention were not. Analyses of the data by the Reliable Change Index indicated improvement of clinical significance occurred in non-verbal areas. In contrast to the control group who deteriorated, language skills in the intervention group remained stable. Improvements were significantly associated with higher stress in the families. CONCLUSION: Improvements following the provision of a home-based programme to preschool children with developmental disabilities were sustained 1 year later. Children from highly stressed families appeared to benefit most, reinforcing the importance of involving families in early childhood intervention programmes.

Learning and memory in 5-HT(1A)-receptor mutant mice.

The serotonin 1A (5-HT(1A))-receptor is involved in a wide range of physiological functions, but has also been implicated in the pathophysiology of anxiety disorders and depression. Although the 5-HT(1A)-receptor is one of the best described receptor subtypes of the serotonergic system, its complex distribution pattern, pre- and postsynaptic localisation, and its impact on various neurotransmitters aggravate the attribution of 5-HT(1A)-agonistic effects to behavioural outcomes. The role of 5-HT(1A)-receptors for cognitive processes seems undisputed. However, the exact involvement of pre- and postsynaptic sites remains unexplained. Genetically modified animals are a complementary approach to pharmacological studies for further investigations of the role of the 5-HT(1A)-receptor. Next to 5-HT(1A)-receptor knockout mice, two transgenic mouse lines exist that either overexpress the 5-HT(1A)-receptor transiently or permanently. The latter mouse line stands out due to the fact that a distinct overexpression is primarily found in the outer cortical layers and hippocampus, both projection areas of serotonergic neurons. Here, we discuss the findings obtained from 5-HT(1A)-receptor knockout and overexpressing mice concerning their learning and memory abilities.

Cerebral palsy in Victoria, Australia: mortality and causes of death.

OBJECTIVE: To study the causes of death and the characteristics of children with cerebral palsy that had died over a 25-year period in Victoria, Australia. METHODOLOGY: Names of children that had died were collected from the Victorian Cerebral Palsy Register. Their hospital records were studied and information was gathered about age of death, motor impairment, the presence or absence of associated disabilities and cause of death. RESULTS: One hundred and fifty-five children had died during the period 1970-95. The majority of children had severe spastic quadriplegia, intellectual disability and epilepsy. The predominant cause of death was pneumonia, although for many children who died at home the cause was unknown. CONCLUSIONS: Children with cerebral palsy are a diverse group and those with a severe motor deficit have a reduced life expectancy. Lung disease remains an important cause of morbidity and mortality for this group. Further information about the causes of death is needed, particularly for those children that die at home.

Maternal serum triglyceride, glucose tolerance, and neonatal birth weight ratio in pregnancy.

OBJECTIVE: To determine the value of measuring serum triglyceride (TG) levels early in pregnancy for predicting late-gestation glucose tolerance and neonatal birth weight ratio (BWR) (birth weight corrected for gestational age). RESEARCH DESIGN AND METHODS: The relationships between morning nonfasting TG measured early in pregnancy (gestational age 12 +/- 6 weeks [mean +/- SD]) and glucose tolerance measured by a 3-h 50-g oral glucose tolerance test (OGTT) late in pregnancy (gestational age 30 +/- 3 weeks) and BWR were investigated in 388 women attending routine antenatal care. The data were analyzed for all women in addition to subgroups of Australian/Western European-born (n = 246) and Asian-born (n = 97) women. RESULTS: Morning nonfasting TG positively correlated with the OGTT glucose area under the curve (OGTT-GAUC) (r = 0.23, P < 0.0001) in all subjects. This correlation was stronger in the subset of subjects who had TG measured between 9 and 12 weeks of gestation (r = 0.35, P = 0.0001) and was particularly strong in Asian-born women who had TG measured within this period (r = 0.71, P < 0.0001). Mean TG and the 2- and 3-h OGTT values were higher in Asian-born subjects compared with Australian/Western European-born subjects (P = 0.004, P < 0.0001, and P = 0.02, respectively). TG correlated positively with BWR in all subjects (r = 0.12, P = 0.02), in Asian-born subjects (r = 0.23, P = 0.02), and in subjects with gestational diabetes mellitus (GDM) (r = 0.60, P = < 0.001). CONCLUSIONS: TG, if measured between 9 and 12 weeks of gestation, has moderate predictive value for subsequent glucose tolerance in pregnancy. TG is also predictive of BWR in GDM subjects. Further studies are warranted to investigate the role of early TG measurement in the screening and management of GDM. Metabolic heterogeneity exists between Asian-born and Australian/Western European-born women, the significance of which is still unclear and warrants further study.

