Is the atopic march related to confounding by genetics and early-life environment? A systematic review of sibship and twin data.

A popular hypothesis known as the atopic march proposes a set of sequential allergy and respiratory disorders in early childhood contributes enormously to the burden of disease in developed countries. Although the concept of the atopic march has been refined and strengthened by many cross-sectional and longitudinal studies linking eczema as the initial manifestation with progression to hay fever and then asthma, there is yet no definitive proof that the atopic march is the primary causal factor in childhood allergic disease. This debate is mainly related to the controversy around potential confounding of these associations by genetic and environmental factors. Family studies are ideally suited to unravelling the role of these factors. While multiple reviews have synthesized evidence from studies investigating this question, no review to date has explored specific evidence generated by twin and sibling studies to understand the aetiology of atopic march diseases. Our aim was to conduct a systematic review of twin and sibling studies that examine the allergic phenotypes that form the atopic march, to determine whether such analyses of data from these studies attempt to control for the effect confounding by shared factors, and to report estimates of the magnitude of associations between multiple phenotypes. Our review suggests that (1) genetics play a bigger role predisposing eczema to hay fever and eczema to asthma than environmental factors, and (2) the link between eczema and asthma and hay fever is independent of shared early-life environmental factors.

The skin barrier function gene SPINK5 is associated with challenge-proven IgE-mediated food allergy in infants.

BACKGROUND: A defective skin barrier is hypothesized to be an important route of sensitization to dietary antigens and may lead to food allergy in some children. Missense mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) skin barrier gene have previously been associated with allergic conditions. OBJECTIVE: To determine whether genetic variants in and around SPINK5 are associated with IgE-mediated food allergy. METHOD: We genotyped 71 "tag" single nucleotide polymorphisms (tag-SNPs) within a region spanning ~263 kb including SPINK5 (~61 kb) in n=722 (n=367 food-allergic, n=199 food-sensitized-tolerant and n=156 non-food-allergic controls) 12-month-old infants (discovery sample) phenotyped for food allergy with the gold standard oral food challenge. Transepidermal water loss (TEWL) measures were collected at 12 months from a subset (n=150) of these individuals. SNPs were tested for association with food allergy using the Cochran-Mantel-Haenszel test adjusting for ancestry strata. Association analyses were replicated in an independent sample group derived from four paediatric cohorts, total n=533 (n=203 food-allergic, n=330 non-food-allergic), mean age 2.5 years, with food allergy defined by either clinical history of reactivity, 95% positive predictive value (PPV) or challenge, corrected for ancestry by principal components. RESULTS: SPINK5 variant rs9325071 (A⟶G) was associated with challenge-proven food allergy in the discovery sample (P=.001, OR=2.95, CI=1.49-5.83). This association was further supported by replication (P=.007, OR=1.58, CI=1.13-2.20) and by meta-analysis (P=.0004, OR=1.65). Variant rs9325071 is associated with decreased SPINK5 gene expression in the skin in publicly available genotype-tissue expression data, and we generated preliminary evidence for association of this SNP with elevated TEWL also. CONCLUSIONS: We report, for the first time, association between SPINK5 variant rs9325071 and challenge-proven IgE-mediated food allergy.

Nut allergy prevalence and differences between Asian-born children and Australian-born children of Asian descent: a state-wide survey of children at primary school entry in Victoria, Australia.

