Reproductive technologies and the risk of birth defects.

BACKGROUND: The extent to which birth defects after infertility treatment may be explained by underlying parental factors is uncertain. METHODS: We linked a census of treatment with assisted reproductive technology in South Australia to a registry of births and terminations with a gestation period of at least 20 weeks or a birth weight of at least 400 g and registries of birth defects (including cerebral palsy and terminations for defects at any gestational period). We compared risks of birth defects (diagnosed before a child's fifth birthday) among pregnancies in women who received treatment with assisted reproductive technology, spontaneous pregnancies (i.e., without assisted conception) in women who had a previous birth with assisted conception, pregnancies in women with a record of infertility but no treatment with assisted reproductive technology, and pregnancies in women with no record of infertility. RESULTS: Of the 308,974 births, 6163 resulted from assisted conception. The unadjusted odds ratio for any birth defect in pregnancies involving assisted conception (513 defects, 8.3%) as compared with pregnancies not involving assisted conception (17,546 defects, 5.8%) was 1.47 (95% confidence interval [CI], 1.33 to 1.62); the multivariate-adjusted odds ratio was 1.28 (95% CI, 1.16 to 1.41). The corresponding odds ratios with in vitro fertilization (IVF) (165 birth defects, 7.2%) were 1.26 (95% CI, 1.07 to 1.48) and 1.07 (95% CI, 0.90 to 1.26), and the odds ratios with intracytoplasmic sperm injection (ICSI) (139 defects, 9.9%) were 1.77 (95% CI, 1.47 to 2.12) and 1.57 (95% CI, 1.30 to 1.90). A history of infertility, either with or without assisted conception, was also significantly associated with birth defects. CONCLUSIONS: The increased risk of birth defects associated with IVF was no longer significant after adjustment for parental factors. The risk of birth defects associated with ICSI remained increased after multivariate adjustment, although the possibility of residual confounding cannot be excluded. (Funded by the National Health and Medical Research Council and the Australian Research Council.).

Fetal MBL2 haplotypes combined with viral exposure are associated with adverse pregnancy outcomes.

OBJECTIVE: To investigate the roles of inherited polymorphisms in the MBL2 gene and exposure to viral infection in the development of a range of adverse pregnancy outcomes, including birthweight  < 10th percentile (small-for-gestational age, SGA), antepartum hemorrhage (APH), pregnancy-induced hypertensive disorders (PIHD), and preterm birth (PTB). METHODS: This was a case-control study using DNA from newborn screening cards of 717 cases (babies with at least one of the adverse pregnancy outcomes listed above) and 609 controls, to screen for six polymorphisms within the MBL2 gene. These combine to create haplotypes with high (HYPA), intermediate (LYQA, LYPA), low (LXPA), and defective (HYPD, LYQC, LYPB) circulating MBL2 levels. RESULTS: Significant associations were found between variant MBL2 haplotypes and SGA (LYPA  < 32 weeks OR 5.37, 95% CI 1.50-17.27), antepartum hemorrhage (LYPA  < 37 weeks OR 2.29, 95% CI 1.25-4.18), and PIHD (LYQC < 32 weeks (OR 17.89, 95% CI 2.20-139.57). Evidence of exposure to infection increased the effect of these associations, (SGA OR 17.00, 95% CI 1.03-252.48; APH OR 5.67, 95% CI 1.73-18.84; PIHD OR 23.80, 95% CI 1.08-1414.76), while no evidence of exposure to infection demonstrated no associations. PTB was significantly associated with the defective HYPD haplotype with evidence of exposure to infection (OR 6.14, 95% CI 1.21-29.89). CONCLUSIONS: This research suggests that the combination of fetal MBL2 haplotypes and exposure to in utero viral infection increases the risk of adverse pregnancy outcomes, including PTB, antepartum hemorrhage, small-for-gestational age and PIHD.

The Australian cerebral palsy research study--protocol for a national collaborative study investigating genomic and clinical associations with cerebral palsy.

AIM: Previous studies have proposed a link between the presence of specific single nucleotide polymorphisms (SNPs) and cerebral palsy and the majority of these associations remain to be confirmed or rejected by prospective studies with sufficient statistical power. Prior studies have also given little attention to the interaction of genomic characteristics and clinical risk factors. METHODS: This paper describes the design of a prospective case-control study to test these genetic associations in conjunction with more stringent data collection in respect to clinical features associated with pregnancy, particularly maternal infection. Here we consider the ethical requirements, our hypothesis that genetic susceptibility modifies the risk of cerebral palsy in the presence of perinatal environmental triggers, a priori primary and secondary aims, power calculations, participant recruitment strategies, data linkage, sampling methods of genetic material and subsequent SNP analysis, collection of clinical data and the proposed final statistical analysis.

