Creatine and pregnancy outcomes: a prospective cohort study of creatine metabolism in low-risk pregnant females.

BACKGROUND: Physiological adaptations during pregnancy alter nutrient and energy metabolism. Creatine may be important for maintaining cellular energy homeostasis throughout pregnancy. However, the impact of pregnancy on endogenous and exogenous creatine availability has never been comprehensively explored. OBJECTIVES: To undertake a prospective cohort study and determine the physiological ranges of creatine and associated metabolites throughout human pregnancy. METHODS: Females with a singleton low-risk pregnancy were recruited at an Australian health service. Maternal blood and urine were collected at 5-time points from 10-36 weeks of gestation, and cord blood and placental samples were collected at birth. Creatine and associated amino acids and metabolites of creatine synthesis were analyzed. Dietary data were captured to determine effects of exogenous creatine intake. Associations between creatine metabolism and neonatal growth parameters were examined. RESULTS: Two hundred and eighty-two females were included. Maternal plasma creatine remained stable throughout pregnancy [ß: -0.003 µM; 95% confidence interval (CI): -0.07, 0.07; P = 0.94], though urinary creatine declined in late gestation (ß: 0.38 µM/mmol/L creatinine (CRN); 95% CI: -0.47, -0.29; P < 0.0001). Plasma guanidinoacetate (GAA; the precursor to creatine during endogenous synthesis) fell from 10-29 weeks of gestation before rising until birth (ß: -0.38 µM/mmol/L CRN; 95% CI: -0.47, -0.29; P < 0.0001). Urinary GAA followed an opposing pattern (ß: 2.52 µM/mmol/L CRN; 95% CI: 1.47, 3.58, P < 0.001). Animal protein intake was positively correlated with maternal plasma creatine until ∼32 weeks of gestation (ß: 0.07-0.18 µM; 95% CI: 0.006, 0.25; P ≤ 0.001). There were no links between creatine and neonatal growth, but increased urinary GAA in early pregnancy was associated with a slight reduction in head circumference at birth (ß: -0.01 cm; 95% CI: -0.02, -0.004; P = 0.003). CONCLUSIONS: Although maternal plasma creatine concentrations were highly conserved, creatine metabolism appears to adjust throughout pregnancy. An ability to maintain creatine concentrations through diet and shifts in endogenous synthesis may impact fetal growth. This trial was registered at [registry name] as ACTRN12618001558213.

Fetal surveillance from 39 weeks' gestation to reduce stillbirth in South Asian-born women.

BACKGROUND: In July 2017, the State of Victoria's largest maternity service implemented a new clinical guideline to reduce the rates of stillbirth at term for South Asian women. OBJECTIVE: This study aimed to evaluate the impact of offering fetal surveillance from 39 weeks to South Asian-born women on rates of stillbirth and neonatal and obstetrical interventions. STUDY DESIGN: This was a cohort study of all women receiving antenatal care at 3 large metropolitan university-affiliated teaching hospitals in Victoria, who gave birth in the term period between January 2016 and December 2020. Differences in rates of stillbirth, neonatal deaths, perinatal morbidities, and interventions after July 2017 were determined. Multigroup interrupted time-series analysis was used to assess changes in rates of stillbirth and induction of labor. RESULTS: A total of 3506 South Asian-born women gave birth before, and 8532 after the change in practice. There was a 64% reduction in term stillbirth (95% confidence interval, 87% to 2%; P=.047) after the change in practice from 2.3 per 1000 births to 0.8 per 1000 births. The rates of early neonatal death (3.1/1000 vs 1.3/1000; P=.03) and special care nursery admission (16.5% vs 11.1%; P<.001) also decreased. There were no significant differences in admission to the neonatal intensive care unit, 5-minute Apgar score <7, or birthweight, or differences in the trends of induction of labor per month. CONCLUSION: Fetal monitoring from 39 weeks may offer an alternative to routine earlier induction of labor to reduce the rates of stillbirth without causing an increase in neonatal morbidity and attenuating trends in obstetrical interventions.

South-Asian women's experiences of earlier additional, fetal monitoring to reduce stillbirth: An exploratory qualitative study.