BACKGROUND: Asian infants born in Australia are three times more likely to develop nut allergy than non-Asian infants, and rates of challenge-proven food allergy in infants have been found to be unexpectedly high in metropolitan Melbourne. To further investigate the risk factors for nut allergy, we assessed the whole-of-state prevalence distribution of parent-reported nut allergy in 5-year-old children entering school. METHODS: Using the 2010 School Entrant Health Questionnaire administered to all 5-year-old children in Victoria, Australia, we assessed the prevalence of parent-reported nut allergy (tree nut and peanut) and whether this was altered by region of residence, socio-economic status, country of birth or history of migration. Prevalence was calculated as observed proportion with 95% confidence intervals (CI). Risk factors were evaluated using multivariable logistic regression and adjusted for appropriate confounders. RESULTS: Parent-reported nut allergy prevalence was 3.1% (95% CI 2.9-3.2) amongst a cohort of nearly 60 000 children. It was more common amongst children of mothers with higher education and socio-economic index and less prevalent amongst children in regional Victoria than in Melbourne. While children born in Australia to Asian-born mothers (aOR 2.67, 95% CI 2.28-3.27) were more likely to have nut allergy than non-Asian children, children born in Asia who subsequently migrated to Australia were at decreased risk of nut allergy (aOR 0.1, 95% CI 0.03-0.31). CONCLUSION: Migration from Asia after the early infant period appears protective for the development of nut allergy. Additionally, rural regions have lower rates of nut allergy than urban areas.

Timing of routine infant vaccinations and risk of food allergy and eczema at one year of age.

BACKGROUND: Epidemiological evidence suggests that routine vaccinations can have nontargeted effects on susceptibility to infections and allergic disease. Such effects may depend on age at vaccination, and a delay in pertussis vaccination has been linked to reduced risk of allergic disease. We aimed to test the hypothesis that delay in vaccines containing diphtheria-tetanus-acellular pertussis (DTaP) is associated with reduced risk of food allergy and other allergic diseases. METHODS: HealthNuts is a population-based cohort in Melbourne, Australia. Twelve-month-old infants were skin prick-tested to common food allergens, and sensitized infants were offered oral food challenges to determine food allergy status. In this data linkage study, vaccination data for children in the HealthNuts cohort were obtained from the Australian Childhood Immunisation Register. Associations were examined between age at the first dose of DTaP and allergic disease. RESULTS: Of 4433 children, 109 (2.5%) received the first dose of DTaP one month late (delayed DTaP). Overall, delayed DTaP was not associated with primary outcomes of food allergy (adjusted odds ratio (aOR) 0.77; 95% CI: 0.36-1.62, P = 0.49) or atopic sensitization (aOR: 0.66; 95% CI: 0.35-1.24, P = 0.19). Amongst secondary outcomes, delayed DTaP was associated with reduced eczema (aOR: 0.57; 95% CI: 0.34-0.97, P = 0.04) and reduced use of eczema medication (aOR: 0.45; 95% CI: 0.24-0.83, P = 0.01). CONCLUSIONS: There was no overall association between delayed DTaP and food allergy; however, children with delayed DTaP had less eczema and less use of eczema medication. Timing of routine infant immunizations may affect susceptibility to allergic disease.

Which infants with eczema are at risk of food allergy? Results from a population-based cohort.

BACKGROUND: The relationship between early onset eczema and food allergy among infants has never been examined in a population-based sample using the gold standard for diagnosis, oral food challenge. OBJECTIVE: We characterised the risk of challenge-proven food allergy among infants with eczema in the general population. METHODS: One-year-old infants (n = 4453 meeting criteria for this analysis) were assessed for history of eczema, received a nurse-administered eczema examination and underwent skin prick testing to peanut, egg and sesame. Those with a detectable wheal to one of the test foods underwent an oral food challenge irrespective of wheal size. The risk of food allergy, stratified by eczema severity and age of onset, was estimated using multivariate logistic regression with population sampling weights. RESULTS: One in five infants with eczema were allergic to peanut, egg white or sesame, compared to one in twenty-five infants without eczema (OR 6.2, 95% CI 4.9, 7.9, P < 0.001). The prevalence of peanut allergy was low in the absence of eczema (0.7% 95% CI 0.4, 1.1). Infants with eczema were 11.0 times more likely to develop peanut allergy (95% CI 6.6, 18.6) and 5.8 times more likely to develop egg allergy (95% CI 4.6, 7.4) by 12 months than infants without eczema. 50.8% of infants (95% CI 42.8, 58.9) with early eczema onset (<3 months) who required doctor-prescribed topical corticosteroid treatment developed challenge-proven food allergy. CONCLUSION AND CLINICAL RELEVANCE: Eczema, across the clinical severity spectrum in infancy, is a strong risk factor for IgE-mediated food allergy. Infants with eczema were six times more likely to have egg allergy and 11 times more likely to have peanut allergy by 12 months than infants without eczema. Our data suggest that a heightened awareness of food allergy risk among healthcare practitioners treating infants with eczema, especially if early onset and severe, is warranted.