Genetic susceptibility to viral exposure may increase the risk of cerebral palsy.

AIM: Cytokine polymorphisms may alter the fetal inflammatory response, increasing susceptibility to cerebral palsy (CP). This study investigates associations between selected inflammatory mediator and cytokine gene polymorphisms (Toll-like receptor-4 (TLR-4) Asp299Gly, interleukin-6 G-174C and interleukin-4 C-589T) and CP from 443 CP infants and 883 control infants. Results were correlated with viral nucleic acids in the same samples. RESULTS: At all gestational ages (GA), TLR-4 was associated with a decreased risk of developing CP (homozygous/heterozygous odds ratio (OR) 0.70, 95% confidence interval (CI) 0.50-0.98) and interleukin (IL)-6 was associated with an increased risk of developing hemiplegia (OR 1.38, 95% CI 1.05-1.83). For infants born 32-36 weeks GA, there was a tenfold increase in the risk of quadriplegic CP with homozygous/heterozygous IL-6 (OR 10.42, 95% CI 1.34-80.82). Viral exposure in combination with IL-4 in preterm infants was associated with a fourfold increased risk of quadriplegia (homozygous/heterozygous OR 4.25, 95% CI 1.21-14.95). In very preterm infants, the absence of detectable viral exposure in combination with IL-4 decreased the risk of developing CP (homozygous/heterozygous OR 0.31, 95% CI 0.13-0.76). CONCLUSION: Polymorphisms in TLR-4 may be associated with a decreased risk of CP. Polymorphisms in IL-6 or IL-4 may act as susceptibility genes, in the presence of viral exposure, for the development of hemiplegic and quadriplegic CP. These associations require confirmation but they suggest a hypothesis for CP causation due to double jeopardy from neurotropic viral exposure and genetic susceptibility to infection.

Association between Apolipoprotein E genotype and cerebral palsy is not confirmed in a Caucasian population.

Apolipoprotein E (APOE) plays a significant role in lipid metabolism and has been implicated in the growth and repair of injured neurons. Two small studies have suggested an association between APOE genotype and cerebral palsy. We investigated if APOE genotype is associated with an increased risk for cerebral palsy, influences the type of cerebral palsy or interacts with prenatal viral infection to influence risk of cerebral palsy. The population-based case-control study comprised newborn screening cards of 443 Caucasian patients with cerebral palsy and 883 Caucasian matched controls. APOE genotyping was performed on DNA extracted from dried blood spots. Allelic and genotypic frequencies did not differ between cases and controls and combined frequencies were 0.10 (epsilon2), 0.76 (epsilon3), 0.14 (epsilon4), 0.03 (epsilon2/epsilon2), 0.10 (epsilon2/epsilon3), 0.03 (epsilon2/epsilon4), 0.02 (epsilon4/epsilon4), 0.21 (epsilon3/epsilon4), 0.61 (epsilon3/epsilon3). APOE genotype was correlated with cerebral palsy, type of cerebral palsy, gestation at birth and the presence of viral nucleic acids detected in previous work. Analysis by gestational age (all gestational ages, >/=37, 32-36 and <32 weeks) and type of cerebral palsy (all types, diplegia, hemiplegia and quadriplegia) showed no association between APOE genotype and cerebral palsy in this Caucasian population. An association between prenatal viral infection, APOE genotype and cerebral palsy was not demonstrated. These results did not confirm an association between APOE genotype, cerebral palsy, type of cerebral palsy and prenatal infection in a Caucasian population. Given the low frequency of APOE epsilon2 and some of the heterozygote and homozygote combinations in this study, a larger study is assessing this further.

Mannose-binding lectin haplotypes may be associated with cerebral palsy only after perinatal viral exposure.