BACKGROUND: In an attempt to reduce the rates of stillbirth at term among South-Asian born women, Victoria's largest maternity service, Monash Health, implemented a new clinical guideline in 2017 that recommended additional earlier, twice weekly monitoring to assess fetal wellbeing from 39 weeks for South-Asian women. In acknowledging the importance of woman centred, culturally responsive care, this study aimed to understand South-Asian women's, experiences, of the additional earlier fetal monitoring. METHODS: An exploratory qualitative study was conducted using semi-structured phone interviews six weeks postpartum, across June and July 2021, with South-Asian born women who underwent the earlier monitoring from 39 weeks. Women were asked questions regarding their understanding of the monitoring, their experiences of the monitoring process and any impact the monitoring or results had on their pregnancy, labour and birth. Interviews were recorded and transcribed verbatim. Data were analysed using a thematic approach and an inductive coding strategy. RESULTS: Seventeen women from India, Sri Lanka, Pakistan and Afghanistan were interviewed. the main themes were i: gaining peace of mind, need for better communication, did the women really have a choice? and comparisons to maternity care in the country of origin. Women experienced positive reassurance of their baby's well-being from the monitoring and were happy with the earlier, extra care. However, women described receiving variable explanations of the purpose of the monitoring. Ineffective communication and logistical barriers were highlighted to negatively impact women's ability to engage in shared decision making and their overall experience of the earlier monitoring. CONCLUSIONS: The additional monitoring is reported by these women to have an overall positive impact on their maternity care. Future work should explore the experiences of non-English speaking South-Asian women and those who declined monitoring.

Risk of Adverse Outcomes in Females Taking Oral Creatine Monohydrate: A Systematic Review and Meta-Analysis.

Creatine Monohydrate (CrM) is a dietary supplement routinely used as an ergogenic aid for sport and training, and as a potential therapeutic aid to augment different disease processes. Despite its increased use in recent years, studies reporting potential adverse outcomes of CrM have been mostly derived from male or mixed sex populations. A systematic search was conducted, which included female participants on CrM, where adverse outcomes were reported, with meta-analysis performed where appropriate. Six hundred and fifty-six studies were identified where creatine supplementation was the primary intervention; fifty-eight were female only studies (9%). Twenty-nine studies monitored for adverse outcomes, with 951 participants. There were no deaths or serious adverse outcomes reported. There were no significant differences in total adverse events, (risk ratio (RR) 1.24 (95% CI 0.51, 2.98)), gastrointestinal events, (RR 1.09 (95% CI 0.53, 2.24)), or weight gain, (mean difference (MD) 1.24 kg pre-intervention, (95% CI -0.34, 2.82)) to 1.37 kg post-intervention (95% CI -0.50, 3.23)), in CrM supplemented females, when stratified by dosing regimen and subject to meta-analysis. No statistically significant difference was reported in measures of renal or hepatic function. In conclusion, mortality and serious adverse events are not associated with CrM supplementation in females. Nor does the use of creatine supplementation increase the risk of total adverse outcomes, weight gain or renal and hepatic complications in females. However, all future studies of creatine supplementation in females should consider surveillance and comprehensive reporting of adverse outcomes to better inform participants and health professionals involved in future trials.

Rates of stillbirth by maternal region of birth and gestational age in New South Wales, Australia 2004-2015.

BACKGROUND: Research suggests that in Australia, maternal region of birth is a risk factor for stillbirth. AIMS: We aimed to examine the relationship between stillbirth and maternal region of birth in New South Wales (NSW), Australia from 2004 to 2015. METHODS: Adjusted logistic regression was used to determine odds of stillbirth by maternal region of birth, compared with Australian or New Zealand-born (AUS/NZ-born) women. Intervention rates (induction or pre-labour caesarean) by maternal region of birth, over time, were also examined. Interaction terms were used to assess change in relative odds of stillbirth, over two time periods (2004-2011 and 2012-2015). RESULTS: There were 944 457 singleton births ≥24 weeks gestation that met the study inclusion criteria and 3221 of these were stillbirths, giving a stillbirth rate of 3.4 per 1000 births. After adjustment for confounders, South Asian (adjusted odds ratio (aOR) 1.42, 95% CI 1.24-1.62), Oceanian (aOR 1.45, 95% CI 1.17-1.80) and African (aOR 1.46, 96% CI 1.19-1.80) born women had significantly higher odds of stillbirth that AUS/NZ-born women. Intervention rates increased from the earlier to the later time period by 13.1% across the study population, but the increase was larger in African and South Asian-born women (18.1% and 19.6% respectively) than AUS/NZ-born women (11.2%). There was a significant interaction between ethnicity and time period for South Asian-born women in the all-births model, with their stillbirth rates becoming closer to AUS/NZ-born women in the later period. CONCLUSION: South Asian, African and Oceanian maternal region of birth are independent risk factors for stillbirth in NSW.

