A H MacLennan

University of Adelaide, Adelaide, South Australia, Australia

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Publications (182)749.55 Total impact

  • Michael O'Callaghan, Alastair Maclennan
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    ABSTRACT: To examine the association of cesarean delivery and cerebral palsy using a systematic literature review and meta-analysis. MEDLINE, Embase, and ClinicalTrials.gov were systematically searched for articles relating to cerebral palsy and cesarean delivery from inception until December 2012. Only articles reporting confirmed cases of cerebral palsy were included. Meta-analysis was used to assess combined results and also the following subgroups: emergency cesarean; elective cesarean; term delivery; preterm delivery; and delivery of breech-presenting newborns. Literature searches returned 1,874 articles with 58 considered in full. Studies were selected if they reported an endpoint of cerebral palsy, an intervention or risk of cesarean delivery, were in English, and gave sufficient details to perform meta-analysis. Nine case-control and four cohort studies were included in the overall analysis. Meta-analysis showed no overall association of cesarean delivery with cerebral palsy (odds ratio [OR] 1.29; 95% confidence interval [CI] 0.92-1.79; 3,810 case group participants and 1,692,580 control group participants). Emergency cesarean delivery was associated with increased risk of cerebral palsy (OR 2.17; 95% CI 1.58-2.98), whereas there was no significant association between elective cesarean delivery and cerebral palsy (OR 0.81; 95% CI 0.41-1.58). Any type of cesarean delivery (elective or emergency) for term newborns was associated with cerebral palsy (OR 1.6; 95% CI 1.05-2.44), whereas there was no association between any type of cesarean delivery and cerebral palsy in preterm newborns (OR 0.81; 95% CI 0.47-1.40). Cesarean delivery did not significantly modify cerebral palsy risk for breech-presenting newborns (OR 0.51; 95% CI 0.13-2.05). A review of the literature does not support the use of elective or emergency cesarean delivery to prevent cerebral palsy.
    Obstetrics and Gynecology 11/2013; · 4.37 Impact Factor
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    ABSTRACT: Benign hereditary chorea caused by mutations in the NK2 homeobox 1 gene (NKX2-1), shares clinical features with ataxic and dyskinetic cerebral palsy (CP), resulting in the possibility of misdiagnosis. A father and his two children were considered to have ataxic CP until a possible diagnosis of benign familial chorea was made in the children in early teenage. The father's neurological condition had not been appreciated prior to examination of the affected son. Whole exome sequencing of blood derived DNA and bioinformatics analysis were performed. A 7 bp deletion in exon 1 of NKX2-1, resulting in a frame shift and creation of a premature termination codon, was identified in all affected individuals. Screening of 60 unrelated individuals with a diagnosis of dyskinetic or ataxic CP did not identify NKX2-1 mutations. BHC can be confused with ataxic and dyskinetic CP. Occasionally these children have a mutation in NKX2-1.
    European journal of medical genetics 07/2013; · 1.57 Impact Factor
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    ABSTRACT: Background:To replicate single nucleotide polymorphism (SNP) associations with preterm birth (PTB; birth <37 completed weeks of gestation) and synthesise currently available evidence using meta-analysis.Methods:Spontaneous PTB cases and controls were selected from an existing cohort. Candidate SNPs were taken from an existing genotype panel. A systematic review was conducted for each SNP in the panel to determine suitability as a PTB candidate. Those with significant associations previously reported in Caucasians were selected for replication. Candidate SNPs were already genotyped in cases and controls and clinical data accessed from state perinatal and cerebral palsy databases. Association analysis was conducted between each SNP and PTB and meta-analysis conducted if there were ≥three studies in the literature. Maternal and fetal SNPs were considered as separate candidates.Results:A cohort of 170 cases and 583 controls was formed. Eight SNPs from the original panel of genotyped SNPs were selected as PTB candidates and replication based on systematic literature review results. In our cohort, fetal Factor V Leiden (FVL) was significantly associated with PTB (OR 2.6, 95% CI 1.31-5.17) and meta-analysis confirmed this association (OR 2.71, 95% CI 1.15-6.4).Conclusion:Replication and meta-analysis support an increased risk of PTB in Caucasians with the fetal FVL mutation.Pediatric Research (2013); doi:10.1038/pr.2013.117.