OBJECTIVE: The objective of the study was to investigate the associations between infection, polymorphisms in the mannose-binding lectin gene (MBL), and cerebral palsy (CP). STUDY DESIGN: This was a case-control study using deoxyribonucleic acid from newborn screening cards of 443 Caucasian CP cases and 883 Caucasian controls to screen for 6 polymorphisms within the MBL gene. These polymorphisms combine to create haplotypes with high (HYPA), intermediate (LYQA, LYPA), low (LXPA), and defective (HYPD, LYQC, LYPB) circulating MBL levels. RESULTS: chi(2) Analyses demonstrated significant differences between CP cases and controls (less than 37 weeks chi(2) 14.99, P = .02; less than 32 weeks chi(2) 13.62, P = .02). The MBL haplotype LYPA was associated with CP at all gestations (odds ratio [OR] 1.57, 95% confidence interval [CI], 1.00 to 2.46), less than 37 weeks (OR 2.43, 95% CI, 1.41 to 4.18), and less than 32 weeks (OR 2.54, 95% CI, 1.34 to 4.76). LYPA was also associated with hemiplegic CP for babies born at less than 37 weeks (OR 2.77, 95% CI, 1.02 to 7.26) and less than 32 weeks (OR 4.48, 95% CI, 1.55 to 12.65). HYPD was associated with quadriplegic CP at all gestations (OR 3.47, 95% CI, 1.41 to 8.31) as well as for babies born at less than 32 weeks (OR 7.86, 95% CI, 1.67 to 29.48). Subanalysis on samples previously testing positive for exposure to viral infection demonstrated similar patterns of significance as those presented above, whereas analysis on samples negative for exposure to viral infection showed no positive associations between any of the MBL haplotypes and CP. Potential type I error from multiple analyses is a caveat. CONCLUSION: MBL haplotypes LYPA or HYPD may be associated with an increased risk of CP in the presence of exposure to viral infection and may act as susceptibility factors for CP.

Endometrial cells as a predictor of uterine cancer.

BACKGROUND: With the recent cervix screening national guidelines recommending against reporting of benign endometrial cells, we examined South Australian data to see what impact this would have on detecting uterine cancers. AIMS: To test whether benign endometrial cells detected in cervical cytology testing confer an increased risk of uterine cancer, and to ascertain what percentage of uterine cancers will be missed in cervical screening programs if these cells are not reported. METHODS: The study was a retrospective cohort design of 1585 women with shed endometrial cells, each matched with three women without shed cells. All were linked with cancer registry data to check for uterine cancer diagnosis. Cox proportional hazards regression was used to check for any increase in cancer risk with shed endometrial cells. Using the calculated relative risks for uterine cancer diagnosis, we estimated the number of uterine cancers in South Australia associated with benign endometrial cells. RESULTS: The presence of benign endometrial cells in a cervical cytology test increases the risk of uterine cancer sixfold. However, screening women with benign cells would involve a major increase in pathology work for only an 18% increase in uterine cancers detected. CONCLUSIONS: Until cytology systems have a higher sensitivity in detecting which benign endometrial cells are associated with uterine cancer, pathology laboratories are unlikely to be required to report these cells on tests. Inability to adjust for symptomatic status may have reduced the relevance of the results in this study.

Changes in incidence of in situ and invasive breast cancer by histology type following mammography screening.

OBJECTIVE: To investigate secular trends and correlates of incidence of breast cancer by histology type following the introduction of population-based mammography screening. METHODS: Analysis of age-standardised incidence rates for 1,423 in situ and 16,157 invasive carcinomas recorded on the South Australian population-based cancer registry for the 1985-2004 diagnostic period. Multiple logistic regression was undertaken to compare socio-demographic characteristics by histology. Progression from in situ disease was investigated using the Kaplan-Meier method. RESULTS: The incidence of in situ lesions increased approximately seven-fold over the 20-year period, compared with an increase of about 40% for invasive cancers. The increase for in situ lesions was due to increases for ductal carcinomas, with little change for lobular lesions. By comparison, the percentage increase in incidence for invasive cancer was greater for lobular than ductal cancers. Both for in situ and invasive cancers, percentage increases were greatest for the screening target age range of 50-69 years. One in 14 in situ cases was found to progress to invasive cancer within seven years of diagnosis, but insufficient detail was available to determine whether the invasive cancers were a progression of the in situ lesions or whether they originated separately. These invasive cancers were smaller than generally applying for other invasive cancers of the female breast. CONCLUSIONS: The larger secular increases in incidence for in situ than invasive cancers would reflect the dominant role of mammography in the detection of ductal carcinoma in situ. The lack of an increase for lobular in situ lesions may have resulted from their poorer radiological visibility. The greater percentage increase for lobular than ductal invasive lesions may have been due to an increase in imaging sensitivity for these lesions, plus real increases in incidence. The smaller sizes of invasive cancers found in women with a prior in situ diagnosis may have resulted from more intensive medical surveillance, although the possibility of biological differences cannot be discounted.

