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Original Article |

Perinatal Factors and the Development of Autism:  A Population Study FREE

Emma J. Glasson, BPsych, BSc (Hons), PhD; Carol Bower, MBBS, MSc, PhD, FAFPHM, DLSHTM; Beverly Petterson, MSc, PhD; Nick de Klerk, BSc, MSc, PhD; Gervase Chaney, MBBS, FRACP; Joachim F. Hallmayer, MD
[+] Author Affiliations

From the Schools of Population Health (Dr Glasson) and Psychiatry andClinical Neurosciences (Drs Glasson and Hallmayer), and the Telethon Institutefor Child Health Research, Centre for Child Health Research (Drs Glasson,Bower, Petterson, and de Klerk), University of Western Australia, Perth, Australia;the Centre for Clinical Research in Neuropsychiatry, Graylands Hospital, Perth(Drs Glasson and Hallmayer); the Disability Services Commission, Perth (DrPetterson); Princess Margaret Hospital, Perth (Dr Chaney); and the Departmentof Psychiatry and Behavioral Sciences, Stanford University School of Medicine,Stanford, Calif (Dr Hallmayer). Dr Glasson is no longer with the Centre forClinical Research in Neuropsychiatry, Graylands Hospital, Perth.


Arch Gen Psychiatry. 2004;61(6):618-627. doi:10.1001/archpsyc.61.6.618.
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Background  Autism is considered to have a genetic basis, although exposure to certain stimuli in the prenatal period has been implicated to be causal in some cases. Some investigations have shown an association with obstetric complications but findings have been inconsistent owing to differences in sampling and methods.

Objective  To examine the association of obstetric factors with autism spectrum disorders for a cohort of children, using obstetric data contained in a statutory database collected at the time of birth.

Design  Subjects born in Western Australia between 1980 and 1995 and diagnosed with an autism spectrum disorder by 1999 were included as cases (n = 465). Siblings of the cases (n = 481) and a random population-based control group (n = 1313) were compared with the cases on obstetric information contained in the Maternal and Child Health Research Database of Western Australia.

Results  Compared with control subjects, cases had significantly older parents and were more likely to be firstborn. Case mothers had greater frequencies of threatened abortion, epidural caudal anesthesia use, labor induction, and a labor duration of less than 1 hour. Cases were more likely to have experienced fetal distress, been delivered by an elective or emergency cesarean section, and had an Apgar score of less than 6 at 1 minute. Cases with a diagnosis of autism had more complications than those with pervasive developmental disorder not otherwise specified or Asperger syndrome. Nonaffected siblings of cases were more similar to cases than control subjects in their profile of complications.

Conclusions  Autism is unlikely to be caused by a single obstetric factor. The increased prevalence of obstetric complications among autism cases is most likely due to the underlying genetic factors or an interaction of these factors with the environment.

Autism is a developmental disorder that is characterized by severe impairmentin social interaction and communication and by the presence of stereotypicbehavior.1 It has an estimated prevalence of10 to 20 per 10 000 individuals.24 Autismis diagnosed by clinical criteria,1,5 usuallyaround 3 to 4 years of age when social and communication milestones are notachieved. Symptoms are often noticed by 12 months of age,6 andaffected people show large individual differences in their symptomatology.7 Autism is part of a spectrum of disorders that includesAsperger syndrome and pervasive developmental disorder not otherwise specified(PDD-NOS).1 The latter 2 diagnoses are madewhen affected individuals have fewer or milder symptoms. The prevalence ofall autism spectrum disorders is estimated at approximately 60 per 10 000people.8

The genetic basis of autism spectrum disorders is supported by clusteringin families, higher concordance in monozygotic twins than in dizygotic twins,and evidence for the broader phenotype, or variable expressivity, in otherfamily members.913 Theprecise mechanisms leading to the development of autism or autistic symptomsare unknown, but it is likely that many different genes are involved.14

In some cases, neurological differences,1517 earrotation,18 and the distinct phalanx ratios19 suggest that a prenatal influence has acted in adirect or contributory manner. Specific prenatal factors have also been observed.2030 Thedevelopment of autistic symptoms may be dependent on the timing of exposureand/or genetic predisposition to certain environmental stimuli before birth.

During the past 30 years, numerous investigations have attempted toidentify a pattern or causal pathway from the obstetric experience of peoplewho develop autism. Generally, an increase in the number of obstetric complicationshas been observed, with the most consistent findings being advanced maternalage, maternal bleeding during early pregnancy, maternal medication use duringpregnancy, and an increased risk of autism among firstborn infants. However,findings are inconsistent and often contradictory because of considerablevariation in methods, sample size, variable selection, analyses, data quality,and control groups. Sample size has typically ranged between 53 and 87 cases,3135 withthe larger samples using retrospectively collected obstetric data from medicalrecords and/or maternal interviews.3638

The largest and most recent study compared 408 children identified forautism in the Swedish Inpatient Register with 2040 matched infants from theSwedish Medical Birth Register.39 The autismgroup was characterized by maternal smoking during early pregnancy, a cesareansection delivery, small size for gestational age, low Apgar scores, maternalbirth outside Europe and North America, and congenital malformations. Whilethe Hultman et al39 study is large and rigorous,no comparison was made with siblings, thereby restricting the interpretationof the influence of either genetics or the maternal environment. An increasein obstetric complications has also been observed in some nonautistic siblinggroups,31,40 suggesting that autismis not necessarily caused by the complications but rather may be an epiphenomenonof a strongly genetic disorder.35

The population of Western Australia is approximately 1.9 million people,73% of whom reside in the metropolitan area of Perth.41 Forevery birth since 1980, obstetric data, including information on parentaldemographics, maternal obstetric history, pregnancy, delivery, and neonatedata, are recorded in the state Maternal and Child Health Research Database(MCHRDB).42 Diagnoses and service deliveryfor people with autism are centralized by the state government, and historically,diagnoses have been made at 5 centers. Diagnoses are made using the criteriaspecified in the DSM for the period.1,43,44 TheGillberg criteria45 for Asperger syndrome aresometimes used as a supplement to, or instead of, the DSM criteria for Asperger syndrome because of the perceived value of thedetailed qualitative descriptions they offer for the diagnostic process.