Update of growth percentiles for infants born in an Australian population.

Growth percentiles require periodic revision because of changes in the ethnic mix of a population and socioeconomic factors. Anthropometric measurements were derived from singleton livebirths, without lethal malformations, from 22 completed weeks' gestation, at the Mercy Hospital for Women, Melbourne, from 1980 to 1989 (49,429 infants). Infants were included if reasonable assessment of gestation was available. Birth-weight percentiles were derived for the study group, male and female infants separately and for infants whose mothers were born in South-East Asia (Vietnam, Laos and Cambodia). Percentile charts for length, head circumference and ponderal index were also prepared. When compared with the intrauterine birth-weight growth curves reported by Kitchen et al (4) there was generally an elevation of all percentiles. Male infants were larger than female infants. Infants delivered by mothers born in South-East Asia were smaller than the study group as a whole, although the 10th percentiles for birth-weight were similar to the study group especially from 36-39 weeks' gestation. Periodic review of local standards is required to correctly categorize newborn infants' growth characteristics; factors such as sex of the infant and ethnic origin of the mother should be considered.

Amniotic fluid insulin values in women with gestational diabetes as a predictor of emerging diabetes mellitus.

Amniotic fluid insulin levels were estimated in 30 women with insulin-dependent diabetes, 216 with gestational diabetes and 27 with normal glucose tolerance. Results were correlated with birth-weight, incidences of fetal macrosomia and neonatal hypoglycaemia, and the risk of the mothers with gestational diabetes developing diabetes mellitus on follow-up. The women with prepregnancy diabetes had significantly higher amniotic fluid insulin values and showed a significant correlation between raised liquor insulin values (> 97th percentile) and hypoglycaemia in the infant (p = 0.039). In the gestational diabetic pregnancies there were highly significant associations between elevated liquor insulin values and macrosomia (p < 0.0045) and birth-weight (p < 0.00004), and a weak correlation with neonatal blood glucose levels (p = 0.042). Women with gestational diabetes who later developed permanent diabetes mellitus had higher mean amniotic fluid insulin levels than those whose glucose tolerance remained normal on follow-up (p < or = 0.0072) and more of them had a level greater than the 97th percentile than those whose glucose tolerance remained normal (odds ratio 6.48, 95% confidence interval 1.51-27.8, p = 0.0094). However a high amniotic fluid insulin level was of less clinical value for detection of women destined to develop diabetes (7 of 25, 28%) than was the need for insulin therapy during pregnancy (18 of 39, 46%).

Gestational diabetes and follow-up among immigrant Vietnam-born women.

Gestational diabetes is associated with an increased risk of fetal macrosomia and perinatal death. Immigrant mothers from Vietnam who delivered in the Mercy Hospital for Women between January 1, 1979 and December 31, 1990 were investigated to assess their risk of gestational diabetes, the factors that were associated with gestational diabetes, and the prevalence of diabetes mellitus on follow-up. These mothers were compared with Australian-born mothers attending the same hospital and who delivered in the same period. Using a logistic regression model, gestational diabetes was found to be more common in Vietnam-born mothers who were older, who were primigravidas, or were underweight and the risk of gestational diabetes increased over the time period of the study. The adjusted relative risk of gestational diabetes for Vietnam-born women was 1.43 (95% confidence limits 1.10, 1.86) compared with Australian-born women. The incidence of gestational diabetes was 7.8% (144 of 1,839) in Vietnam-born mothers and 4.3% (1,173 of 27,086) in Australian-born mothers. Vietnam-born mothers also had a greater risk of diabetes mellitus on follow-up; 25% (17 of 68) of those with follow-up testing had developed diabetes mellitus within 9 years of diagnosis of gestational diabetes, in comparison with an incidence of 9% (52 of 581) of Australian-born mothers with follow-up testing. Vietnam-born mothers should have glucose tolerance testing performed during pregnancy to detect gestational diabetes and those diagnosed should have long-term follow-up to detect the development of diabetes mellitus.