The Effects of Early-Onset Pre-Eclampsia on Placental Creatine Metabolism in the Third Trimester.

Creatine is a metabolite important for cellular energy homeostasis as it provides spatio-temporal adenosine triphosphate (ATP) buffering for cells with fluctuating energy demands. Here, we examined whether placental creatine metabolism was altered in cases of early-onset pre-eclampsia (PE), a condition known to cause placental metabolic dysfunction. We studied third trimester human placentae collected between 27-40 weeks' gestation from women with early-onset PE (n = 20) and gestation-matched normotensive control pregnancies (n = 20). Placental total creatine and creatine precursor guanidinoacetate (GAA) content were measured. mRNA expression of the creatine synthesizing enzymes arginine:glycine aminotransferase (GATM) and guanidinoacetate methyltransferase (GAMT), the creatine transporter (SLC6A8), and the creatine kinases (mitochondrial CKMT1A & cytosolic BBCK) was assessed. Placental protein levels of arginine:glycine aminotransferase (AGAT), GAMT, CKMT1A and BBCK were also determined. Key findings; total creatine content of PE placentae was 38% higher than controls (p < 0.01). mRNA expression of GATM (p < 0.001), GAMT (p < 0.001), SLC6A8 (p = 0.021) and BBCK (p < 0.001) was also elevated in PE placentae. No differences in GAA content, nor protein levels of AGAT, GAMT, BBCK or CKMT1A were observed between cohorts. Advancing gestation and birth weight were associated with a down-regulation in placental GATM mRNA expression, and a reduction in GAA content, in control placentae. These relationships were absent in PE cases. Our results suggest PE placentae may have an ongoing reliance on the creatine kinase circuit for maintenance of cellular energetics with increased total creatine content and transcriptional changes to creatine synthesizing enzymes and the creatine transporter. Understanding the functional consequences of these changes warrants further investigation.

Placental creatine metabolism in cases of placental insufficiency and reduced fetal growth.

Creatine is a metabolite involved in cellular energy homeostasis. In this study, we examined placental creatine content, and expression of the enzymes required for creatine synthesis, transport and the creatine kinase reaction, in pregnancies complicated by low birthweight. We studied first trimester chorionic villus biopsies (CVBs) of small for gestational age (SGA) and appropriately grown infants (AGA), along with third trimester placental samples from fetal growth restricted (FGR) and healthy gestation-matched controls. Placental creatine and creatine precursor (guanidinoacetate-GAA) levels were measured. Maternal and cord serum from control and FGR pregnancies were also analyzed for creatine concentration. mRNA expression of the creatine transporter (SLC6A8); synthesizing enzymes arginine:glycine aminotransferase (GATM) and guanidinoacetate methyltransferase (GAMT); mitochondrial (mtCK) and cytosolic (BBCK) creatine kinases; and amino acid transporters (SLC7A1 & SLC7A2) was assessed in both CVBs and placental samples. Protein levels of AGAT (arginine:glycine aminotransferase), GAMT, mtCK and BBCK were also measured in placental samples. Key findings; total creatine content of the third trimester FGR placentae was 43% higher than controls. The increased creatine content of placental tissue was not reflected in maternal or fetal serum from FGR pregnancies. Tissue concentrations of GAA were lower in the third trimester FGR placentae compared to controls, with lower GATM and GAMT mRNA expression also observed. No differences in the mRNA expression of GATM, GAMT or SLC6A8 were observed between CVBs from SGA and AGA pregnancies. These results suggest placental creatine metabolism in FGR pregnancies is altered in late gestation. The relevance of these changes on placental bioenergetics should be the focus of future investigations.

Protect-me: a parallel-group, triple blinded, placebo-controlled randomised clinical trial protocol assessing antenatal maternal melatonin supplementation for fetal neuroprotection in early-onset fetal growth restriction.