The aim of the present study was to use the centralized resources containedin Western Australia to improve on the methods used in previous studies thathave investigated the correlation between obstetric experience and autismdevelopment. Although no single factor from the prenatal environment has beenidentified to cause autistic symptoms later in life, certain variables, suchas advanced maternal age, have sometimes emerged as risk factors. The methodsused by each study have varied significantly to the point where it is difficultto compare across samples. It is possible that the methodological differences,such as small sample size, have had an effect on the findings.

The present study used a large population-based sample with high-qualitydata and rigorous research methods to identify risk factors from prenataland perinatal experience for developing autism. It included a comparison groupof siblings to measure familial differences and compared diagnostic subgroupswithin the autism spectrum. It is unique for incorporating the largest numberof autistic cases born in a geographic region, using obstetric data collectedat the time of birth, comparing cases with a large population-based controlgroup and comparing cases with siblings.

CASE ASCERTAINMENT

Approval to obtain diagnostic information was received from the ethicscommittees of the 5 diagnostic centers, as well as the University of WesternAustralia, Perth. Diagnostic reports of all persons born after 1980 identifiedas having an autism spectrum disorder or autistic features before 1997 werepersonally examined by a pediatric registrar (G.C.) involved in autism assessments.Those who had been assessed using the DSM criteriafor an autism spectrum disorder according to the version used in that periodwere included in the study.1,43,44 Thecollection of data by the pediatric registrar was limited by what was containedin the files, so descriptive information, such as IQ, was not available forevery case. Diagnoses made between 1997 and 1999 from the 2 main diagnosticcenters that are responsible for at least 90% of all diagnoses and registrationsand who were subject to centralized diagnoses during this period were added.Since June 1997, for a child to receive government funding for early interventionservices in Western Australia, autism spectrum diagnoses must incorporateassessments by a pediatrician, speech pathologist, and a clinical psychologistwho must all agree on the diagnosis. This ensured a comprehensive listingof people born since 1980, diagnosed between 1986 and 1999.

DATA LINKAGE

Cases were electronically linked to the MCHRDB using probabilistic recordlinkage methods46 and manual checking to confirmpossible matches. Based on the number of cases reviewed by the pediatric registrar,it was predicted prior to case extraction that approximately 350 autism caseswould be identified. For such a sample size, to detect a 2.2-fold increasein the risk of bleeding during pregnancy (one of the more consistent findingsin previous studies with a prevalence of 3.7% for all births in the MCHRDB)at 80% power and 5% level of significance, 3 control subjects per case wouldbe needed. Five hundred one autism cases were identified and linked to theirbirth record, and sibling data were also extracted. The control group (n =1503) was matched for sex but otherwise randomly selected across the samerange of birth years as the cases (1980-1997). After case ascertainment, itwas apparent that cases born in 1996 and 1997 were few in number (n = 36)because they were diagnosed at an especially young age (younger than 3 years).The pattern of symptoms that appears in very young children with autism maydiffer from that seen at the more prototypic age of 4 or 5 years. Includingthese children may have introduced a bias, particularly because most childrenborn in these birth years who develop autism but were not yet diagnosed wouldhave been omitted. Therefore, these cases were excluded from the study alongwith any control subject or sibling born in the same 2-year period.

VARIABLE SELECTION

The following variables were selected from the MCHRDB:

  • Parental characteristics. Maternal and paternal age at the timeof the infant's birth.

  • Pregnancy characteristics. Pregnancy complications (threatenedabortion at <20 weeks' gestation; urinary tract infection; preeclampsia;antepartum hemorrhage; premature membrane rupture; and "other," as coded by International Classification of Diseases, Ninth Revision (ICD-9) classifications47).

  • Labor and delivery characteristics. Type of anesthesia used, laboronset, labor complications (precipitate delivery, fetal distress, umbilicalcord around neck, cephalopelvic disproportion, postpartum hemorrhage >500mL, and "other," coded by ICD-9 classifications),hours of labor, type of delivery, and birth presentation.

  • Infant characteristics. Birth order, gestational age, head circumference,length, weight, Apgar scores at 1 and 5 minutes, time to spontaneous respiration,and time spent in special care.

STATISTICAL ANALYSES

Analyses were performed using the Statistical Package for the SocialSciences version 10.0 (SPSS Inc, Chicago, Ill). Comparisons were made on eachvariable using χ2 tests; odds ratios (ORs) were used for categoricalvariables and t tests for continuous variables. Toinvestigate the possible effect of several variables simultaneously, casesand control subjects were compared using binary logistic regression, and ORsand 95% confidence intervals (CIs) were calculated, with values of P<.05 considered significant.

A total of 465 linked cases was identified (314 autism, 67 Aspergersyndrome, and 84 PDD-NOS) (Table 1).There were 1313 control subjects and 481 siblings of cases. One hundred thirtycases were singletons, 200 had 1 sibling, 97 had 2 siblings, and 30 had 3or more siblings. Eight cases had a sibling who also had been diagnosed withan autism spectrum disorder, including 1 set of concordant male twins, andthese siblings were all included in the case group. Three of the sibling pairsdid not have any other siblings, and the remaining 5 pairs had 1 unaffectedsibling. The random removal of 1 of each of the sibling pairs from the casegroup or the removal of all familial cases from the case group did not alterthe research findings.

Table Graphic Jump LocationTable 1. Number of Autism Cases, Their Siblings, and Control Subjectsby Sex
UNIVARIATE ANALYSES
Cases Compared With Control Subjects