Excessive birth weight and maternal glucose tolerance--a 19-year review.

The incidence of birth-weight of 4,540 g (10 lb) or more rose from 0.87% in the years 1971 to 1977 to 1.16% in the 12 years from 1978 to 1989 with a concomitant increase in hyperglycaemia in our antenatal population. The relationship between excessive birth-weight and maternal glucose tolerance was investigated in the light of these observations. The results from glucose tolerance tests performed routinely during the pregnancies of 510 women who delivered infants with a birth-weight of 4,540 g or more were compared with those from a control series of 5,003 women with consecutively tested pregnancies. Glucose tolerance in subsequent pregnancies was also compared with the control series, and in 1991 the study group women were investigated for emergence of permanent diabetes mellitus. Excessive birth-weight was associated with maternal hyperglycaemia (p < 0.05) but not with gestational diabetes; 79% of infants with birth-weight > or = 4,540 g were born to mothers who were not hyperglycaemic. There was no increase in glucose intolerance in subsequent pregnancies in the study group and only 2 of 49 women with follow-up testing had diabetes mellitus. Birth-weight > or = 4,540 g occurred in 1.1% of the total population and 1.1% of women with gestational diabetes, and was related to maternal hyperglycaemia in about 1 in 5 cases. The increased incidence of excessive birth-weight infants was not related to the increased incidence of gestational diabetes in our pregnant population. Birth-weight > or = 4,540 g had a poor association with later development of diabetes.

Obstetric and birthweight differences between Vietnam-born and Australian-born women.

OBJECTIVES: To measure the frequency of obstetrical complications and assess the outcome of pregnancies in Vietnam-born mothers; to compute birthweight percentile charts for their infants; and to compare these parameters in Vietnam-born women with those of a control group of Australian-born women. DESIGN: A retrospective study of all pregnancies in Vietnam-born and Australian-born mothers managed in the Mercy Hospital for Women over a 10-year period, 1979-1988 inclusive. SETTING: The Mercy Hospital for Women provides primary and secondary obstetric care to public and private patients. PATIENTS: All women born in Australia or Vietnam who delivered in the Mercy Hospital for Women, Melbourne, over the 10-year period and their infants. Twins, stillborn babies and infants with congenital malformations were not included in the calculation of birthweight percentiles. RESULTS: Gestational diabetes (7.3% v. 4.3%, P less than 0.0001) and low oestriol excretion (14.4% v. 10.8%, P less than 0.0001) were more common whereas essential hypertension (0.3% v. 1.2%, P less than 0.001) and pre eclampsia (3.7% v. 8.6%, P less than 0.0001) were less common among Vietnam-born mothers. Intervention for labour and delivery was less common among Vietnam-born mothers: induction of labour (7.1% v. 24.7%, P less than 0.0001) and forceps delivery (17.8% v. 21.9%, P less than 0.001); caesarean section rates were similar. Infants of Vietnam-born mothers were significantly lighter than those of Australian-born; percentile charts for birthweight and gestational age are presented. CONCLUSIONS: Pregnancies among Vietnam-born women migrants in Australia were associated with few complications in spite of a higher incidence of gestational diabetes and a low oestriol excretion. The infants were lighter than those born to Australian-born mothers. Our percentile charts for birthweight relative to gestational age will provide a more accurate assessment of intrauterine growth for these infants.