Differential factors associated with challenge-proven food allergy phenotypes in a population cohort of infants: a latent class analysis.

BACKGROUND: Food allergy, eczema and wheeze are early manifestations of allergic disease and commonly co-occur in infancy although their interrelationship is not well understood. Data from population studies are essential to determine whether there are differential drivers of multi-allergy phenotypes. We aimed to define phenotypes and risk factors of allergic disease using latent class analysis (LCA). METHODS: The HealthNuts study is a prospective, population-based cohort of 5276 12-month-old infants in Melbourne, Australia. LCA was performed using the following baseline data collected at age 12 months: food sensitization (skin prick test ≥ 2 mm) and allergy (oral food challenge) to egg, peanut and sesame; early (< 4 months) and late-onset eczema; and wheeze in the first year of life. Risk factors were modelled using multinomial logistic regression. RESULTS: Five distinct phenotypes were identified: no allergic disease (70%), non-food-sensitized eczema (16%), single egg allergy (9%), multiple food allergies (predominantly peanut) (3%) and multiple food allergies (predominantly egg) (2%). Compared to the baseline group of no allergic disease, shared risk factors for all allergic phenotypes were parents born overseas (particularly Asia), delayed introduction of egg, male gender (except for single egg allergy) and family history of allergic disease, whilst exposure to pet dogs was protective for all phenotypes. Other factors including filaggrin mutations, vitamin D and the presence of older siblings differed by phenotype. CONCLUSIONS AND CLINICAL RELEVANCE: Multiple outcomes in infancy can be used to determine five distinct allergy phenotypes at the population level, which have both shared and separate risk factors suggesting differential mechanisms of disease.

Increased risk of peanut allergy in infants of Asian-born parents compared to those of Australian-born parents.

BACKGROUND: Asian infants appear to be over-represented among patients with clinical food allergy in Australia, but this has not been formally examined at the population level. Any difference in prevalence according to parental country of birth may be secondary to modifiable lifestyle factors. We aimed to quantify (i) differences in the prevalence of peanut allergy by parental country of birth and (ii) contribution of measured environmental exposures to these differences. METHODS: The population-based HealthNuts study in Melbourne, Australia, screened 5276 infants (74% participation) with skin prick tests and sensitized infants underwent food challenge. Of these, 535 had a parent born in East Asia and 574 in UK/Europe. Associations between parents' country of birth and offspring peanut allergy were examined using multiple logistic regression. RESULTS: Compared to infants with two Australian-born parents, peanut allergy was more common among infants with parent/s born in East Asia (OR 3.4, 95% CI 2.2-5.1) but not those with parent/s born in the UK/Europe (OR 0.8, 95% CI 0.4-1.5). Paradoxically rates of allergic disease were lower among Asian parents. A higher prevalence of eczema among infants of Asian parents explained around 30% of the increase in peanut allergy, while differences in dog ownership explained around 18%. CONCLUSIONS: The high peanut allergy prevalence among infants of Asian-born parents appears to have occurred in a single generation and was not present among infants with parents migrating from other countries, suggesting gene-environment interactions are important. The role of eczema and microbial exposure in food allergy prevention warrants exploration.

Characterization of plasma cytokines in an infant population cohort of challenge-proven food allergy.