Case parents were significantly older than control subject parents.The mean age of case mothers was 28.62 years, and the mean age of controlsubject mothers was 27.01 years. (t = 5.71; P<.001); the mean age of case fathers was 31.74 years,and the mean age of control subject fathers was 30.31 years (t = 4.19; P<.001) (Table 2). Among case pregnancies, 175 mothers (37.6%) had at least1 pregnancy complication recorded compared with 426 control subject mothers(32.4%). Case mothers were more likely to experience a threatened abortionbefore 20 weeks' gestation (OR, 2.41; 95% CI, 1.56-3.73) (Table 3) and significantly more "other" pregnancy complicationsthan mothers of control subjects (OR, 1.36; 95% CI, 1.04-1.78). Case and controlsubject mothers experienced 92 different conditions within the "other" pregnancycategory and had up to 3 conditions listed each. The most common conditions(hypertension, early labor, and fetal/placental problems) were found in similarproportions in both the case and control subject groups. Case mothers hadhigher frequencies of anesthesia use during labor (327 [88.6%] of 369 caseswith data recorded since 1986 compared with 616 [85.2%] of 723 control subjectswith data recorded since 1986), specifically an epidural caudal anesthesia(OR, 1.68; 95% CI, 1.12-2.51).Case mothers were more likely to experienceno labor (OR, 2.04; 95% CI, 1.50-2.76), be induced (OR, 1.43; 95% CI, 1.12-1.83),or have a labor duration of less than 1 hour (89 cases [19.1%]; 155 controlsubjects [11.8%]) (OR, 1.8; 95% CI, 1.3-2.4). More case mothers experienceda labor complication (290 cases [62.4%]; 680 control subjects [51.8%]). Casemothers had greater frequencies of postpartum hemorrhage (OR, 2.33; 95% CI,1.11-4.89) and "other" labor complications (OR, 1.55; 95% CI, 1.24-1.92).There were 120 differently coded "other" labor complications across case andcontrol subject mothers. Case mothers were more likely to have an electivecesarean section (OR, 2.05; 95% CI, 1.49-2.82) or an emergency cesarean section(OR, 1.57; 95% CI, 1.11-2.22).

Table Graphic Jump LocationTable 2. Cases Compared With Control Subjects for Continuous Variables
Table Graphic Jump LocationTable 3. Cases Compared With Control Subjects for Dichotomous Variablesof Pregnancy, Labor, and Infant Characteristics

Control subject mothers had higher parity than the case mothers (P = .01) (Table 4).Among the cases, there were 13 twin pairs, 1 of which was concordant (oneautism diagnosis and one PDD-NOS diagnosis). Of the 12 discordant pairs, 10were diagnosed with autism and 2 with PDD-NOS. Seven twin pairs were the samesex, but information on zygosity was not known from the birth records. Therate of twinning in this sample has been previously described48 anddoes not implicate twinning as a risk factor for autism.

Table Graphic Jump LocationTable 4. Birth Order Frequencies in Cases and Control Subjects*

Cases were more likely to have experienced fetal distress during labor(OR, 1.64; 95% CI, 1.15-2.34). Apgar scores calculated at 1 minute showedthat significantly more cases achieved a score of 6 or less (54 [19.5%] of277 cases with data recorded since 1991; 66 [12.9%] of 512 control subjectswith data recorded since 1991)(OR, 1.6; 95% CI, 1.1-2.4), and cases were morelikely to have taken more than 1 minute before the onset of spontaneous respiration(OR, 1.4; 95% CI, 1.0-1.9). Apgar scores at 5 minutes showed that fewer casesachieved a score of at least 8 (437 cases [94.2%]; 1258 control subjects [96.1%]),but differences were not significant (OR, 0.7; 95% CI, 0.4-1.1). No differencesin gestational age (including the proportion of premature infants), weightfor gestational age, head circumference, or length were observed between casesand control subjects. Female cases were shorter in length (t = 2.47; P = .01) and had a longer gestationalage (t = −2.73; P =.007) compared with male cases. Female control subjects weighed less (t = 1.98; P = .048) and had alonger gestational age (t = −2.26; P = .02) than male control subjects.

Comparison of Cases With Their Siblings

Compared with their siblings, cases were more likely to have been induced(OR, 1.40; 95% CI, 1.03-1.90), experienced fetal distress (OR, 1.64; 95% CI,1.15-2.34), had an Apgar score at 1 minute of 6 or less (OR, 1.64; 95% CI,1.02-2.65), and needed longer than 1 minute to breathe spontaneously (OR,1.81; 95% CI, 1.21-2.69) (Table 5).The cases had a higher rate of threatened abortion than their siblings, butthis was not statistically significant (OR, 1.60; 95% CI, 0.96-2.68). Whenadjusted for sex, these differences remained. The cases did not differ fromtheir siblings on any of the continuous variables tested.

Table Graphic Jump LocationTable 5. Cases Compared With Their Siblings for Dichotomous Variablesof Pregnancy, Labor, and Infant Characteristics
Comparison by Diagnostic Grouping

When compared with control subjects, the diagnostic groupings differedin their pattern of obstetric experience (Table 6). The autism group had the greatest number of complications.The PDD-NOS group had similar types of complications to the autism group,but fewer variables reached statistical significance. The Asperger syndromegroup had the fewest obstetric differences and was distinguished by a lackof significantly increased pregnancy and labor complications requiring forcepsor vacuum extraction and by having private health insurance. When comparedwith the autism group on the same variables, the PDD-NOS group only differedby having a greater risk of cephalopelvic disproportion (OR, 3.0; 95% CI,1.3-6.8). Compared with the autism group, the Asperger cases were more likelyto have a vacuum or forceps delivery (OR, 2.5; 95% CI, 1.3-4.7) and have privatehealth insurance (OR, 2.4; 95% CI, 1.3-4.2).

Table Graphic Jump LocationTable 6. Each Autism Diagnostic Grouping Compared With Control Subjectsfor Dichotomous Variables of Pregnancy, Labor, and Infant Characteristics*
LOGISTIC REGRESSION ANALYSIS

Year of birth and birth order were entered into the regression analysisalong with all other variables. Numerous interactions were also included,but none were significant. After the deletion of 3 individuals with missingvalues, 1775 were available for the analysis (464 cases and 1311 control subjects). Table 7 shows regression coefficients,Wald statistics, ORs, and 95% CIs for ORs for each of the 6 predictors. Themodel predictors using autism as an outcome were year of birth (cases weremore likely to be recently born), birth order (cases were more likely to befirstborn), maternal age (cases were more likely to have an older mother),threatened abortion (more likely to be present in cases), fetal distress (morelikely to be present in cases), and elective cesarean section (more likelyto be present in cases).