Associations between fetal inherited thrombophilia and adverse pregnancy outcomes.

OBJECTIVE: The purpose of this study was to investigate associations between fetal inherited thrombophilia and adverse pregnancy outcomes, including pregnancy-induced hypertensive disorders (PIHD), antepartum hemorrhage (APH), small-for-gestational age <10th percentile (SGA), and preterm birth (PTB). STUDY DESIGN: Seven hundred and seventeen cases and 609 controls were genotyped for Factor V Leiden (FVL, G1691A), Prothrombin gene mutation (PGM, G20210A), and Methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C using DNA from newborn screening cards. RESULTS: For babies born <28 weeks' gestation, PGM was associated with an increased risk of SGA (OR 6.40, 95%CI 1.66-24.71) and APH with SGA (OR 6.35, 95%CI 1.63-24.75). Homozygous MTHFR A1298C was associated with an increased risk of SGA for babies born 28-31 weeks gestation (OR 4.00, 95%CI 1.04-15.37), and with APH and SGA for babies born <32 weeks' gestation (OR 3.57, 95%CI 1.09-11.66). Homozygous MTHFR C677T was associated with a reduced risk of PTB and SGA (OR 0.52, 95%CI 0.28-0.96) for babies born 32 to 36 weeks' gestation. Homozygous FVL decreased the risk of PTB <32 weeks' gestation (OR 0.55, 95%CI 0.31-0.98). CONCLUSION: Fetal thrombophilic polymorphisms may be related to adverse pregnancy outcomes, in particular SGA.

The association between inherited cytokine polymorphisms and cerebral palsy.

OBJECTIVE: The purpose of this study was to investigate associations between inherited cytokine polymorphisms and cerebral palsy. STUDY DESIGN: This was a case-control study that used DNA from the newborn infant screening cards of 443 white infants with cerebral palsy and 883 white control infants to test for the following cytokine polymorphisms: tumor necrosis factor-alpha-308, mannose-binding lectin-221, and 3 polymorphisms in exon-1 of the mannose-binding lectin gene at codon-52, -54, and -57. RESULTS: At all gestational ages mannose-binding lectin codon-54 increased the risk of the development of diplegia (homozygous or heterozygous odds ratio, 1.55; 95% CI, 1.03-2.32). For babies who were born at term, the risk of the development of quadriplegia was associated with heterozygous tumor necrosis factor-alpha (odds ratio, 1.82; 95% CI, 1.04-3.15), and mannose-binding lectin codon-54 was associated with diplegia (homozygous or heterozygous odds ratio, 2.12; 95% CI, 1.10-4.05). The presence of any polymorphism in mannose-binding lectin exon-1 at term approximately doubled the risk of the development of diplegia (odds ratio, 1.94; 95% CI, 1.05-3.62). Homozygous or heterozygous tumor necrosis factor-alpha was associated with hemiplegia for babies who were born at <32 weeks of gestation (odds ratio, 2.38; 95% CI, 1.02-5.58). Overall, the presence of any cytokine polymorphism was associated with cerebral palsy (odds ratio, 1.37; 95% CI, 1.02-1.84). CONCLUSION: Carriage of polymorphisms in the tumor necrosis factor-alpha and mannose-binding lectin genes are associated with an increased risk of cerebral palsy.

Neurotropic viruses and cerebral palsy: population based case-control study.

OBJECTIVE: To investigate the association between cerebral palsy and direct evidence for perinatal exposure to neurotropic viruses. DESIGN: Population based case-control study. SETTING: Adelaide Women's and Children's Hospital Research Laboratory. PARTICIPANTS AND MAIN OUTCOME MEASURES: Newborn screening cards of 443 white case patients with cerebral palsy and 883 white controls were tested for viral nucleic acids from enteroviruses and herpes viruses by using polymerase chain reaction. Herpes group A viruses included herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpes virus 8 (HHV-8), and herpes group B viruses included varicella zoster virus (VZV) and human herpes viruses 6 and 7 (HHV-6 and HHV-7). RESULTS: The prevalence of viral nucleic acids in the control population was high: 39.8% of controls tested positive, and the prevalence was highest in preterm babies. The detection of herpes group B viral nucleic acids increased the risk of developing cerebral palsy (odds ratio 1.68, 95% confidence interval 1.09 to 2.59). CONCLUSIONS: Perinatal exposure to neurotropic viruses is associated with preterm delivery and cerebral palsy.