BACKGROUND: Sensitization to food allergens indicates the production of food-specific IgE; however, sensitization is not a definite indicator of allergic reaction upon ingestion (N Engl J Med, 344, 2001, 30: J Allergy Clin Immunol, 120, 2007, 491). Currently, food challenge is the best approach to identify the presence or absence of allergy. While 95% positive predictive values (PPVs) thresholds for sIgE can assist with identifying increased likelihood of allergy among those who are sensitized, there are no specific biological markers that differentiate between allergic and sensitized individuals. OBJECTIVES: To determine whether plasma serum cytokine profiles predict (i) sensitization to peanut and egg and (ii) food allergy among sensitized infants. METHODS: Peanut-sensitized (PT) and egg-sensitized 14-month-old infants and nonsensitized controls enrolled in HealthNuts, a population-based study of food allergy, underwent an oral food challenge (OFC). Blood was collected within 1 h after OFC. Serum levels of Th1, Th2 and regulatory cytokines were determined in allergic (n = 79), sensitized (n = 40) and nonsensitized, nonallergic (n = 37) infants by multiplex assay. RESULTS: Food-sensitized infants had significantly higher plasma IL-4, IL-13, IL-12p70 and lower IL-10 levels compared to nonsensitized infants. IL-10 and IL-6 levels were significantly higher in sensitized compared with allergic infants. Egg-allergic infants had significantly higher IL-13 and IL-12p70 levels compared to peanut-allergic (PA) infants. CONCLUSION: Levels of Th2-related cytokines in plasma are higher in food-sensitized infants, irrespective of clinical food allergy status. In contrast, IL-10 levels appear to predict food allergy among sensitized infants. Differences in IL-13 and IL-12p70 between egg- and peanut-allergic infants could help explain the different resolution rates of the allergies.

The prevalence and socio-demographic risk factors of clinical eczema in infancy: a population-based observational study.

BACKGROUND: Socio-demographic predictors for the development of clinically observed, infantile eczema have not been formally examined in a large population-based study. Few studies of eczema risk factors have included current, objective eczema outcomes as well as parent-reported history. OBJECTIVES: We aimed to measure the population prevalence of infantile eczema using novel sampling methodology, and identify socio-demographic risk factors for eczema in the first year of life. METHODS: A population-based cross-sectional study of infantile allergy (the HealthNuts study, n = 4972, response rate 74.1%) was conducted from 2008-2011 in Melbourne, Australia. Infants were examined for current eczema at age 12 months (mean 12.7, SD 0.7). Parents provided information about the infants' history of eczema and demographic factors. Factors associated with eczema were modelled using multinomial logistic regression. RESULTS: The population prevalence of observed eczema at 12 months was 20.3% (95% CI 19.0, 21.5), while cumulative prevalence for parent-reported eczema was 28.0% (95% CI 26.7, 29.4). The strongest predictors of eczema were maternal eczema and asthma (multinomial (M)-OR 1.7, P < 0.001, and M-OR 1.4, P = 0.007), male sex (M-OR 1.4, P < 0.001), and East Asian ethnicity (M-OR 1.6, P < 0.001) with over 80% of infants with all risk factors exhibiting eczema. East Asian parents, particularly recent migrants, reported fewer allergies than other parents. CONCLUSIONS AND CLINICAL RELEVANCE: Approximately, one in three infants developed eczema by 12 months of age. East Asian infants are at increased risk of eczema despite their parents having lower rates of allergy than non-Asian parents. Gene-environment interactions may explain the differential effect seen in this minority group.

Frequent baked egg ingestion was not associated with change in rate of decline in egg skin prick test in children with challenge confirmed egg allergy.