Table Graphic Jump LocationTable 7. Logistic Regression Model With 6 Explanatory Variables (AllCases Compared With Control Subjects)

To our knowledge, this study is the largest reported population-basedsample to date of people born and diagnosed with an autism spectrum disorderwithin a single geographical area, using prospectively collected obstetricdata and comparing siblings and autism subgroups in a single research design.The findings indicate that individuals diagnosed within the autism spectrumare more likely to have experienced obstetric difficulties during pregnancy,labor, delivery, and the neonatal period compared with people without an autismdiagnosis. This is in agreement with the general interpretations in previousstudies.31,32,3436,39,49,50

The study sample is representative of the Western Australian populationat a point in time but was restricted to cases who had received a formal diagnosisin the autism spectrum. Therefore, a proportion of cases are likely to havebeen missed from the case ascertainment process, in particular milder and/orolder cases who were not referred for autism services. The study also doesnot include cases who were born between 1980 and 1995 but subsequently diagnosedafter 1999.

Advanced maternal age in case mothers was one of the strongest findingsof the study. Increased maternal age has previously been found as a risk factorin autism, regardless of the range of birth years examined.5154 Theeffect in this study was incremental such that younger mothers had the lowestrisk and older mothers had the highest risk. In the Croen et al55 studythat compared maternal age of 4356 autism cases born in California with nearly3.5 million control subject mothers, the risk of mothers 35 years or olderhaving a child with autism was increased 3-fold compared with mothers youngerthan 20 years.55 This effect was also foundin the present data and in the recent Swedish cohort of 408 cases.39 Older mothers have an increased risk of complicationsduring labor and delivery,56,57 possiblyattributable to the dysfunction of the uterine muscles and blood supply thatoccurs with age,57 which may be compoundedby older mothers delivering a larger number of firstborn cases. However, inthe present study, increased maternal age emerged as an independent risk factorafter adjustment for the other variables.

Paternal age was also greater in fathers of cases compared with fathersof control subjects. Paternal age is not usually addressed or has been foundto be unimportant53 in previous studies. Increasedpaternal age has been documented in patients with schizophrenia.58,59 Ithas a recognized effect in autosomal dominant mutations such as Apert syndromeand achondroplasia,60,61 in Downsyndrome,62 and also in the inheritance of MeCP2 mutations in girls with Rett syndrome.63 Increasedpaternal age did not emerge as a significant predictor in the regression analysisand was statistically weaker in the univariate analyses, suggesting that itseffect is most likely to be related to increased maternal age.

Threatened abortions were significantly more common in the case pregnanciescompared with control subjects and attained the highest OR value. Bleedingduring pregnancy has previously been reported in case mothers32,34,36,39,40,64 andalso an increased number of prior miscarriages.65,66 Ahigher prevalence of previous miscarriages and stillbirths among case motherswas not observed in the present dataset.

Elective cesarean sections were more common among case births and theirsiblings compared with control subjects and emerged as a risk factor afteradjusting for maternal age and year of birth. The prevalence of cesarean sectionshas increased in recent decades, the reasons for which are both socially andmedically complex.6769 Themost common antecedents for a cesarean section are previous cesarean section,failure to progress in labor, fetal distress, multiple pregnancies, breechpresentation, and unstable lie.70,71 Recently,there has been an increasing trend for women to request a cesarean delivery,and this is becoming the most popular reason for having the procedure.72,73 Unfortunately, the reasons for performingcesarean section deliveries are not recorded in the MCHRDB, and thus, inferencescannot be made from the available data.

Epidural caudal anesthesia was more commonly administered to case mothersduring labor and may have been used for cesarean section or maternal painrelief.74,75 Physiological responsesto pain include increased blood pressure and decreased uterine blood flowand may negatively affect the fetus by altering heart rate and increasingoxygen consumption.75,76 Epiduralanesthesia is considered the most effective method of pain relief during labor,71,77 but it is a cause of intrapartumfever and may have adverse effects on the fetus if the fetal core temperaturebecomes elevated above the maternal core temperature.76 Adverseeffects such as low Apgar scores may be observed at birth and may also beassociated with administration of epidural caudal anesthesia and the decisionto perform an elective caesarean section in some cases.

In laboratory experiments, cesarean section deliveries can produce ratswith significantly increased binding of dopamine D1 receptors in the nucleusaccumbens compared with rats delivered vaginally.78 Theeffect is enhanced by anesthesia and may be related to the presence of hypoxia.The increase in D1-receptor binding is only evident in the rat brain duringadulthood, possibly owing to an interaction with events during development.This may be more severe in rats that are genetically susceptible because thereare different responses among rat strains.78 Insome individuals with autism, problem behaviors may be managed effectivelywith dopamine inhibitors.79 These individualsmay represent a subgroup whose etiology involves early damage to the ventralbasal ganglia, which may be associated with cerebral changes that are initiatedat birth.

The presence of fetal distress, no labor, caesarean section delivery,and poor condition at birth (as measured by a low Apgar score at 1 minuteand taking greater than 1 minute to spontaneously respirate) was characteristicof the case group. This suggests an association with anoxia and/or placentaldeficiency, evidence of which was found in the Hultman et al39 cohort.Anoxia is often caused by placental abruption that typically results in deliverywithin 1 hour, meconium staining, abnormal fetal heart patterns, and umbilicalcord blood acidity.80 There are no data onthe long-term effects of abnormal placentas, reflecting the lack of knowledgeabout its role in development. This is an important direction for future research.The simultaneous presence of anoxia and hyperthermia before birth has beenshown to produce neurological consequences in animal offspring and could thereforebe a potential source of injury to neonates.8183

Although the case group spent less time in special care when comparedwith the statistical mean, both groups were similar using the median statistic.This indicates that some control subjects spent lengthy periods in specialcare, and this has affected the comparison of the 2 groups. Unfortunately,the reasons for requiring special care are not available from the MCHRDB,and thus, no judgments can be made on the qualitative differences in the 2groups' need for care.

Cases were more likely to be firstborn compared with control subjects.The finding is consistent with other reports of first births carrying a riskfor autism.31,36,54 Theearlier finding of autism cases more commonly being born fourth or later31,34,54 was not observed.Those born first or fourth or later naturally have more complications, butthe autism group experienced more complications at all birth orders. A possibleexplanation is that pregnancy complications are part of the phenotypic expressionof some of the group of autism genes rather than a contributory cause.