    Pediatric Research 07/2013; · 2.84 Impact Factor
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    ABSTRACT: AIM: This study aims to examine single nucleotide polymorphism (SNP) associations with cerebral palsy in a multi-variable analysis adjusting for potential clinical confounders and to assess SNP-SNP and SNP-maternal infection interactions as contributors to cerebral palsy. METHODS: A case control study including 587 children with cerebral palsy and 1154 control children without cerebral palsy. Thirty-nine candidate SNPs were genotyped in both mother and child. Data linkage to perinatal notes and cerebral palsy registers was performed with a supplementary maternal pregnancy questionnaire. History of known maternal infection during pregnancy was extracted from perinatal databases. RESULTS: Both maternal and fetal carriage of inducible nitric oxide synthase SNP rs1137933 were significantly negatively associated with cerebral palsy in infants born at less than 32 weeks gestation after adjustment for potential clinical confounders and correction for multiple testing (odds ratio 0.55, 95% confidence interval 0.38-0.79; odds ratio 0.57, 95% confidence interval 0.4-0.82, respectively). Analysis did not show any statistically significant SNP-SNP or SNP-maternal infection interactions after correction for multiple testing. CONCLUSIONS: Maternal and child inducible nitric oxide synthase SNPs are associated with reduced risk of cerebral palsy in infants born very preterm. There was no evidence for statistically significant SNP-SNP or SNP-maternal infection interactions as modulators of cerebral palsy risk.
    Journal of Paediatrics and Child Health 06/2013; · 1.19 Impact Factor
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    ABSTRACT: Recent studies have established the role of rare copy number variants (CNVs) in several neurological disorders but the contribution of rare CNVs to cerebral palsy (CP) is not known. Fifty Caucasian families having children with CP were studied using two microarray designs. Potentially pathogenic, rare (<1% population frequency) CNVs were identified, and their frequency determined, by comparing the CNVs found in cases with 8329 adult controls with no known neurological disorders. Ten of the 50 cases (20%) had rare CNVs of potential relevance to CP; there were a total of 14 CNVs, which were observed in <0.1% (<8/8329) of the control population. Eight inherited from an unaffected mother: a 751-kb deletion including FSCB, a 1.5-Mb duplication of 7q21.13, a 534-kb duplication of 15q11.2, a 446-kb duplication including CTNND2, a 219-kb duplication including MCPH1, a 169-kb duplication of 22q13.33, a 64-kb duplication of MC2R, and a 135-bp exonic deletion of SLC06A1. Three inherited from an unaffected father: a 386-kb deletion of 12p12.2-p12.1, a 234-kb duplication of 10q26.13, and a 4-kb exonic deletion of COPS3. The inheritance was unknown for three CNVs: a 157-bp exonic deletion of ACOX1, a 693-kb duplication of 17q25.3, and a 265-kb duplication of DAAM1. This is the first systematic study of CNVs in CP, and although it did not identify de novo mutations, has shown inherited, rare CNVs involving potentially pathogenic genes and pathways requiring further investigation.European Journal of Human Genetics advance online publication, 22 May 2013; doi:10.1038/ejhg.2013.93.