BACKGROUND: It is controversial whether egg-allergic children should strictly avoid all forms of egg, or if regular ingestion of baked egg will either delay or hasten the resolution of egg allergy. OBJECTIVE: This is the first study to examine the relationship between frequency of baked egg ingestion and rate of decline in egg skin prick test size in egg-allergic children. METHODOLOGY: This was a retrospective clinical cohort study. All children with challenge-proven egg allergy who attended the Royal Children's Hospital Allergy Department 1996-2005 and had at least two egg skin prick tests performed in this period were included (n = 125). Frequency of baked egg ingestion was assessed by telephone questionnaire as follows: (a) frequent (> once per week), (b) regular (> once every 3 months, up to ≤ once per week) or (c) strict avoidance (≤ once every 3 months). The relationship between frequency of baked egg ingestion and rate of decline in egg skin prick test size was examined by multiple linear regression, adjusting for potential confounders. RESULTS: Mean rate of decline in egg skin prick test size in all children was 0.7 mm/year (95% CI 0.5-1.0 mm/year). There was no evidence (P = 0.57) that the rate of decline in egg skin prick test size differed between children who undertook frequent ingestion (n = 21, mean 0.4 mm/year, 95% CI -0.3-1.2 mm/year), regular ingestion (n = 37, mean 0.9 mm/year, 95% CI 0.4-1.4 mm/year) or strict avoidance (n = 67, mean 0.7 mm/year, 95% CI 0.4-1.1 mm/year) of baked egg. CONCLUSIONS: Compared with strict dietary avoidance, frequent consumption of baked egg was not associated with a different rate of decline in egg skin prick test size in egg-allergic children. CLINICAL RELEVANCE: Given that dietary restrictions can adversely impact on the family, it is reasonable to consider liberalizing baked egg in the diet of egg-allergic children.

Environmental and demographic risk factors for egg allergy in a population-based study of infants.

BACKGROUND: Although egg allergy is the most common food allergy in infants and young children, risk factors for egg allergy remain largely unknown. This study examined the relationship between environmental and demographic factors and egg allergy in a population-based infant cohort. METHODS: In a study of 5276 infants (HealthNuts), infants underwent skin prick testing (SPT) to egg white at 12 months of age. Questionnaire data on relevant exposures were obtained. 699/873 (80%) infants eligible for oral food challenge (detectable wheal on SPT) attended for formal assessment of egg allergy status; 453 had confirmed egg allergy (positive challenge and SPT ≥ 2 mm). Associations between environmental and demographic factors and egg allergy were investigated using multivariable logistic regression. RESULTS: Children with older siblings and those with a pet dog at home were less likely to develop egg allergy by 1 year of age (adjusted OR [aOR], 0.72; 95% CI, 0.62, 0.83 per sibling; and aOR, 0.72; 95% CI, 0.52, 0.99, respectively). Caesarean section delivery, antibiotic use in infancy, childcare attendance and maternal age were not associated with egg allergy. History of allergic disease in an immediate family member and having parents born in East Asia were strong risk factors for infantile egg allergy (aOR, 1.82; 95% CI, 1.40, 2.36; and aOR, 3.30; 95% CI, 2.45, 4.45, respectively). CONCLUSIONS: Exposure in the first year of life to siblings and dogs may decrease the risk of subsequent egg allergy. Infants with a family history of allergy and those with parents born in East Asia are at increased risk of egg allergy.

Pets at birth do not increase allergic disease in at-risk children.