Overall, case siblings had fewer complications than their affected siblingsbut more than control subjects. They had similar experiences to the casesduring the pregnancy period but experienced less fetal distress during labor,were less likely to be induced than the cases, and were more likely to takemore than 1 minute for spontaneous respiration. These findings remained afteradjusting for sex. Several inferences can be made from this relationship.First, the obstetric complications may represent a compromised maternal environmentto which all offspring are exposed but autism develops in only some offspring,either because of certain environmental stimuli or a particular genotype thatis vulnerable to develop the disorder. Second, if the development of autismdepends on having a certain number of genes, then siblings who share somegenes may also show complications in utero and may also have milder autistictraits. Siblings and other close relatives of people with autism often showmild autistic traits on cognitive assessments.912 Thisis consistent with the hypothesis that shared genes cause similarities inutero and those with the autism genotype will develop the disorder and siblingswho share some of the genes show milder symptomatology.

Alternatively, individuals with autism may react differently to thesame environmental stimuli and may have less tolerance to the prenatal experiencecompared with their siblings. Given that siblings had similar obstetric experiencesto the cases, some other factor could be influential in late pregnancy forthe case births, but not for siblings, to cause autism. It could also be thatthe measurement of complications is too crude and that a more refined measurementmay reveal the subtle differences of the prenatal experience of the childwith autism.

When compared with the control group, the profile of obstetric complicationsdiffered by autism subgroup, whereby the Asperger syndrome group had fewercomplications than the PDD-NOS group, which in turn had fewer, but similar,complications than the autism group. This pattern suggests there is a positiverelationship between autism severity and adverse obstetric experience. TheAsperger syndrome group had a more favorable experience during the pregnancyand labor periods. Previous investigations of the obstetric experience forpeople with Asperger syndrome have used small sample sizes, ranging from 10to 23 cases.45,84,85 Allreport an increase in complications in the Asperger groups compared with thecontrol subjects but fewer than the autism groups, which is similar to thepresent dataset. Fewer complications may be related to the decreased probabilityof people with Asperger syndrome having comorbid medical conditions.86 Clinically, people diagnosed with Asperger syndromegenerally have better-developed language skills and a higher level of intelligencethan those with autism.2,6,87,88 Autismcases who have a lower IQ have been shown to experience more obstetric complications33,40,64,89 andalso more severe symptoms than those with a high IQ.90 Itis therefore likely that IQ is a factor that is associated with obstetricexperience.

This research has used a population-based cohort of people diagnosedwith autism spectrum disorders to investigate whether the etiology or natureof autism can be defined by the presence of particular biological characteristicsaround the time of birth. For some cases, differences in the environment and/orin their reaction to it occur in utero, as seen by an increased number ofrisk factors and obstetric complications that differentiate the experienceof autism cases from nonautistic control subjects. The strongest findingswere increased maternal age and a threatened abortion during pregnancy. Itis unlikely that single factors or events cause autistic disorders, althoughit is possible that early nongenetic influences may act on the causal pathwayfor some cases. The observed complications are generally nonspecific and cannotpredict autism development. This research supports the hypothesis that thedevelopment of autism spectrum disorders is dependent on the genotype, andthe presence of complications can be explained by a compromised prenatal experiencefor that genotype.

Corresponding author: Emma Glasson, School of Population Health,University of Western Australia, 35 Stirling Hwy, Crawley WA 6009, Australia(e-mail: emma.glasson@health.wa.gov.au).

Submitted for publication June 2, 2003; final revision received January21, 2004; accepted January 28, 2004.

Data from this study were presented at the Inaugural World Autism Congress:Unity Through Diversity; November 13, 2002; Melbourne, Australia.