    European journal of human genetics: EJHG 05/2013; · 3.56 Impact Factor
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    ABSTRACT: Arthrogryposis multiplex congenita (AMC) is caused by heterogeneous pathologies leading to multiple antenatal joint contractures through fetal akinesia. Understanding the pathophysiology of this disorder is important for clinical care of the affected individuals and genetic counseling of the families. We thus aimed to establish the genetic basis of an AMC subtype that is associated with multiple dysmorphic features and intellectual disability (ID). We used haplotype analysis, next-generation sequencing, array comparative genomic hybridization, and chromosome breakpoint mapping to identify the pathogenic mutations in families and simplex cases. Suspected disease variants were verified by cosegregation analysis. We identified disease-causing mutations in the zinc-finger gene ZC4H2 in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy. Several heterozygous females were also affected, but to a lesser degree. Furthermore, we found two ZC4H2 deletions and one rearrangement in two female and one male unrelated simplex cases, respectively. In mouse primary hippocampal neurons, transiently produced ZC4H2 localized to the postsynaptic compartment of excitatory synapses, and the altered protein influenced dendritic spine density. In zebrafish, antisense-morpholino-mediated zc4h2 knockdown caused abnormal swimming and impaired α-motoneuron development. All missense mutations identified herein failed to rescue the swimming defect of zebrafish morphants. We conclude that ZC4H2 point mutations, rearrangements, and small deletions cause a clinically variable broad-spectrum neurodevelopmental disorder of the central and peripheral nervous systems in both familial and simplex cases of both sexes. Our results highlight the importance of ZC4H2 for genetic testing of individuals presenting with ID plus muscle weakness and minor or major forms of AMC.
    The American Journal of Human Genetics 04/2013; · 11.20 Impact Factor
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    ABSTRACT: To explore the additive effect of urinary incontinence, in people with comorbid depression, on health related quality of life. Males and females, 15 to 95 years (n = 3010, response rate 70.2%) were interviewed face to face in the 1998 Autumn South Australian Health Omnibus Survey. Self-reported urinary incontinence was found in 20.3% (n=610), and depression as defined by the PRIME-MD in 15.2% (n=459) of the survey population. Urinary incontinence with comorbid depression was found in 4.3% of the overall population. Univariate analysis showed that respondents with urinary incontinence and comorbid depression were more likely to be aged between 15 and 34 years and never married when compared to those with incontinence only. Multivariate analysis demonstrated that in people with incontinence, the risk of having comorbid depression was increased by an overall health status of Fair or Poor, or the perception that their incontinence was moderately or very serious. Respondents reporting that they experienced incontinence with comorbid depression scored significantly lower than those experiencing incontinence without depression on all dimensions of the SF-36.The interaction of the presence of incontinence and the presence of depression was significantly associated with the dimensions of physical functioning. Depression and incontinence both reduce QOL. When they occur together there appears to be an additive effect which affects both physical and mental health, perhaps by increasing a person's negative perceptions of their illness. Clinicians should identify and manage comorbid depression when treating patients who have incontinence to improve their overall QOL.
    BMC Urology 01/2013; 13:11. · 1.94 Impact Factor
  • Michael E. O'Callaghan, Alastair H. MacLennan
    American journal of obstetrics and gynecology 11/2012; · 3.97 Impact Factor
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    A Pines, D W Sturdee, A H MacLennan
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    ABSTRACT: The quality of life of countless menopausal women world-wide has been significantly diminished following the sensationalist reporting of the Women's Health Initiative (WHI) and the resulting 50% or more decline in the use of hormone replacement therapy (HRT) over the subsequent 10 years. Quality of life is difficult to measure as there are so many contributing factors and a large number of different instruments, some of which assess general health and only a few which specifically include symptoms related to menopause. HRT improves quality of life of symptomatic menopausal women and some studies of the effects of HRT provide reliable evidence on quality of life other than reduction in vasomotor symptoms. Until there is a better understanding of the minimal risks of HRT for the majority of women, too many will continue to suffer a reduced quality of life unnecessarily.