INTRODUCTION: Fetal growth restriction (FGR) is a serious pregnancy complication, associated with increased rates of perinatal death and morbidity among survivors. Most commonly FGR results from placental insufficiency, where the placenta fails to deliver the oxygen and nutrients required for normal fetal growth. This leads to fetal oxidative stress, resulting in organ damage through lipid peroxidation. The early developing brain is particularly susceptible, such that FGR is associated with poorer neurodevelopment, witnessed as cognitive and behavioural dysfunction, and cerebral palsy. Promisingly, melatonin, a lipid soluble antioxidant is neuroprotective in animal models of FGR. We present a protocol outlining a randomised, placebo-controlled trial to explore whether antenatal maternal melatonin supplementation in pregnancies with severe, early-onset FGR can improve neurodevelopment among survivors at 2 years of age. METHODS AND ANALYSES: We will recruit 336 women with a singleton pregnancy complicated by FGR between 23+0 and 31+6 weeks gestation. Participants will be randomised, stratified by gestational age, to either 30 mg melatonin per day or a visually identical placebo, continued until birth. Measures of maternal and fetal health will be collected until birth. Timing of birth will be determined by the treating clinical team in discussion with the woman. Neonatal and infant neurodevelopmental assessments will be undertaken, consisting of brain MRI at term corrected age, general movements assessment at term and 3 months' corrected age, and Bayley Scales of Infant & Toddler Development-III and Infant Toddler Social Emotional Assessment at 2.5 years corrected age. Analyses will be on intention to treat. The primary outcome is a difference of 5 points in the cognitive domain of the Bayley-III. Secondary outcomes address maternal and fetal safety. ETHICS AND DISSEMINATION: This trial has Monash Health Human Research and Ethics committee approval (17-0000-583A). Findings will be disseminated through peer-reviewed publications, conference presentations and to participants. TRIAL REGISTRATION NUMBER: ACTRN12617001515381; Pre-results.

UNICORN Babies: Understanding Circulating and Cerebral Creatine Levels of the Preterm Infant. An Observational Study Protocol.

Creatine is an essential metabolite for brain function, with a fundamental role in cellular (ATP) energy homeostasis. It is hypothesized that preterm infants will become creatine deplete in the early postnatal period, due to premature delivery from a maternal source of creatine and a limited supply of creatine in newborn nutrition. This potential alteration to brain metabolism may contribute to, or compound, poor neurological outcomes in this high-risk population. Understanding Creatine for Neurological Health in Babies (UNICORN) is an observational study of circulating and cerebral creatine levels in preterm infants. We will recruit preterm infants at gestational ages 23+0-26+6, 27+0-29+6, 30+0-32+6, 33+0-36+6, and a term reference group at 39+0-40+6 weeks of gestation, with 20 infants in each gestational age group. At birth, a maternal capillary blood sample, as well as a venous cord blood sample, will be collected. For preterm infants, serial infant plasma (heel prick), urine, and nutrition samples [total parenteral nutrition (TPN), breast milk, or formula] will be collected between birth and term "due date." Key fetomaternal information, including demographics, smoking status, and maternal diet, will also be collected. At term corrected postnatal age (CPA), each infant will undergo an MRI/1H-MRS scan to evaluate brain structure and measure cerebral creatine content. A general movements assessment (GMA) will also be conducted. At 3 months of CPA, infants will undergo a second GMA as well as further neurodevelopmental evaluation using the Developmental Assessment of Young Children - Second Edition (DAYC-2) assessment tool. The primary outcome measures for this study are cerebral creatine content at CPA and plasma and urine creatine and guanidinoacetate (creatine precursor) concentrations in the early postnatal period. We will also determine associations between (1) creatine levels at term CPA and neurodevelopmental outcomes (MRI, GMA, and DAY-C); (2) dietary creatine intake and circulating and cerebral creatine content; and (3) creatine levels and maternal characteristics. Novel approaches are needed to try and improve preterm-associated brain injury. Inclusion of creatine in preterm nutrition may better support ex utero brain development through improved cerebral cellular energy availability during a period of significant brain growth and development. Ethics Ref: HDEC 18/CEN/7 New Zealand. ACTRN: ACTRN12618000871246.

Creatine and pregnancy outcomes, a prospective cohort study in low-risk pregnant women: study protocol.