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Deykin  EYMacMahon  B Viral exposure and autism. Am J Epidemiol. 1979;109628- 638
PubMed
Ivarsson  SABjerre  IVegfors  PAhlfors  K Autism as one of several disabilities in two children with congenitalcytomegalovirus infection. Neuropediatrics. 1990;21102- 103
PubMed
Markowitz  PI Autism in a child with congenital cytomegalovirus infection. J Autism Dev Disord. 1983;13249- 253
PubMed
Stubbs  EGAsh  EWilliams  CP Autism and congenital cytomegalovirus. J Autism Dev Disord. 1984;14183- 189
PubMed
Tanoue  YOda  SAsano  FKawashima  K Epidemiology of infantile autism in Southern Ibaraki, Japan: differencesin prevalence in birth cohorts. J Autism Dev Disord. 1988;18155- 166
PubMed
Ghaziuddin  MTsai  LYEilers  LGhaziuddin  N Brief report: autism and herpes simplex encephalitis. J Autism Dev Disord. 1992;22107- 113
PubMed
Davis  EFennoy  ILaraque  DKanem  NBrown  GMitchell  J Autism and developmental abnormalities in children with perinatal cocaineexposure. J Natl Med Assoc. 1992;84315- 319
PubMed
Stromland  KNordin  VMiller  MAkerstrom  BGillberg  C Autism in thalidomide embryopathy: a population study. Dev Med Child Neurol. 1994;36351- 356
PubMed
Moore  SJTurnpenny  PQuinn  AGlover  SLloyd  DJMontgomery  TDean  JCS A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet. 2000;37489- 497
PubMed
Williams  GKing  JCunningham  MStephan  MKerr  BHersh  JH Fetal valproate syndrome and autism: additional evidence of an association. Dev Med Child Neurol. 2001;43202- 206
PubMed
Bolton  PFMurphy  MMacDonald  HWhitlock  BAPickles  ARutter  M Obstetric complications in autism: consequences or causes of the condition? J Am Acad Child Adolesc Psychiatry. 1997;36272- 281
PubMed
Juul-Dam  NTownsend  JCourchesne  E Prenatal, perinatal, and neonatal factors in autism, pervasive developmentaldisorder–not otherwise specified, and the general population. Pediatrics. [serial online]2001;107e63Available athttp://pediatrics.aappublications.org/cgi/content/full/107/4/e63May 2, 2003.
PubMed
Levy  SZoltak  BSaelens  T A comparison of obstetrical records of autistic and nonautistic referralsfor psychoeducational evaluations. J Autism Dev Disord. 1988;18573- 581
PubMed
Piven  JSimon  JChase  GAWzorek  MLanda  RGayle  JFolstein  S The etiology of autism: pre-, peri- and neonatal factors. J Am Acad Child Adolesc Psychiatry. 1993;321256- 1263
PubMed
Zwaigenbaum  LSzatmari  PJones  MBBryson  SEMacLean  JEMahoney  WBartolucci  GTuff  L Pregnancy and birth complications in autism and liability to the broaderautism phenotype. J Am Acad Child Adolesc Psychiatry. 2002;41572- 579
PubMed
Deykin  EYMacMahon  B Pregnancy, delivery, and neonatal complications among autistic children. Am J Dis Child. 1980;134860- 864
PubMed
Mason-Brothers  ARitvo  ERPingree  CPetersen  PBJenson  WRMcMahon  WMFreeman  BJJorde  LBSpencer  MJMo  A The UCLA-University of Utah epidemiologic survey of autism: prenatal,perinatal, and postnatal factors. Pediatrics. 1990;86514- 519
PubMed
Wilkerson  DSVolpe  AGDean  RSTitus  JB Perinatal complications as predictors of infantile autism. Int J Neurosci. 2002;1121085- 1098
PubMed
Hultman  CMSparen  PCnattangius  S Perinatal risk factors for infantile autism. Epidemiology. 2002;13417- 423
PubMed
Bryson  SESmith  IMEastwood  D Obstetric suboptimality in autistic children. J Am Acad Child Adolesc Psychiatry. 1988;27418- 422
PubMed
Australian Bureau of Statistics, Census of Population and Housing: Selected Socialand Housing Characteristics, Australia 2001, Cat. No. 2015.0.  Canberra Australian Bureau of Statistics2001;
Stanley  FJCroft  MLGibbins  JRead  AW A population database for maternal and child health research in WesternAustralia using record linkage. Paediatr Perinat Epidemiol. 1994;8433- 447
PubMed
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders,Third Edition.  Washington, DC American Psychiatric Association1980;
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders,Revised Third Edition.  Washington, DC American Psychiatric Association1987;
Gillberg  C Asperger syndrome in 23 Swedish children. Dev Med Child Neurol. 1989;31520- 531
PubMed
Holman  CDBass  AJRouse  ILHobbs  MS Population-based linkage of health records in Western Australia: developmentof a health services research linked database. Aust N Z J Public Health. 1999;23451- 452
PubMed
World Health Organization, International Classification of Diseases, Ninth Revision(ICD-9).  Geneva, Switzerland World Health Organization1977;
Hallmayer  JGlasson  EJBower  CPetterson  BCroen  LGrether  JRisch  N On the twin risk in autism. Am J Hum Genet. 2002;71941- 946
PubMed
Links  PSStockwell  MAbichandani  FSimeon  J Minor physical anomalies in childhood autism, part I: their relationshipto pre- and perinatal complications. J Autism Dev Disord. 1980;10273- 285
PubMed
Mason-Brothers  ARitvo  ERGuze  BMo  AFreeman  BJFunderburk  SJSchroth  PC Pre-, peri-, and postnatal factors in 181 autistic patients from singleand multiple incidence families. J Am Acad Child Adolesc Psychiatry. 1987;2639- 42
PubMed
Gillberg  C Maternal age and infantile autism. J Autism Dev Disord. 1980;10293- 297
PubMed
Hoshino  YKumashiro  HYashima  YTachibana  RWatanabe  M The epidemiological study of autism in Fukushima-ken. Folia Psychiatr Neurol Jpn. 1982;36115- 124
PubMed
Mouridsen  SERich  BIsager  T Brief report: parental age in infantile autism, autistic-like conditions,and borderline childhood psychosis. J Autism Dev Disord. 1993;23387- 396
PubMed