Incidence and severity of gestational diabetes mellitus according to country of birth in women living in Australia.

Gestational diabetes mellitus (GDM) was diagnosed in 1928 of 35,253 (5.5%) tested pregnancies at the Mercy Maternity Hospital in Melbourne between 1979 and the end of 1988. Compared with women born in Australia and New Zealand, the incidence of GDM was significantly greater in women born on the Indian subcontinent (15%); in women born in Africa (9.4%), Vietnam (7.3%), Mediterranean countries (7.3%), and Egypt and Arabic countries (7.2%); and in Chinese (13.9%) and other Asian (10.9%) women. There was no significant difference for women born in the United Kingdom and northern Europe (5.2%), Oceania (5.7%), North America (4.0%), or South America (2.2%). With the World Health Organization criteria as a guide to the severity of hyperglycemia, compared with mothers born in Australia and New Zealand, there were significant increases in the incidences of the more severe grades of GDM in parturients born in the Mediterranean region, Asia, the Indian subcontinent, Egypt, and Arabic countries. The incidence of GDM increased significantly in all racial groups, rising from 3.3% during 1979-1983 to 7.5% during 1984-1988.

Urinary oestriol assay for monitoring fetoplacental function.

During the years 1971-1984 urinary oestriol excretion was tested in 51,427 patients (group 1). One or more low oestriol value was found in 10.7% of patients; in this group the stillbirth rate was 6.8 times higher, the neonatal death rate 3.8 times higher, and fetal growth retardation rate 3.5 times higher than in patients with normal oestriol values (all p less than 0.00001). During the years 1985-1989 a further 20,635 patients were tested (group 2) and 7.6% had one or more low oestriol value. The perinatal mortality rate in patients with normal oestriol excretion fell from 0.8% in group 1 to 0.5% in group 2 (p less than 0.005), and in patients with low oestriol excretion from 4.2% in group 1 to 2.4% in group 2 (p less than 0.002). However, patients in group 2 with low oestriol values still had significantly unfavourable results, compared to those with normal oestriol values--stillbirth rate 3.3 times higher, neonatal death rate 4.6 times higher, and fetal growth retardation rate 3.2 times higher (all p less than 0.00001). Intravenous dextrose and aminoacid infusions were given to 967 patients who had persistently low oestriol values in spite of rest in hospital, in an attempt to correct fetoplacental function; the perinatal mortality rate was 0.9% in the 660 (68.3%) who responded favourably, and 9.8% in the 307 (31.7%) who did not respond (p less than 0.0001).

Incidence and severity of gestational diabetes in Bahrain and Australia.

The incidence and severity of gestational diabetes in a series of 5,199 predominantly Arab patients in Bahrain, and 2,643 of mixed racial origin in Australia were studied. The incidence of gestational diabetes in Bahrain (5.4%) was less than in Australia (7.2%) but the more severe degrees were 3 times more common in Bahrain (p less than 0.001). The incidence of gestational diabetes was significantly increased with increasing maternal age and parity. A notable difference between the 2 populations occurred in the groups weighing less than 70 kg. Although Bahrain had a higher proportion of patients weighing less than 70 kg (64.7% versus 55.9%; p less than 0.001) there was a significantly higher incidence of gestational diabetes in this group in the Australian series (13.9% versus 3.7%, p less than 0.001). Postnatal testing of 165 gestational diabetics in Bahrain and 194 in Australia indicated that although the severe degrees of glucose intolerance were more likely to persist postnatally, it was impossible to predict in the individual patient the change in glucose tolerance that would occur after delivery. All gestational diabetics should therefore have a postnatal glucose tolerance test.

Induction of ovulation with subcutaneous pulsatile gonadotropin-releasing hormone: correlation with body weight and other parameters.