INTRODUCTION: The creatine kinase circuit is central to the regulation of high-energy phosphate metabolism and the maintenance of cellular energy turnover. This circuit is fuelled by creatine, an amino acid derivative that can be obtained from a diet containing animal products, and by synthesis in the body de novo. A recent retrospective study conducted in a cohort of 287 pregnant women determined that maternal excreted levels of creatine may be associated with fetal growth. This prospective study aims to overcome some of the limitations associated with the previous study and thoroughly characterise creatine homeostasis throughout gestation in a low-risk pregnant population. METHODS AND ANALYSIS: This study is recruiting women with a singleton low-risk pregnancy who are attending Monash Health, in Melbourne, Australia. Maternal blood and urine samples, along with dietary surveys, are collected at five time points during pregnancy and then at delivery. Cord blood and placenta (including membranes and cord) are collected at birth. A biobank of tissue samples for future research is being established. Primary outcome measures will include creatine, creatine kinase and associated metabolites in antenatal bloods and urine, cord bloods and placenta, along with molecular analysis of the creatine transporter (SLC6A8) and synthesising enzymes L - arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) in placental tissues. Secondary outcome measures include dietary protein intake over pregnancy and any associations with maternal creatine, pregnancy events and birth outcomes. ETHICS AND DISSEMINATION: Ethical approval was granted in August 2015 from Monash Health (Ref: 14140B) and Monash University (Ref: 7785). Study outcomes will be disseminated at international conferences and published in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: ACTRN12618001558213; Pre-results.

Planned private homebirth in Victoria 2000-2015: a retrospective cohort study of Victorian perinatal data.

BACKGROUND: The outcomes for planned homebirth in Victoria are unknown. We aimed to compare the rates of outcomes for high risk and low risk women who planned to birth at home compared to those who planned to birth in hospital. METHODS: We undertook a population based cohort study of all births in Victoria, Australia 2000-2015. Women were defined as being of low or high risk of adverse pregnancy outcomes according to the eligibility criteria for homebirth and either planning to birth at home or in a hospital setting at the at the onset of labour. Rates of perinatal and maternal mortality and morbidity as well as obstetric interventions were compared. RESULTS: Three thousand nine hundred forty-five women planned to give birth at home with a privately practising midwife and 829,286 women planned to give birth in a hospital setting. Regardless of risk status, planned homebirth was associated with significantly lower rates of all obstetric interventions and higher rates of spontaneous vaginal birth (p ≤ 0.0001 for all). For low risk women the rates of perinatal mortality were similar (1.6 per 1000 v's 1.7 per 1000; p = 0.90) and overall composite perinatal (3.6% v's 13.4%; p ≤ 0.001) and maternal morbidities (10.7% v's 17.3%; p ≤ 0.001) were significantly lower for those planning a homebirth. Planned homebirth among high risk women was associated with significantly higher rates of perinatal mortality (9.3 per 1000 v's 3.5 per 1000; p = 0.009) but an overall significant decrease in composite perinatal (7.8% v's 16.9%; p ≤ 0.001) and maternal morbidities (16.7% v's 24.6%; p ≤ 0.001). CONCLUSION: Regardless of risk status, planned homebirth was associated with significantly lower rates of obstetric interventions and combined overall maternal and perinatal morbidities. For low risk women, planned homebirth was also associated with similar risks of perinatal mortality, however for women with recognized risk factors, planned homebirth was associated with significantly higher rates of perinatal mortality.

Maternal region of birth and stillbirth in Victoria, Australia 2000-2011: A retrospective cohort study of Victorian perinatal data.

BACKGROUND: There is growing evidence from high-income countries that maternal country of birth is a risk factor for stillbirth. We aimed to examine the association between maternal region of birth and stillbirth between 2000 and 2011 inclusive in Victoria, Australia. METHODS: Retrospective population based cohort study of all singleton births at 24 or more weeks gestational age from 2000-2011 in Victoria, Australia. Stillbirths due to termination of pregnancy, babies with congenital anomalies and Indigenous mothers were excluded. Main Outcome Measure: Stillbirth. RESULTS: Over the 12-year period there were 685,869 singleton births and 2299 stillbirths, giving an overall stillbirth rate of 3·4 per 1000 births. After adjustment for risk factors, compared to women born in Australia/New Zealand, women born in South Asia (aOR 1.27, 95% CI 1.01-1.53, p = 0.01), were more likely to have a stillbirth whereas women born in South East and East Asia were (aOR 0.60, (95% CI 0.49-0.72, p<0.001) less likely to have a stillbirth. Additionally, the increasing rate of stillbirth as gestation length progressed began to rise earlier and more steeply in the South Asian compared to Australian/New Zealand born women. The following risk factors were also significantly associated with an increased odds of stillbirth in multivariate analyses: maternal age <20 and 35 years and more, nulliparity, low socio-economic status, previous stillbirth, no ultrasound reported in 1st trimester, pre-existing hypertension, antepartum haemorrhage and failure to detect growth restriction antenatally. CONCLUSION: Maternal region of birth is an independent risk factor for stillbirth. Improvements in the rate of stillbirth, particularly late pregnancy stillbirth, are likely to be gained in high-income settings where clinical care is informed by maternal region of birth.