Tsai  LYStewart  MA Etiological implication of maternal age and birth order in infantileautism. J Autism Dev Disord. 1983;1357- 65
PubMed
Croen  LGrether  JSelvin  S Descriptive epidemiology of autism in a California population: whois at risk? J Autism Dev Disord. 2002;32217- 224
PubMed
Ezra  YMcParland  PFarine  D High delivery intervention rates in nulliparous women over age 35. Eur J Obstet Gynecol Reprod Biol. 1995;62203- 207
PubMed
Rosenthal  ANPaterson-Brown  S Is there an incremental rise in the risk of obstetric interventionwith increasing maternal age? Br J Obstet Gynaecol. 1998;1051064- 1069
PubMed
Hare  EHMoran  PA Raised paternal age in psychiatric patients: evidence for the constitutionalhypothesis. Br J Psychiatry. 1979;134169- 177
PubMed
Malaspina  DHarlap  SFennig  SHeiman  DNahon  DFeldman  DSusser  ES Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatr. 2001;58361- 367
PubMed
Crow  JF The high spontaneous mutation rate: is it a health risk? Proc Natl Acad Sci U S A. 1997;948380- 8386
PubMed
Risch  NReich  EWWishnick  MMMcCarthy  JG Spontaneous mutation and parental age in humans. Am J Hum Genet. 1987;41218- 248
PubMed
Stene  JStene  EStengel-Rutkowski  SMurken  JD Paternal age and Down's syndrome: data from prenatal diagnosis. Hum Genet. 1981;59119- 124
PubMed
Girard  MCouvert  PCarrie  ATardieu  MChelly  JBeldjord  C Parental origin of de novo MECP2 mutations in Rett syndrome. Eur J Hum Genet. 2001;9231- 236
PubMed
Gillberg  CGillberg  IC Infantile autism: a total population study of reduced optimality inthe pre- peri- and neonatal period. J Autism Dev Disord. 1983;13153- 166
PubMed
Funderburk  SJCarter  JTanguay  PFreeman  BJWestlake  JR Prenatal reproductive problems and gestational hormonal exposure inautistic and schizophrenic children. J Autism Dev Disord. 1983;13325- 332
PubMed
Warren  RPCole  POdell  DPingree  CWarren  WLWhite  EYonk  JSingh  VK Detection of maternal antibodies in infantile autism. J Am Acad Child Adolesc Psychiatry. 1990;29873- 877
PubMed
Gee  VO'Neill  MT Perinatal Statistics in Western Australia, 1999.Seventeenth Annual Report of the Western Australian Midwives' NotificationSystem.  Perth, Australia Health Department of Western Australia2001;
Hueston  WJMcClaflin  RR Variations in cesarean delivery for fetal distress. J Fam Pract. 1996;43461- 467
PubMed
Showalter  EGriffin  A All women should have a choice. BMJ. 1999;3191401
Humphrey  MD The Obstetrics Manual.  Revised ed. Sydney, Australia McGraw-Hill1999;
McCarthy  AHunter  B Obstetrics and Gynaecology.  London, England Churchill-Livingstone1998;
Eftekhar  KSteer  P Women choose caesarean section. BMJ. 2000;3201073
Quinlivan  JAPetersen  RWNichols  CN Patient preference the leading indication for elective caesarean sectionin public patients—results of a 2-year prospective audit in a teachinghospital. Aust N Z J Obstet Gynaecol. 1999;39207- 214
PubMed
Crawford  JS Principles and Practice of Obstetric Anaesthesia. 5th London, England Blackwell Scientific Publications1984;
Hood  DD Maternal and fetal morbidity and mortality. James  FMWheeler  ASDewan  DMedsObstetricAnesthesia The Complicated Patient. 2nd Philadelphia, Pa FA DavisCo1988;57- 75
Newton  ER Epidural analgesia, intrapartum fever, and neonatal outcomes. Birth. 2000;27206- 208
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Impey  LMacQuillan  KRobson  M Epidural analgesia need not increase operative delivery rates. Am J Obstet Gynecol. 2000;182358- 363
PubMed
Boksa  PZhang  YBestawros  A Dopamine D1 receptor changes due to caesarean section birth: effectsof anesthesia, developmental time course, and functional consequences. Exp Neurol. 2002;175388- 397
PubMed
Buitelaar  JWillemsen-Swinkels  S Medication treatment in subjects with autistic spectrum disorders. Eur Child Adolesc Psychiatry. 2000;9I85- I97
PubMed
Altshuler  G Placental insights into neurodevelopmental and other childhood diseases. Semin Pediatr Neurol. 1995;290- 99
PubMed
Nakai  AShibazaki  YTaniuchi  YOya  AAsakura  HKuroda  SKishino  TAraki  T Influence of mild hypothermia on delayed mitochondrial dysfunctionafter transient intrauterine ischemia in the immature rat brain. Brain Res Dev Brain Res. 2001;1281- 7
PubMed
Suzuki  SMuratat  TJiang  LPower  GG Hyperthermia prevents metabolic and cerebral flow responses to hypoxiain the fetal sheep. J Soc Gynecol Investig. 2000;745- 50
PubMed
Wood  SCGonzales  R Hypothermia in hypoxic animals: mechanisms, mediators, and functionalsignificance. Comp Biochem Physiol B. 1996;11337- 43
PubMed
Ghaziuddin  MShakal  JTsai  L Obstetric factors in Asperger syndrome: comparison with high-functioningautism. J Intellect Disabil Res. 1995;39538- 543
PubMed
Rickerby  GCarruthers  AMitchell  M Biological factors associated with Asperger syndrome. J Autism Dev Disord. 1991;21341- 348
PubMed
Ehlers  SGillberg  C The epidemiology of Asperger syndrome: a total population study. J Child Psychol Psychiatry. 1993;341327- 1350
PubMed
Mayes  SDCalhoun  SLCrites  DL Does DSM-IV Asperger's disorder exist? J Abnorm Child Psychol. 2001;29263- 271
PubMed
Volkmar  FRKlin  A Asperger's disorder and higher functioning autism: same or different? Int Rev Res Ment Retard. 2000;2383- 110
Lord  CMulloy  CWendelboe  MSchopler  E Pre- and perinatal factors in high-functioning females and males withautism. J Autism Dev Disord. 1991;21197- 209
PubMed
Spiker  DLotspeich  LJDimiceli  SMyers  RMRisch  N Behavioral phenotypic variation in autism multiplex families: evidencefor a continuous severity gradient. Am J Med Genet. 2002;114129- 136
PubMed