Associations between inherited thrombophilias, gestational age, and cerebral palsy.

OBJECTIVE: This study was undertaken to investigate associations between inherited thrombophilic polymorphisms and cerebral palsy (CP) in a large case-control study. STUDY DESIGN: This is a population-based case-control study. Genomic DNA from newborn screening cards of 443 white CP cases and 883 white controls was tested for factor V Leiden (FVL, G1691A), prothrombin gene mutation (PGM, G20210A), and methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C. RESULTS: MTHFR C677T was associated with an increased risk of developing any CP (32-36 weeks' gestation, homozygous odds ratio [OR] 2.55, 95% CI 1.12-5.74; heterozygous OR 1.91, 95% CI 1.01-3.66). MTHFR C677T was also associated with diplegia at both less than 32 weeks' gestation (homozygous OR 2.76, 95% CI 1.21-6.12) and all gestations (heterozygous OR 1.58 95%, CI 1.02-2.45). For children less than 32 weeks, FVL homozygosity may be associated with an increase in the risk of developing quadriplegia (OR 9.12, 95% CI 0.86-53.71). MTHFR A1298C (heterozygous) was associated with a reduced risk of diplegia developing at 32 to 36 weeks' gestation (OR 0.16, 95% CI 0.02-0.70). There were no associations between any type of CP and thrombophilia for children born 37 weeks or greater. Heterozygous PGM and homozygous MTHFR C677T combined were associated with quadriplegia at all gestational ages (OR 5.33, 95% CI 1.06-23.25). CONCLUSION: MTHFR C677T approximately doubles the risk of CP in preterm infants. A combination of homozygous MTHFR C677T and heterozygous PGM increases the risk of quadriplegia 5-fold at all gestational ages.

The prevalence of inherited thrombophilias in a Caucasian Australian population.

AIMS: To describe the prevalence of four inherited thrombophilias and their combinations for the first time in a large Caucasian Australian population. METHODS: Newborn screening cards of 883 Caucasian babies born in South Australia in 1986-1999 were de-identified and tested for the following inherited thrombophilic polymorphisms: factor V Leiden (G1691A), prothrombin gene mutation (G20210A), methylenetetrahydrofolate reductase gene (MTHFR) C677T and A1298C, as well as compound heterozygosity for the MTHFR polymorphisms. RESULTS: The birth prevalences of heterozygosity and homozygosity for the four thrombophilic polymorphisms were: factor V Leiden 9.5% and 0.7%, prothrombin gene 4.1% and 0.2%, MTHFR C677T 37.3% and 12.4%, and MTHFR A1298C 38.3% and 11.8%, respectively. Compound heterozygosity for MTHFR C677T and A1298C was seen in 16.6% of the population. Overall, 64.2% and 24.5% of the population studied were homozygous and heterozygous, respectively, for at least one of the four polymorphisms studied. CONCLUSION: Inherited thrombophilic polymorphisms are common in the Caucasian Australian population. Knowledge of the background prevalence of these polymorphisms will allow further study of their associations in future disease research.

Hypertension during pregnancy in South Australia, part 1: pregnancy outcomes.