The optimal gestation for pertussis vaccination during pregnancy: a prospective cohort study.

BACKGROUND: There is an increasing incidence of pertussis infection in infants too young to be adequately protected via vaccination. Maternal pertussis vaccination during the third trimester of pregnancy is a new strategy to provide protection to newborn infants. OBJECTIVE: This study sought to determine the optimal gestational window for vaccination in the third trimester. STUDY DESIGN: This prospective study recruited 3 groups of women: an early vaccination group, vaccinated between 28-32 weeks' gestation; a late vaccination group, vaccinated between 33-36 weeks' gestation; and an unvaccinated control group. Maternal venous blood was taken prior to pertussis vaccination. At birth, infant cord blood was collected to determine antibody levels to pertussis toxin (PT), pertactin (PRN), and filamentous hemagglutinin (FHA). RESULTS: In all, 154 women were recruited from April through September 2014. There was no significant difference between maternal PRN and FHA antibody levels among the 3 groups, however, PT was higher in the early compared to late vaccination group (P = .05). Cord blood antibody levels to PT, PRN, and FHA were significantly higher in those born to vaccinated women compared with unvaccinated controls (P < .001, P = .001, and P < .001, respectively). Vaccination between 28-32 weeks' gestation resulted in significantly higher cord blood PT (4.18.0 vs 3.50 IU/mL, P = .009), PRN (5.83 vs 5.31 IU/mL, P = .03), and FHA (5.56 vs 5.03 IU/mL, P = .03) antibody levels than vaccination between 33-36 weeks' gestation. When adjusted for maternal prevaccination antibody levels, PT levels in early vs late vaccination approached significance (P = .06). PRN levels were significantly higher in the early vaccination group (P = .003). There was no significant difference for FHA antibody levels between the 2 groups (P = .16). CONCLUSION: Maternal vaccination during the third trimester is effective in affording higher levels of pertussis antibody protection to the newborn infant. Vaccination early in the third trimester appears more effective than later in pregnancy.

Association of obesity and systemic factors with bone marrow lesions at the knee: a systematic review.

OBJECTIVE: The objective of this study was to systematically review the literature to determine whether obesity and systemic factors, including age, gender, heritability, dietary factors, smoking, serum and urine biomarkers of cartilage or bone metabolism, bone-related factors, and medication, are associated with knee bone marrow lesions (BMLs) identified on magnetic resonance imaging in asymptomatic pre-osteoarthritis and osteoarthritis populations. METHODS: Electronic searches of MEDLINE and EMBASE were performed from January 1, 1996 to September 30, 2012 using the following keywords: bone marrow lesion(s), bone marrow (o)edema, osteoarthritis, and knee. Studies examining obesity and non-biomechanical factors in relation to the presence, incidence, or change in BMLs were included. Two independent reviewers extracted data and assessed methodological quality of selected studies. Due to the heterogeneity of the studies, we performed a best evidence synthesis. RESULTS: Among 30 studies, 17 were considered high quality. The study populations were heterogeneous in terms of symptoms and radiographic knee osteoarthritis. There was strong evidence for an association between serum lipids and BMLs and no association between age and BMLs. There was moderate evidence for a relationship between obesity and BMLs. There was limited evidence for gender, smoking, C-telopeptide of type I collagen, anti-bone-resorptive treatments, licofelone, and chondroitin sulfate. There was a paucity of evidence for heritability and conflicting evidence for dietary fatty acids. CONCLUSION: There is strong evidence for serum lipids and moderate evidence for obesity as risk factors for knee BMLs. Given the role of BMLs in the pathogenesis of knee osteoarthritis, identification of modifiable risk factors of BMLs and therapeutic interventions targeting BMLs has the potential to reduce the burden of knee osteoarthritis.