    Climacteric 06/2012; 15(3):213-6. · 2.24 Impact Factor
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    ABSTRACT: Following the announcement of the first results of the Women's Health Initiative (WHI) to the media in 2002, prior to their scientific publication, the resulting panic headlines had an immediate and lasting negative effect on use of menopausal hormone replacement therapy (HRT) around the world. Rates of use dropped by 40-80%. Symptomatic women then sought multiple alternative therapies but the majority of these have no greater effect than the effect seen from placebo in well-conducted trials of HRT. Some of these therapies have risks. Although anecdotally most menopause practitioners after 2002 can attest to having to counsel large numbers of women with debilitating menopausal symptoms who were too frightened to consider HRT, it is difficult to document loss of health-related quality of life in large population studies as they were not conducted. Similarly, the positive or negative effects of the marked decline in HRT on long-term morbidities and mortality have yet to be fully assessed. Recent studies have shown an increase in postmenopausal fractures and in some, but not all, populations a small temporary decline in breast cancer. Cardiovascular outcomes may not be apparent for another decade. Short-term, randomized, placebo-controlled trials confirm that HRT is the only therapy that effectively improves health-related quality of life in symptomatic women through a reduction in vasomotor and urogenital symptoms, joint pains and insomnia, while improving sexuality. The results of the re-analyses of the WHI data and new data from other studies do not justify the continuing negative attitude to HRT in symptomatic women who start HRT near menopause.
    Climacteric 06/2012; 15(3):281-7. · 2.24 Impact Factor
  • B Purbrick, K Stranks, C Sum, A H MacLennan
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    ABSTRACT: The ideal long-term, randomized, placebo-controlled trial of hormone replacement therapy (HRT) from near menopause for up to 30 years to assess major morbidity and mortality is impractical because of high cost, participant retention, therapy compliance, and continuity of research staff and funding. Also the trial regimen may become outdated. It is nihilistic to demand such a long-term trial before endorsing HRT. However, medium-term trials using surrogate measures for long-term morbidity and mortality are possible and two are near completion. If these studies have been able to maintain reasonable participant retention, therapy compliance and minimal breach of protocol, they will set standards for trials of new HRT regimens. This paper discusses lessons learnt from past attempts at long-term trials and suggests the currently optimal protocol and cost of assessing new HRT regimens to optimize potential benefits and minimize adverse effects. A 5-7-year randomized, placebo-controlled trial of a flexible transdermal estrogen regimen ± either a selective estrogen receptor modulator, e.g. bazedoxifene, or micronized progesterone is discussed. Mild to moderately symptomatic women, 1-4 years post menopause, can be recruited via general practice and group meetings. Future trials should be funded by independent agencies and are high priority in women's health.
    Climacteric 06/2012; 15(3):288-93. · 2.24 Impact Factor
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    Alastair H MacLennan, Robert G B Morrison
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    ABSTRACT: Standing up for science.
    The Medical journal of Australia 03/2012; 196(4):225-6. · 2.85 Impact Factor
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    ABSTRACT: Objective: Intrauterine infection is a risk factor for cerebral palsy. Previous work reported a high frequency of viral DNA in newborn screening cards from cerebral palsy cases and controls possibly due to contamination. Methods: Retrospective case-control study using improved methodologies to minimize contamination during PCR-based detection of viral DNA sequences. Newborn screening cards of 339 Caucasian children with cerebral palsy and 594 controls were examined. Viruses tested were herpes simplex viruses 1 and 2 (HSV1 and 2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes viruses 6, 7 and 8 (HHV6, HHV7 and HHV8), and parvovirus B19. Genotyping was performed on DNA extracted from dried blood spots. Results: CMV and EBV were detected in 5 (1.5%) and 3 (0.9%) of 339 cases, respectively, but not in controls (p = 0.047 and 0.006). Frequencies of detection of the other viruses examined were similar for cases and controls. DNA from at least one of the nine viruses tested was found in 4.4% of cases and 3.1% of controls [OR 1.4 95% CI (0.71-2.76)]. Conclusion: Evidence of congenital viral infection was uncommon in cases of cerebral palsy and controls. However, CMV and EBV were significantly associated with cerebral palsy.