BACKGROUND: The literature is contradictory concerning pet exposure and risk of allergic disease in childhood especially among those with a family history of allergy. OBJECTIVE: To investigate the relationship between cat and dog exposure at birth and allergic outcomes over the first 12 years in a birth cohort selected for familial allergy. METHODS: A prospective birth cohort of 620 infants with a family history of allergic diseases was recruited. Data on pet keeping, family demographics and cord blood samples were collected at birth. Information on childhood wheeze, eczema and hay fever was collected 18 times in the first 2 years, at 7 years and at 12 years. Skin prick tests were conducted at 2, 7 and 12 years, and in parents. Regression analyses were used to investigate the relevant associations while adjusting for potential confounders. RESULTS: Exposure to cats or dogs at birth showed a moderate reduction in risk of wheeze (aOR = 0.76; 95% CI 0.53, 1.09) and hay fever (aOR = 0.71; 0.49, 1.02) after 7 years of age. Protective effects were stronger in children of non-sensitized fathers (aOR wheeze 0.55; 0.31, 0.98; aOR hay fever 0.33; 0.15, 0.77 on exposure to cats alone, or cats or dogs at birth). Pet keeping was not related to cord blood IgE or sensitization from 2 to 12 years. CONCLUSIONS AND CLINICAL RELEVANCE: Pets at birth either decreased or had no effect on allergic disease up to age 12. We found no evidence that exposure to cats or dogs at birth increases the risk of allergic disease in high-risk children.

The HealthNuts population-based study of paediatric food allergy: validity, safety and acceptability.

BACKGROUND: The incidence of hospital admissions for food allergy-related anaphylaxis in Australia has increased, in line with world-wide trends. However, a valid measure of food allergy prevalence and risk factor data from a population-based study is still lacking. OBJECTIVE: To describe the study design and methods used to recruit infants from a population for skin prick testing and oral food challenges, and the use of preliminary data to investigate the extent to which the study sample is representative of the target population. METHODS: The study sampling frame design comprises 12-month-old infants presenting for routine scheduled vaccination at immunization clinics in Melbourne, Australia. We compared demographic features of participating families to population summary statistics from the Victorian Perinatal census database, and administered a survey to those non-responders who chose not to participate in the study. RESULTS: Study design proved acceptable to the community with good uptake (response rate 73.4%), with 2171 participants recruited. Demographic information on the study population mirrored the Victorian population with most the population parameters measured falling within our confidence intervals (CI). Use of a non-responder questionnaire revealed that a higher proportion of infants who declined to participate (non-responders) were already eating and tolerating peanuts, than those agreeing to participate (54.4%; 95% CI 50.8, 58.0 vs. 27.4%; 95% CI 25.5, 29.3 among participants). CONCLUSION: A high proportion of individuals approached in a community setting participated in a food allergy study. The study population differed from the eligible sample in relation to family history of allergy and prior consumption and peanut tolerance, providing some insights into the internal validity of the sample. The study exhibited external validity on general demographics to all births in Victoria.

Sibship analysis of associations between SNP haplotypes and a continuous trait with application to mammographic density.

Haplotype-based association studies have been proposed as a powerful comprehensive approach to identify causal genetic variation underlying complex diseases. Data comparisons within families offer the additional advantage of dealing naturally with complex sources of noise, confounding and population stratification. Two problems encountered when investigating associations between haplotypes and a continuous trait using data from sibships are (i) the need to define within-sibship comparisons for sibships of size greater than two and (ii) the difficulty of resolving the joint distribution of haplotype pairs within sibships in the absence of parental genotypes. We therefore propose first a method of orthogonal transformation of both outcomes and exposures that allow the decomposition of between- and within-sibship regression effects when sibship size is greater than two. We conducted a simulation study, which confirmed analysis using all members of a sibship is statistically more powerful than methods based on cross-sectional analysis or using subsets of sib-pairs. Second, we propose a simple permutation approach to avoid errors of inference due to the within-sibship correlation of any errors in haplotype assignment. These methods were applied to investigate the association between mammographic density (MD), a continuously distributed and heritable risk factor for breast cancer, and single nucleotide polymorphisms (SNPs) and haplotypes from the VDR gene using data from a study of 430 twins and sisters. We found evidence of association between MD and a 4-SNP VDR haplotype. In conclusion, our proposed method retains the benefits of the between- and within-pair analysis for pairs of siblings and can be implemented in standard software.

Rapid decline in presentations of genital warts after the implementation of a national quadrivalent human papillomavirus vaccination programme for young women.