We treated 21 anovulatory infertile patients with subcutaneous pulsatile gonadotropin-releasing hormone (GnRH) administered via a syringe pump. Response to treatment was assessed by urinary estrogen excretion and ultrasound measurement of follicular growth. Ten patients ovulated and 8 subsequently conceived, for a total of 10 pregnancies. Human chorionic gonadotropin (hCG) was not administered routinely, but two patients required hCG to induce follicular rupture. The majority of the patients who conceived had a body mass index (BMI) of less than 21 and a luteinizing hormone (LH)/follicle-stimulating hormone ratio of less than 1. Conversely, those patients with either elevated BMI or LH or both generally failed to respond satisfactorily to this treatment. It is suggested that pulsatile GnRH is most likely to succeed in inducing ovulation if the BMI is less than 21 and the LH is normal, but is unlikely to be successful if there is both an elevated LH and a BMI of greater than 25. Between these two extremes, the response is variable and a therapeutic trial may be appropriate.

Contribution of prematurity and low birth-weight to neonatal death in Chinese and Western populations.

This paper analyses the contribution of low birth-weight (birth-weight between 500 and 2,500 g) and prematurity (gestation less than 37 weeks) to neonatal death in Chinese and Western populations. The incidences of low birth-weight in the Tsan Yuk Hospital, Hong Kong, the State of Victoria, and the Mercy Maternity Hospital, Melbourne, were 4.63%, 4.29% and 5.66% respectively and the incidences of prematurity were 2.08%, 4.89% and 7.42% respectively. The neonatal mortality rate (per 1,000 livebirths) for premature infants born in Victoria was 64, 89 for those born at the Mercy Maternity Hospital and 119 for the Tsan Yuk Hospital. This paper has demonstrated that a striking differences exists in prematurity rates between Chinese and Western populations, and also that the mortality rate of premature infants is lower in Western populations. If the reason for the lower incidence of prematurity in the Chinese population could be determined and the mortality of premature infants maintained in the Western population, a significant lowering of perinatal mortality would result. Studies to determine causes for premature births in Chinese and Western populations should therefore be undertaken.

Survey of hand symptoms in pregnancy.

In a study of 1216 pregnancies, 427 (35%) patients reported hand symptoms. Symptoms of the same quality and distribution were reported by 40 (30%) of 132 control subjects within the previous year, and although invariably mild, these symptoms suggest that pregnancy may aggravate a pre-existing condition. Fewer than 20% of the 427 affected patients described a classic median-nerve symptom distribution (carpal tunnel syndrome), while 12% of patients described an ulnar-nerve distribution, which is thought to represent a genuine and previously underestimated occurrence of ulnar-nerve neuropathy in pregnancy. In 69% of patients, hand symptoms were generalized. Most symptoms were bilateral, commenced in the third trimester and resolved soon after delivery. There was a significant correlation of hand symptoms in pregnancy with the presence of preeclampsia, tight rings, the weight at confinement, the birth weight and a history of premenstrual bloating. Operative intervention was not required for any patient.

A reappraisal of urinary oestriol excretion as a screening test in pregnancy.

During the years 1971-1982 urinary oestriol excretion was tested in 38,536 patients (group 1). One or more low oestriol value was found in 11.0% of patients; in this group the stillbirth rate was 8 times higher, the neonatal death rate 4 times higher, and fetal growth retardation rate 4 times higher than in patients with normal oestriol values (all p less than 0.001). During the years 1982-1984 a further 12,887 patients were tested (group 2) and 9.5% had one or more low oestriol value. The perinatal mortality rate in patients with normal oestriol excretion fell from 0.8% in group 1 to 0.5% in group 2 (p less than 0.05), and in patients with low oestriol excretion from 4.7% in group 1 to 2.4% in group 2 (p less than 0.01). However, patients in group 2 with low oestriol values still had significantly unfavourable results, compared to those with normal oestriol values--stillbirth rate 4 times higher, neonatal death rate 5 times higher, and fetal growth retardation rate 4 times higher (all p less than 0.001). Although perinatal results have improved, fetal growth retardation and the risk of perinatal death are still identified by urinary oestriol assay.