    The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 02/2012; 25(10):2078-81. · 1.36 Impact Factor
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    ABSTRACT: Previous studies have suggested associations between certain genetic variants and susceptibility to cerebral palsy (CP). This study was designed to assess established and novel maternal and child genetic and epidemiologic risk factors for CP along with their interactions. DNA from 587 case and 1154 control mother-child pairs was analyzed. A panel of 35 candidate single nucleotide polymorphisms (SNPs) were examined and included SNPs in genes associated with (1) thrombophilia, (2) inflammation, and (3) risk factors for CP (eg, preterm birth). Comparisons were specified a priori and made by using a χ(2) test. There were 40 fetal and 28 maternal associations with CP when analyzed by CP subtype, gestational age, genotypes of apolipoprotein E, and haplotypes of mannose-binding-lectin. After Bonferroni correction for multiple testing, no fetal or maternal candidate SNP was associated with CP or its subtypes. Only fetal carriage of prothrombin gene mutation remained marginally associated with hemiplegia in term infants born to mothers with a reported infection during pregnancy. Odds ratio directions of fetal SNP associations were compared with previously reported studies and confirmed no trend toward association. Except for the prothrombin gene mutation, individual maternal and fetal SNPs in our candidate panel were not found to be associated with CP outcome. Past reported SNP associations with CP were not confirmed, possibly reflecting type I error from small numbers and multiple testing in the original reports.
    PEDIATRICS 02/2012; 129(2):e414-23. · 5.30 Impact Factor
  • Alastair H MacLennan
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    ABSTRACT: The Australian Federal Productivity Commission is proposing two new schemes to better support those with major disability. The main National Disability Insurance Scheme (NDIS) will provide long-term care and support for the disabled. A smaller scheme, the National Injury Insurance Scheme (NIIS), will provide 'no-fault 'support for those following an accident or 'medical injury'. It is proposed that cerebral palsy (CP) is part of the NIIS. While this brings quicker and more equitable benefits to CP families, the scheme labels CP as a 'medical accident' and infers preventability. Obstetricians will fund much of the system. Despite being labelled a 'no-fault' system, maternity staff can still be litigated for extensive 'head of damages', eg loss of earning capacity. An additional option is for federal/state legislation to introduce a true 'no-fault' lifetime pension specifically for all children on CP registers. This pension would be graded by degree of disability and dependent on waiving civil litigation. Savings in medico-legal costs and potentially a 7% reduction in caesarean delivery would cover the estimated annual cost of $50 000 per annum indexed life pension for severe CP cases and the total annual cost of AUD $93 million for Australia. This pension and the NDIS would help cover the needs of children with CP without recourse to prolonged litigation and without detriment to the maternity services of Australia, caused by defensive obstetrics and maternity hospital closure because of CP litigation.
    Australian and New Zealand Journal of Obstetrics and Gynaecology 12/2011; 51(6):479-84. · 1.30 Impact Factor
  • Alastair H Maclennan, David Morris
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    ABSTRACT: This educational and entertaining quiz on menopausal management issues involves delegate interaction and debate and was designed for The Australasian Menopause Society Annual Congress in 2011. Multidisciplinary groups of delegates discussed each question and, after 2 minutes, their team captain electronically voted for the team's consensus as to the best answer. The quiz is called an ?Ambrose OSCE?. ?Ambrose? comes from the golf competition where the team's ?best shot? is chosen and ?OSCE? is from Oral Structured Clinical Exams. The distributions of the teams? answers were displayed to the audience and the panel member who set each question explained why they allocated marks between 22 and +2 to these answers, e.g. 22 for an out-of-bounds answer, 21 for a hazardous answer, 0 for an ineffectual answer, +1 for a good shot and 12 for ?nearest to the pin?. A cumulative score for each team was kept and this leader board was regularly displayed. Try answering these questions with your clinical team and see how you fare. Each answer is the opinion of the expert, backed by references. The winning score was 26! The weighted scores for the answers to the questions and explanations for the best answers can be found at the end of this issue of Climacteric.