Figures

Tables

Table Graphic Jump LocationTable 5. Cases Compared With Their Siblings for Dichotomous Variablesof Pregnancy, Labor, and Infant Characteristics
Table Graphic Jump LocationTable 6. Each Autism Diagnostic Grouping Compared With Control Subjectsfor Dichotomous Variables of Pregnancy, Labor, and Infant Characteristics*
Table Graphic Jump LocationTable 7. Logistic Regression Model With 6 Explanatory Variables (AllCases Compared With Control Subjects)
Table Graphic Jump LocationTable 4. Birth Order Frequencies in Cases and Control Subjects*
Table Graphic Jump LocationTable 3. Cases Compared With Control Subjects for Dichotomous Variablesof Pregnancy, Labor, and Infant Characteristics
Table Graphic Jump LocationTable 2. Cases Compared With Control Subjects for Continuous Variables
Table Graphic Jump LocationTable 1. Number of Autism Cases, Their Siblings, and Control Subjectsby Sex

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Davis  EFennoy  ILaraque  DKanem  NBrown  GMitchell  J Autism and developmental abnormalities in children with perinatal cocaineexposure. J Natl Med Assoc. 1992;84315- 319
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Stromland  KNordin  VMiller  MAkerstrom  BGillberg  C Autism in thalidomide embryopathy: a population study. Dev Med Child Neurol. 1994;36351- 356
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Moore  SJTurnpenny  PQuinn  AGlover  SLloyd  DJMontgomery  TDean  JCS A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet. 2000;37489- 497
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Williams  GKing  JCunningham  MStephan  MKerr  BHersh  JH Fetal valproate syndrome and autism: additional evidence of an association. Dev Med Child Neurol. 2001;43202- 206
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Bolton  PFMurphy  MMacDonald  HWhitlock  BAPickles  ARutter  M Obstetric complications in autism: consequences or causes of the condition? J Am Acad Child Adolesc Psychiatry. 1997;36272- 281
PubMed
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PubMed
Levy  SZoltak  BSaelens  T A comparison of obstetrical records of autistic and nonautistic referralsfor psychoeducational evaluations. J Autism Dev Disord. 1988;18573- 581
PubMed
Piven  JSimon  JChase  GAWzorek  MLanda  RGayle  JFolstein  S The etiology of autism: pre-, peri- and neonatal factors. J Am Acad Child Adolesc Psychiatry. 1993;321256- 1263
PubMed
Zwaigenbaum  LSzatmari  PJones  MBBryson  SEMacLean  JEMahoney  WBartolucci  GTuff  L Pregnancy and birth complications in autism and liability to the broaderautism phenotype. J Am Acad Child Adolesc Psychiatry. 2002;41572- 579
PubMed
Deykin  EYMacMahon  B Pregnancy, delivery, and neonatal complications among autistic children. Am J Dis Child. 1980;134860- 864
PubMed
Mason-Brothers  ARitvo  ERPingree  CPetersen  PBJenson  WRMcMahon  WMFreeman  BJJorde  LBSpencer  MJMo  A The UCLA-University of Utah epidemiologic survey of autism: prenatal,perinatal, and postnatal factors. Pediatrics. 1990;86514- 519
PubMed
Wilkerson  DSVolpe  AGDean  RSTitus  JB Perinatal complications as predictors of infantile autism. Int J Neurosci. 2002;1121085- 1098
PubMed
Hultman  CMSparen  PCnattangius  S Perinatal risk factors for infantile autism. Epidemiology. 2002;13417- 423
PubMed
Bryson  SESmith  IMEastwood  D Obstetric suboptimality in autistic children. J Am Acad Child Adolesc Psychiatry. 1988;27418- 422
PubMed
Australian Bureau of Statistics, Census of Population and Housing: Selected Socialand Housing Characteristics, Australia 2001, Cat. No. 2015.0.  Canberra Australian Bureau of Statistics2001;
Stanley  FJCroft  MLGibbins  JRead  AW A population database for maternal and child health research in WesternAustralia using record linkage. Paediatr Perinat Epidemiol. 1994;8433- 447
PubMed
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders,Third Edition.  Washington, DC American Psychiatric Association1980;
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders,Revised Third Edition.  Washington, DC American Psychiatric Association1987;
Gillberg  C Asperger syndrome in 23 Swedish children. Dev Med Child Neurol. 1989;31520- 531
PubMed
Holman  CDBass  AJRouse  ILHobbs  MS Population-based linkage of health records in Western Australia: developmentof a health services research linked database. Aust N Z J Public Health. 1999;23451- 452
PubMed
World Health Organization, International Classification of Diseases, Ninth Revision(ICD-9).  Geneva, Switzerland World Health Organization1977;
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PubMed
Links  PSStockwell  MAbichandani  FSimeon  J Minor physical anomalies in childhood autism, part I: their relationshipto pre- and perinatal complications. J Autism Dev Disord. 1980;10273- 285
PubMed
Mason-Brothers  ARitvo  ERGuze  BMo  AFreeman  BJFunderburk  SJSchroth  PC Pre-, peri-, and postnatal factors in 181 autistic patients from singleand multiple incidence families. J Am Acad Child Adolesc Psychiatry. 1987;2639- 42
PubMed
Gillberg  C Maternal age and infantile autism. J Autism Dev Disord. 1980;10293- 297
PubMed
Hoshino  YKumashiro  HYashima  YTachibana  RWatanabe  M The epidemiological study of autism in Fukushima-ken. Folia Psychiatr Neurol Jpn. 1982;36115- 124
PubMed
Mouridsen  SERich  BIsager  T Brief report: parental age in infantile autism, autistic-like conditions,and borderline childhood psychosis. J Autism Dev Disord. 1993;23387- 396
PubMed
Tsai  LYStewart  MA Etiological implication of maternal age and birth order in infantileautism. J Autism Dev Disord. 1983;1357- 65
PubMed
Croen  LGrether  JSelvin  S Descriptive epidemiology of autism in a California population: whois at risk? J Autism Dev Disord. 2002;32217- 224
PubMed
Ezra  YMcParland  PFarine  D High delivery intervention rates in nulliparous women over age 35. Eur J Obstet Gynecol Reprod Biol. 1995;62203- 207
PubMed
Rosenthal  ANPaterson-Brown  S Is there an incremental rise in the risk of obstetric interventionwith increasing maternal age? Br J Obstet Gynaecol. 1998;1051064- 1069
PubMed
Hare  EHMoran  PA Raised paternal age in psychiatric patients: evidence for the constitutionalhypothesis. Br J Psychiatry. 1979;134169- 177
PubMed
Malaspina  DHarlap  SFennig  SHeiman  DNahon  DFeldman  DSusser  ES Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatr. 2001;58361- 367
PubMed
Crow  JF The high spontaneous mutation rate: is it a health risk? Proc Natl Acad Sci U S A. 1997;948380- 8386
PubMed
Risch  NReich  EWWishnick  MMMcCarthy  JG Spontaneous mutation and parental age in humans. Am J Hum Genet. 1987;41218- 248
PubMed
Stene  JStene  EStengel-Rutkowski  SMurken  JD Paternal age and Down's syndrome: data from prenatal diagnosis. Hum Genet. 1981;59119- 124
PubMed
Girard  MCouvert  PCarrie  ATardieu  MChelly  JBeldjord  C Parental origin of de novo MECP2 mutations in Rett syndrome. Eur J Hum Genet. 2001;9231- 236
PubMed
Gillberg  CGillberg  IC Infantile autism: a total population study of reduced optimality inthe pre- peri- and neonatal period. J Autism Dev Disord. 1983;13153- 166
PubMed
Funderburk  SJCarter  JTanguay  PFreeman  BJWestlake  JR Prenatal reproductive problems and gestational hormonal exposure inautistic and schizophrenic children. J Autism Dev Disord. 1983;13325- 332
PubMed
Warren  RPCole  POdell  DPingree  CWarren  WLWhite  EYonk  JSingh  VK Detection of maternal antibodies in infantile autism. J Am Acad Child Adolesc Psychiatry. 1990;29873- 877
PubMed
Gee  VO'Neill  MT Perinatal Statistics in Western Australia, 1999.Seventeenth Annual Report of the Western Australian Midwives' NotificationSystem.  Perth, Australia Health Department of Western Australia2001;
Hueston  WJMcClaflin  RR Variations in cesarean delivery for fetal distress. J Fam Pract. 1996;43461- 467
PubMed
Showalter  EGriffin  A All women should have a choice. BMJ. 1999;3191401
Humphrey  MD The Obstetrics Manual.  Revised ed. Sydney, Australia McGraw-Hill1999;
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