BACKGROUND: There have been conflicting reports about pregnancy outcome in the hypertensive disorders of pregnancy. The present study was undertaken to examine outcomes using a population database. AIMS: To examine for differences in a range of pregnancy outcomes between three different groups of hypertensive women and normotensive women in South Australia. METHODS: Nine pregnancy outcomes were compared for 70,386 singleton pregnancies in the South Australian perinatal data collection in 1998-2001, consisting of 639 women with pre-existing hypertension, 5356 women with pregnancy hypertension, 448 women with superimposed pre-eclampsia and 63 943 normotensive women. Means for the four groups were calculated for birthweight, gestational age, the baby's and mother's length of stay. The groups were also compared for perinatal deaths with an earlier period, 1991-1997. RESULTS: While all three hypertensive groups had high incidences of induction of labour and emergency Caesarean, only pre-existing hypertension and superimposed pre-eclampsia were significantly associated with elective Caesarean section. All hypertensive groups had increased risks for low birthweight and preterm birth and special and neonatal intensive care. Uncomplicated pre-existing hypertension was not associated with small for gestational age infants, but with preterm delivery between 32 and 36 weeks' gestation. Superimposed pre-eclampsia had the worst prognosis for perinatal and maternal morbidity. While pregnancy hypertension held the intermediate position, it was not associated with an increase in perinatal mortality. The perinatal mortality rate for women with hypertensive disorders in 1998-2001 was significantly lower than that of an earlier period and equivalent to that for normotensive women. CONCLUSIONS: Superimposed pre-eclampsia occurs in approximately 40% of pregnancies of women with pre-existing hypertension and has the most severe outcomes. The hypertensive disorders are associated with high levels of morbidity and intervention, but the high perinatal mortality associated with these disorders has fallen significantly.

Hypertension during pregnancy in South Australia, part 2: risk factors for adverse maternal and/or perinatal outcome - results of multivariable analysis.

OBJECTIVE: To identify factors associated with adverse pregnancy outcomes among women with hypertension during pregnancy. DESIGN: A population-based retrospective multivariable analysis using the South Australian perinatal data collection. METHODS: Perinatal data on 70,386 singleton births in 1998-2001 were used in multivariable analyses on three groups: all women combined, all hypertensive women and women with pregnancy hypertension only, in order to identify independent risk factors for requirement for level II/III care, preterm birth, small for gestational age (SGA) birth and maternal length of stay greater than 7 days. RESULTS: The risks for the four morbidities were all increased among women with hypertension compared with normotensive women. Those with pre-existing hypertension had the lowest risk (with odds ratios (OR) 1.26-2.90). Pregnancy hypertension held the intermediate position (OR 1.52-5.70), while superimposed pre-eclampsia was associated with the highest risk (OR 2.00-8.75). Among women with hypertension, Aboriginality, older maternal age, nulliparity and pre-existing or gestational diabetes increased the risk for level II/III nursery care, preterm birth and prolonged hospital stay. Smokers had shorter stays, which may be related to their decreased risk of having a Caesarean section or operative vaginal delivery. Asian women, Aboriginal women, smokers and unemployed women had an increased risk for having an SGA baby, while women with pre-existing or gestational diabetes had a reduced risk. CONCLUSIONS: Among hypertensive pregnant women, nulliparity, older maternal age, Aboriginality, unemployment and diabetes are independent risk factors for one or more major adverse pregnancy outcomes. Smoking does not always worsen the outcome for hypertensive women except for SGA births.

Female breast cancers are getting smaller, but socio-demographic differences remain.

OBJECTIVE: To investigate trends towards early detection of infiltrating ductal carcinomas, possible effects on patients' prognosis, and characteristics of women still at high risk of late detection. METHODS: South Australian Cancer Registry data were analysed to compare breast tumour diameters for the 1980-86 and 1997-2002 diagnostic periods by age. Relative survivals for 1980-86 were compared with corresponding survival estimates for 1997-2000, obtained by weighting diameter-specific survivals for 1980-86 to equate with the diameter distribution for 1997-2002. Multivariable logistic regression was used to determine socio-demographic predictors of large diameters (> or =30 mm) in 1997-2002. RESULTS: The proportion of tumours with diameters smaller than 15 mm increased from 13.0% in 1980-86 to 36.7% in 1997-2002, whereas the proportion with large diameters reduced from 43.0% to 18.6%. Estimated changes in 20-year survivals equated with a 33% reduction in breast-cancer mortality among patients aged 50-69 years at diagnosis. Data for 1997-2002 indicate that early diagnosis is not evenly distributed, with large diameters more common in age ranges outside the 50-69 year target for mammography screening; low socio-economic areas; non-Caucasians; patients born in northern/eastern Europe and potentially Asia/Middle East; and in some country locations. CONCLUSIONS AND IMPLICATIONS: Increased emphasis on early detection should be directed at sectors of the population where delays in diagnosis and poorer prognosis are evident. Projected reductions in breast-cancer mortality among patients are indicative of effects of earlier detection on patients' prognosis, but require confirmation with follow-up data. More particularly, parallel studies of effects on population-based mortality are warranted.

Newborn screening in South Australia: is it universal?