OBJECTIVE: This study aimed to determine if the Australian human papillomavirus (HPV) vaccination programme has had a population impact on presentations of genital warts. METHODS: Retrospective study comparing the proportion of new clients with genital warts attending Melbourne Sexual Health Centre (MSHC) from January 2004 to December 2008. Australia provided free quadrivalent HPV vaccine to 12-18-year-old girls in a school-based programme from April 2007, and to women 26 years and younger through general practices from July 2007. RESULTS: 36,055 new clients attended MSHC between 2004 and 2008 and genital warts were diagnosed in 3826 (10.6%; 95% CI 10.3 to 10.9). The proportion of women under 28 years with warts diagnosed decreased by 25.1% (95% CI 30.5% to 19.3%) per quarter in 2008. Comparing this to a negligible increase of 1.8% (95% CI 0.2% to 3.4%) per quarter from the start of 2004 to the end of 2007 also in women under 28 years generates strong evidence of a difference in these two trends (p<0.001). There was no evidence of a difference in trend for the quarterly proportions before and after the end of 2007 for any other subgroup, and on only one occasion was there strong evidence of a trend different to zero, for heterosexual men in 2008 in whom the average quarterly change was a decrease of 5% (95% CI 0.5% to 9.4%; p = 0.031). CONCLUSIONS: The data suggest that a rapid and marked reduction in the incidence of genital warts among vaccinated women may be achievable through an HPV vaccination programme targeting women, and supports some benefit being conferred to heterosexual men.

Missing pelvic inflammatory disease? Substantial differences in the rate at which doctors diagnose PID.

OBJECTIVES: The clinical diagnosis of pelvic inflammatory disease (PID) is subjective. Our aim was to determine if the pattern of diagnosis of PID among experienced clinicians varied compared with the diagnosis of genital warts. METHODS: We conducted a retrospective study of 325 PID diagnoses made by experienced clinicians at Melbourne Sexual Health Centre, Australia (2002-2006), where doctors saw 21 785 unselected female patients in a walk-in service. We compared the proportion of female patients diagnosed as having PID and genital warts between doctors and then compared doctors above (high diagnosing) and below (low diagnosing) the mean rate of PID diagnosis. RESULTS: There were significant and clinically important differences in the proportion of women diagnosed with having PID (0-5.7%) across 23 doctors investigated. Estimated standard deviation in the frequency of PID diagnosis (logit scale) was 1.26 (95% CI 0.81 to 1.95)--approximately four times greater than for warts. Patients seen by high (n = 4673) and low (n = 16 787) diagnosing doctors had similar epidemiological risk profiles suggesting true distribution of PID cases across doctors was similar (p>0.13). Women diagnosed with having PID by high diagnosing doctors compared with low diagnosing doctors were younger (odds ratio 1.7; 95% CI 1.1 to 2.8, p = 0.013) but otherwise had similar epidemiological and clinical features. CONCLUSIONS: Differences in diagnostic rates for PID between doctors are substantial and may be because of PID cases being missed by some doctors.

The efficacy and cost-effectiveness of prophylactic 5-hydroxytryptamine3 receptor antagonists: tropisetron, ondansetron and dolasetron.