Are biomechanical factors, meniscal pathology, and physical activity risk factors for bone marrow lesions at the knee? A systematic review.

OBJECTIVE: To systematically review the literature to determine whether biomechanical factors, meniscal pathology, and physical activity are risk factors for bone marrow lesions (BMLs) at the knee identified from magnetic resonance imaging in pre-osteoarthritis and osteoarthritis populations. METHODS: Electronic searches of MEDLINE and EMBASE were performed from January 1, 1996 to October 31, 2012 using the keywords of bone marrow lesion(s), bone marrow (o)edema, osteoarthritis, and knee. Studies examining biomechanical factors, meniscal pathology, or physical activity in relation to the presence, incidence, or change in BMLs at the knee were included. Two independent reviewers extracted the data and assessed the methodological quality of selected studies. Due to the heterogeneity of the studies, we performed a best evidence synthesis. RESULTS: Fifteen studies were included in this review, of which 9 were considered high quality. The study populations were heterogeneous in terms of the symptoms and radiographic knee osteoarthritis. There was strong evidence for relationships of mechanical knee alignment and meniscal pathology with BMLs in osteoarthritis populations. There was a paucity of evidence for a relationship between physical activity and BMLs. CONCLUSION: Despite the heterogeneity of included studies, these data suggest that mechanical knee alignment and meniscal pathology are risk factors for BMLs in knee osteoarthritis. It suggests that BMLs in individuals with osteoarthritis are more susceptible to mechanical knee alignment. Given the role of BMLs in the pathogenesis of knee osteoarthritis, identifying strategies to modify these risk factors will be important in slowing the progression and reducing the burden of knee osteoarthritis.

The relationship between retinal vessel calibre and knee cartilage and BMLs.

BACKGROUND: Whether the increase in vascular disease prevalence and mortality in OA populations is a result of co-occurrence of cardiovascular disease and OA, which are both common in the older population, is due to OA treatments or to the common association with reduced physical activity and/or obesity is unclear. One way to explore this non-invasively is to examine the cross-sectional relationship between changes in retinal microvasculature, which have been shown to be markers of generalized vascular pathology, and knee structural changes in an asymptomatic community-based population. METHODS: A community sample of 289 (61% women) aged 50-79 years with no knee symptoms underwent magnetic resonance imaging (MRI) of their dominant knee in 2003. Cartilage volume and bone marrow lesions (BMLs) were determined. All subjects also had retinal photographs taken from which retinal arteriolar and venular diameters were determined and summarized as the central retinal arteriolar equivalent (CRAE) and the central retinal venular equivalent (CRVE). RESULTS: Retinal venular diameter was significantly wider in subjects with a BML compared with subjects without a BML (mean (SD) 214.2 (2.8) µm versus 207.5 (1.1) µm respectively independent of age, gender and BMI. A trend for decreased medial tibial cartilage with increasing CRAE was also observed (regression coefficient -2.70 µl, 95%CI-5.74, 0.5, p=0.08). CONCLUSION: These findings suggest that vascular pathology, indicative of inflammatory processes, is associated with early structural knee changes. The role of micro-vascular changes in the pathogenesis of OA warrants further investigation.

Increased fasting serum glucose concentration is associated with adverse knee structural changes in adults with no knee symptoms and diabetes.

OBJECTIVE: There is evidence to suggest that elevated glucose concentration and clinical diabetes are associated with osteoarthritis (OA). However, the association may be confounded by knee symptoms, concomitant treatment for OA or diabetes. We performed a longitudinal cohort study to examine the relationship between serum glucose concentration and knee structure in adults with no knee symptoms or diabetes. METHODS: 179 participants who had fasting serum glucose measurements at 1990-4, with no knee symptoms or diabetes (physician-diagnosed or fasting serum glucose ≥7 mmol/L), underwent knee MRI in 2003-4 and 2 years later. Body mass index was measured at 1990-4 and 2003-4. Cartilage volume and bone marrow lesions were determined from MRI at 2003-4 and 2006-7. RESULTS: Fasting serum glucose concentration was positively associated with the rate of tibial cartilage volume loss over 2 years in women (B=44.2mm(3), 95% CI 4.6, 83.8) but not in men (B=6.0mm(3), 95% CI -68.5, 80.6). Fasting serum glucose concentration was positively associated with incident bone marrow lesions in women (OR=5.76, 95% CI 1.06, 31.21) but not in men (OR=0.11, 95% CI 0.01, 1.79) with significant gender difference (p=0.001 for interaction). CONCLUSION: Increased fasting serum glucose concentration in a non-diabetic population was associated with adverse structural changes at the knee in women but not in men, suggesting that there may be susceptibility to knee structural change even below the arbitrary "diabetic range" of serum glucose levels. The sex differences warrant further investigation as this may be one mechanism underlying the sex difference in knee OA.