OBJECTIVE: To determine the biochemical screening rate of newborns in South Australia and the factors associated with babies not being screened. DESIGN: Matching of data in the SA Newborn Screening Centre database (acquired from Guthrie cards) with the SA perinatal data collection (compiled from supplementary birth records) to determine how many newborns missed screening. Risk factors for missed screening were identified from sociodemographic and clinical variables recorded in the perinatal data collection and analysed by multivariable unconditional logistic regression analysis. PATIENTS AND SETTING: All live births (n = 18,426) in South Australia in 1999, in the 63 hospitals assisting deliveries or in the home. MAIN OUTCOME MEASURES: Rates of biochemical screening and missed screening in all newborns and among various subgroups; adjusted odds ratios (after multivariable logistic regression analysis) for risk factors for missed screening. RESULTS: The newborn screening rate in South Australia in 1999 was 97.8%. Babies born at home, born to an Aboriginal mother, or born to a mother who normally resided in another state were at higher risk of missed screening. Other factors associated with missed screening were having fewer than seven antenatal visits, prematurity (gestational age at birth < 32 weeks), congenital abnormality in the baby, use of paediatric intensive care, early discharge from hospital before 3 days (but especially after less than 1 day), and death of the baby during the neonatal period. CONCLUSION: In South Australia, while 2.2% of all newborns missed screening in 1999, in certain high-risk groups the proportions of unscreened babies were significantly higher. With a 2% missed screening rate, one might expect one newborn with a screening-detectable disorder to elude detection every other year in South Australia.

Use of radiotherapy in the primary treatment of cancer in South Australia.

Previous studies point to a lower use of radiotherapy by Australian cancer patients in lower socioeconomic areas and in country regions that are some distance from urban treatment centres. These were cross-sectional studies with the potential for error from changes in place of residence. We used a cohort design to avoid such error. South Australian patients diagnosed in 1990-1994 were followed until the date of censoring of 31 December 1999 using data from the State Cancer Registry. The percentage found to have had megavoltage therapy in the first 12 months following diagnosis varied by leading primary incidence site from 44% for the prostate to 40% for female breast, 38% for lung, 17% for rectum, 3% for colon and 2% for skin (melanoma). Multivariate analysis indicated that determinants of not receiving megavoltage therapy in the first 12 months were older age, female sex, residence in a country region and country of birth. Melanoma data revealed earlier stages for women than men. If this difference by sex applies to other cancers, it might explain the lower exposure of women to radiotherapy. Fewer older patients received radiotherapy, consistent with trends observed in hospital-based cancer-registry data. The influence on this finding of differences in stage and comorbidity requires additional study. While earlier findings of a lower exposure of country residents to radiotherapy were confirmed, the difference was comparatively small in this study. Variations in exposure by socioeconomic status of residential area were not observed.

Risk factors for hypertension during pregnancy in South Australia.

OBJECTIVE: To identify risk factors for hypertension in pregnancy among South Australian women. DESIGN: A population-based retrospective analysis using the South Australian perinatal data collection for 1998-2001. METHODS: Three groups of women with hypertension (pre-existing hypertension, pregnancy hypertension, and superimposed pre-eclampsia) were compared with normotensive women using unconditional logistic regression analysis on 70,386 singleton births to identify sociodemographic and clinical risk factors for hypertension in pregnancy. RESULTS: Nulliparity, Aboriginal race and Caucasian race (compared with Asian) and pre-existing and gestational diabetes were demonstrated to be risk factors for all hypertensive disorders, as was increasing maternal age for pre-existing hypertension and superimposed pre-eclampsia. Risk was increased for pregnancy hypertension and superimposed pre-eclampsia among women who gave their occupation as 'home duties' and also for superimposed pre-eclampsia among unemployed women. Women with hypertension were more likely to give birth in teaching hospitals. Urinary tract infections were not found to be a risk factor for any type of hypertension. Smoking during pregnancy was protective for all types of hypertension. CONCLUSIONS: The present study used a statewide population perinatal database and has confirmed that Aboriginal race, Caucasians, nulliparity, and pre-existing and gestational diabetes are independent risk factors for all types of hypertension in pregnancy. Increasing maternal age increased the risk for pre-existing hypertension and superimposed pre-eclampsia. There appeared to be appropriate referral of women with hypertensive disorders to teaching hospitals. A new finding is the increased risk among unemployed women and women engaged in home duties.