There are currently three 5-hydroxytryptamine3 (5-HT3) receptor antagonists available in Australia. In this randomized, double-blind, parallel group study the prophylactic antiemetic effect of a single dose of tropisetron 2 mg, ondansetron 4 mg or dolasetron 12.5 mg was compared after major gynaecological surgery. One hundred and eighteen patients (group T n = 42; group O n = 36; group D n = 40) were evaluated for nausea, vomiting, recovery characteristics and satisfaction for 24 hours postoperatively. A cost-effectiveness analysis was performed. Rescue antiemetic, prochlorperazine 12.5 mg i.m., was given if vomiting occurred more than 10 minutes after arrival in the recovery room. If prochlorperazine was ineffective one hour after administration, droperidol 1 mg i.v. was given. There were no significant differences between groups for the incidence of vomiting during consecutive epochs until 24 hours postoperatively or overall (57%, 75% and 72.5% for groups T, O and D respectively, P = 0.18). The incidence and number of rescue antiementic treatments for nausea or vomiting were similar. The incidence of nausea and the overall and interval nausea scores were similar except for lower "worst nausea" score in group T between 12 and 18 hours (P = 0.02). Recovery times, satisfaction and cost per patient did not differ between groups. We conclude that the risk of postoperative nausea and vomiting remained high in this setting despite 5-HT3 receptor antagonist prophylaxis and that the choice between these agents should be based on the lowest available acquisition cost.

The effects of overcoming experimental bladder outflow obstruction in fetal sheep.

OBJECTIVE: To develop an ovine model of fetal bladder outflow obstruction and to investigate the effect on the kidney of surgical relief of the obstruction in the prenatal period. METHODS: Ultrasound examination and amniocentesis were performed on 68 date-bred pregnant ewes at day 57 of pregnancy (term = 150 days). Fetal gender was determined using a molecular technique to identify single male fetuses. The urethra and urachus were ligated at hysterotomy on 20 of these fetuses at 75 days' gestation. Comparisons were made with six controls that did not undergo operation. Changes that occurred in fetal urinary tract appearance were detected using serial ultrasound examinations. Seven obstructed cases chosen at random had further prenatal surgery on day 94 to decompress the obstructed urinary tract by vesicostomy. The animals were killed at 110 days' gestation and post-mortem studies were performed. RESULTS: Fourteen days after surgical obstruction, there were increases in the summed renal lengths (33 mm vs. 28 mm, p = 0.003) and renal pelvis anteroposterior (A-P) diameters (8 mm vs. 5.5 mm, p = 0.02). In the group allocated to receive surgical decompression, 9 days' relief of obstruction resulted in significant reductions in summed renal lengths (30 mm vs. 41 mm, p = 0.024; controls 31 mm) and renal pelvis A-P diameters (5.8 mm vs. 8.9 mm, p = 0.012; controls < 2 mm). Postmortem histological examination in the surgical decompression group revealed an estimated number of glomeruli similar to controls and greater than in the obstructed cases. CONCLUSION: Surgical relief of fetal bladder outflow obstruction in ovine mid-pregnancy results in improved renal appearance on ultrasonic and histopathological examinations.

Prenatal ultrasound biometry related to subsequent blood pressure in childhood.

STUDY OBJECTIVE: To relate measures of fetal growth/size other than birth weight with subsequent blood pressure measured on the same individuals within the context of the "fetal origins of adult disease". DESIGN: A prospective cohort study in which measurements of fetal dimensions obtained by serial ultrasound imaging between 18 and 38 weeks gestation were analysed with reference to systolic blood pressure measurements on the offspring at age 6 years. SETTING: Perth, Western Australia. PARTICIPANTS: A subgroup of 707 eligible mother-fetus pairs from a cohort of 2876 pregnant women and their offspring. The number of mother-fetus pairs varied at each gestational age and by measurement of fetal dimension. Subsequent blood pressure recordings were obtained on approximately 300 of the offspring at age 6 years. MAIN RESULTS: The findings confirmed the inverse association between birth weight and systolic blood pressure at age 6. There was, also, an inverse relation between fetal femur length and systolic blood pressure at age 6, adjusted for current height. Furthermore, an inverse association was demonstrated between a statistically derived measure of fetal growth (conditional z score) between 18 and 38 weeks gestation and later systolic blood pressure at age 6. The effect sizes for all three relations were in the order of 1-2 mm Hg per standard deviation change. CONCLUSION: The mechanisms underpinning the "fetal origins" hypothesis may be operative early in pregnancy and may be reflected in the length of the fetal femur in early to mid-pregnancy.