    Climacteric 12/2011; 14(6):697-702. · 2.24 Impact Factor
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    ABSTRACT: ABSTRACT Objective An overview of the current knowledge on the etiology and treatment of vasomotor symptoms in postmenopausal women. Materials and methods Acknowledged experts in the field contributed a brief assessment of their areas of interest which were combined and edited into the final manuscript. Results Women around the world experience vasomotor symptoms as they enter and complete the menopause transition. Vasomotor symptoms, specifically hot flushes, are caused by a narrowing of the thermoneutral zone in the brain. This effect, although related to estrogen withdrawal, is most likely related to changes in central nervous system neurotransmitters. Peripheral vascular reactivity is also altered in symptomatic women. Estrogen replacement therapy is the most effective treatment for hot flushes. Of the other interventions investigated, selective serotonin and selective norepinephrine reuptake inhibitors and gabapentin show efficacy greater than placebo. Objective monitoring of hot flushes indicates a robust improvement with hormone replacement therapy but little to no change with placebo. These data suggest that the subjective assessment of responses to therapy for vasomotor symptom results in inaccurate data. Hot flushes have recently been associated with increased cardiovascular risks and a lower incidence of breast cancer, but these data require confirmation. Conclusions Vasomotor symptoms are experienced by women of all ethnic groups. They are caused by changes in the central nervous system associated with estrogen withdrawal and are best treated with estrogen replacement therapy. Objective monitoring of hot flushes indicates that placebo has little to no effect on their improvement. Subjective assessments of hot flushes in clinical trials may be inaccurate based on objective measurement of the frequency of hot flushes. Based on preliminary reports, women experiencing hot flushes have an increased risk of cardiovascular disease and a reduced incidence of breast cancer.
    Climacteric 09/2011; 14(5):515-528. · 2.24 Impact Factor
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    ABSTRACT: To estimate epidemiologic risk factors for cerebral palsy. Data were collected by linkage to state-based perinatal repositories and cerebral palsy registers and using a maternal questionnaire. The cohort included 587 individuals with cerebral palsy and 1,154 non-cerebral palsy controls. The following factors were associated with cerebral palsy: recorded maternal infection during pregnancy (41.4% patients compared with 31.3% controls; odds ratio [OR] 1.55, 95% confidence interval 1.26-1.91), small for gestational age ([birth weight less than third customized centile] 43.9% patients compared with 6.3% controls; OR 11.75, 6.25-22.08), gestational age less than 32 weeks (29.3% patients compared with 0.7% controls; OR 59.20, 28.87-121.38), multiple birth (OR 6.62, 4.00-10.95), a relative with cerebral palsy (OR 1.61, 1.12-2.32), breech position (13.7% patients compared with 6.0% controls; OR 2.48, 1.76-3.49), bleeding at any time in pregnancy (29.3% patients compared with 16.9% controls; OR 2.04, 1.61-2.58), male sex (58.8% patients compared with 45.8% controls; OR 1.68, 1.38-2.06), multiple miscarriage (7.7% patients compared with 3.5% controls; OR 2.30, 1.38-3.82), smoking (14.0% patients compared with 10.6% controls; OR 1.37, 1.02-1.85), and illicit drug use (3.3% patients compared with 1.5% controls; OR 2.22, 1.14-4.30). Factors not associated with cerebral palsy were "disappearing twin," diabetes, maternal body mass index, hypertension, alcohol consumption, anemia, maternal hypothyroidism, forceps or vacuum delivery, and maternal age. Preterm birth, intrauterine growth restriction, perinatal infection, and multiple birth present the largest risks for a cerebral palsy outcome. Reassuringly, upper respiratory tract and gastrointestinal infections during pregnancy were not associated with cerebral palsy. II.
    Obstetrics and Gynecology 09/2011; 118(3):576-82. · 4.37 Impact Factor
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    Climacteric 06/2011; 14(3):302-20. · 2.24 Impact Factor

Publication Stats

3k Citations
749.55 Total Impact Points


  • 1979–2013
    • University of Adelaide
      • • Discipline of General Practice
      • • Discipline of Obstetrics and Gynaecology
      Adelaide, South Australia, Australia
  • 2006
    • Stanford University
      • Department of Obstetrics and Gynecology
      Stanford, CA, United States
  • 1998
    • University of Auckland
      • Department of Obstetrics and Gynaecology
      Auckland, Auckland, New Zealand