Effect of long-term vigorous physical activity on healthy adult knee cartilage.

INTRODUCTION: Whether participation in long-term vigorous physical activity affects knee cartilage is unclear and may depend on the state of knee health. We examined the association between vigorous physical activity during a decade and the subsequent changes in knee cartilage among healthy adults. We then examined whether this effect differed in those with and without bone marrow lesions (BMLs), as an indicator of preclinical joint damage. METHODS: A total of 297 healthy adults age 50-79 yr were recruited. Physical activity was assessed via questionnaire at baseline (1990-1994) and at follow-up (2003-2004), and a score for persistence of vigorous physical activity score was determined. Each subject underwent knee magnetic resonance imaging in 2003-2004 and in 2006-2007. Cartilage volume, defects, and BMLs were measured using validated methods. RESULTS: Persistent participation in vigorous physical activity was associated with worsening of medial knee cartilage defects (odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.0-2.3). In the subgroup with BMLs, but not in those without BML, persistent vigorous physical activity was associated with a significant worsening of medial knee cartilage defects (OR = 3.4, 95% CI = 1.0-16.5) and a trend toward an increased rate of loss of medial knee cartilage volume (21.6 mm·yr, 95% CI = -0.4 to 43.6). CONCLUSIONS: In knees with BMLs, persistent participation in vigorous physical activity was associated with adverse cartilage changes in the medial compartment. This suggests that the long-term effects of vigorous physical activity may depend on the preexisting health of the joint.

Sex hormones and structural changes in osteoarthritis: a systematic review.

AIM: To systematically review the evidence for a relationship between sex hormones and structural changes in osteoarthritis (OA). METHODS: Electronic searches of MEDLINE were performed in November-December 2010 and in February 2011 for studies of sex hormones and OA that met a predefined set of criteria. Both controlled trials and observational studies were eligible for inclusion. Two independent reviewers extracted the data and assessed the methodological quality of the included studies. Due to the heterogeneity of the studies, we were unable to perform a best evidence synthesis. However we have provided summaries for each section. RESULTS: Twenty-seven studies were included in this review, of which 11 were considered high quality. The evidence suggests an association between endogenous oestrogen and cartilage turnover and radiographic OA, and between testosterone and cartilage volume. There is also evidence for an association between exogenous oestrogen and cartilage and bone turnover, although its effects on radiographic and MRI structure as well as joint replacement are unclear. The evidence also supports an association between oestrogen receptor α and ß gene polymorphisms and OA. CONCLUSION: Although the heterogeneity of the studies means that there is insufficient evidence to form strong conclusions, the available evidence supports an effect of endogenous and exogenous oestrogen as well as oestrogen receptor polymorphisms on joint health.

Sex differences in the relationship between bone mineral density and tibial cartilage volume.

OBJECTIVE: Although there is a well-established sex difference in the prevalence and severity of OA, the mechanism for this is not clear. The aim of this study was to examine the potential role of BMD and BMC in explaining gender differences in knee cartilage volume. METHODS: A total of 153 subjects aged 25-60 years, 81% female, were recruited. MRI was performed of the dominant knee. Cartilage volume was measured using validated methods. Total body BMD and content was measured using DXA. RESULTS: Total body BMC and BMD was significantly associated with medial cartilage volume in both sexes. However, the associations were stronger in men for BMC (B = 0.52; 95% CI 0.21, 0.83; P for difference = 0.001) and BMD (B = 2242; 95% CI 443, 4041; P for difference = 0.05). Similar results were obtained in the lateral tibial compartment. No significant association was obtained between total body BMD and BMC and patella cartilage volume in either men or women. CONCLUSIONS: In this relatively healthy population, we found a positive relationship between total body BMD and BMC and tibial cartilage volume in the medial and lateral compartments. These relationships were stronger in men than women. Thus, the results of this study may provide some insight into the sex differences in knee cartilage volume, which may in turn facilitate our understanding of the pathogenesis of OA.