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.

Maternal plasma vitamin D levels across pregnancy are not associated with neonatal birthweight: findings from an Australian cohort study of low-risk pregnant women.

BACKGROUND: In utero environments can be highly influential in contributing to the development of offspring obesity. Specifically, vitamin D deficiency during pregnancy is associated with adverse maternal and child health outcomes, however its relationship with offspring obesity remains unclear. We assessed maternal vitamin D status across pregnancy, change in plasma vitamin D concentrations and associations with neonatal birthweight, macrosomia and large for gestational age. METHODS: Women (n = 221) aged 18-40 years with singleton (low-risk) pregnancies, attending antenatal clinics at a tertiary-level maternity hospital were recruited at 10-20 weeks gestation. Medical history, maternal weight and blood samples at three antenatal clinic visits were assessed; early (15 ± 3 weeks), mid (27 ± 2 weeks) and late (36 ± 1 weeks) gestation. Maternal 25(OH)D was analysed from stored plasma samples via liquid chromatography-tandem mass spectrometry (LC/MS/MS). Neonatal growth parameters were collected at birth. Unadjusted and adjusted linear and logistic regression assessed associations of maternal vitamin D with birthweight, macrosomia and large for gestational age. RESULTS: Mean plasma 25(OH)D increased from early (83.8 ± 22.6 nmol/L) to mid (96.5 ± 28.9 nmol/L) and late (100.8 ± 30.8 nmol/L) gestation. Overall 98% of women were taking vitamin D-containing supplements throughout their pregnancy. Prevalence of vitamin D deficiency (25(OH)D < 50 nmol/L) was 6.5%, 6.3% and 6.8% at early, mid and late pregnancy respectively. No statistically significant association was found between 25(OH)D or vitamin D deficiency at any timepoint with neonatal birthweight, macrosomia or large for gestational age. CONCLUSIONS: Prevalence of vitamin D deficiency was low in this cohort of pregnant women and likely related to the high proportion of women taking vitamin D supplements during pregnancy. Maternal 25(OH)D did not impact offspring birth weight or birth size. Future studies in high-risk pregnant populations are needed to further assess maternal vitamin D status and factors in utero which promote early life obesity.

The effect of comorbidities on the sFLT-1:PlGF ratio in preeclampsia.

Research indicates that soluble fms-like tyrosine kinase 1 (sFLT-1) and placental growth factor (PLGF) have diagnostic and prognostic significance for women with preeclampsia. However, sparse research has studied these biomarkers in women with preexisting comorbidities such as chronic hypertension, diabetes mellitus, systemic lupus erythematosus and chronic kidney disease. We undertook a prospective longitudinal cohort study to compare the sFLT-1: PlGF ratio between women with and without comorbidities who did and did not go on to develop preeclampsia. We found that women with comorbidities may develop preeclampsia with a milder elevation in sFLT-1: PlGF than do women without comorbidities. This has clinical and research implications.

The effect of preexisting medical comorbidities on the preeclamptic phenotype: a retrospective cohort study.

Objective:To compare the effect of comorbidities on the phenotype and outcomes of preeclampsia.Methods: A matched retrospective cohort study of women delivering at a tertiary maternity center following a diagnosis of preeclampsia. We collected data on signs and symptoms, biochemical markers, and maternal and perinatal outcomes.Results:We studied 474 women; 158 women with and 316 without comorbidities. Compared to women without comorbidities, women with comorbidities delivered earlier. They suffered fewer maternal but more neonatal complications.Conclusion: Women with comorbidities receive earlier intervention than women without comorbidities, which may lead to fewer maternal complications but worse neonatal outcomes.

Creatine Metabolism in Female Reproduction, Pregnancy and Newborn Health.

Creatine metabolism is an important component of cellular energy homeostasis. Via the creatine kinase circuit, creatine derived from our diet or synthesized endogenously provides spatial and temporal maintenance of intracellular adenosine triphosphate (ATP) production; this is particularly important for cells with high or fluctuating energy demands. The use of this circuit by tissues within the female reproductive system, as well as the placenta and the developing fetus during pregnancy is apparent throughout the literature, with some studies linking perturbations in creatine metabolism to reduced fertility and poor pregnancy outcomes. Maternal dietary creatine supplementation during pregnancy as a safeguard against hypoxia-induced perinatal injury, particularly that of the brain, has also been widely studied in pre-clinical in vitro and small animal models. However, there is still no consensus on whether creatine is essential for successful reproduction. This review consolidates the available literature on creatine metabolism in female reproduction, pregnancy and the early neonatal period. Creatine metabolism is discussed in relation to cellular bioenergetics and de novo synthesis, as well as the potential to use dietary creatine in a reproductive setting. We highlight the apparent knowledge gaps and the research "road forward" to understand, and then utilize, creatine to improve reproductive health and perinatal outcomes.

Early Pregnancy Vitamin D Binding Protein Is Independently Associated with the Development of Gestational Diabetes: A Retrospective Cohort Study.

BACKGROUND: Vitamin D-binding protein (VDBP) has been implicated in several adverse pregnancy outcomes either directly or indirectly via influencing the concentrations of biologically active vitamin D metabolites. However, human studies exploring these metabolites in pregnancy remain sparse. Here, we examine whether VDBP and total, free, and bioavailable 25-hydroxyvitamin D (25(OH)D) metabolites in early pregnancy are associated with subsequent adverse pregnancy outcomes. METHODS: We conducted a retrospective analysis of 304 pregnant women in early pregnancy (<20 weeks gestation). The demographic characteristics, anthropometric data, and total 25(OH)D were measured and plasma or serum samples were collected and bio-banked. Using these samples, we measured VDBP (polyclonal ELISA) and albumin (automated colorimetry), and calculated free and bioavailable 25(OH)D using validated formulae. Pregnancy outcomes were derived from scanned medical records. Regression models were used to analyse the relationships between vitamin D metabolites in early pregnancy and subsequent pregnancy outcomes (gestational diabetes mellitus (GDM), pre-eclampsia, preterm birth), with adjustment for predetermined clinically relevant maternal factors including age, body mass index (BMI), and ethnicity. RESULTS: Lower VDBP concentrations were associated with higher glucose levels and a greater likelihood of developing GDM at 26-28 weeks gestation (odds ratio [OR] (95% CI) = 0.98 (0.97,0.99), p = 0.015). This finding remained significant after adjustment for maternal covariates including age, BMI, and ethnicity (ß = -0.003, p = 0.03). Lower total, free and bioavailable 25(OH)D, but not VDBP, were associated with a shorter length of gestation, but only the relationship with total 25(OH)D remained significant after adjustment for the above maternal covariates (ß = 0.02, p = 0.006). CONCLUSIONS: This is the first study to examine VDBP, and total, free and bioavailable 25(OH)D in relation to pregnancy outcomes in a well characterised multi-ethnic cohort of pregnant women. Our findings show that VDBP and total 25(OH)D are associated with GDM and length of gestation, respectively; however, further investigations using large-scale prospective studies are needed to confirm our findings.

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.

Acceptability of dietary or nutritional supplementation in pregnancy (ADONS) - Exploring the consumer's perspective on introducing creatine monohydrate as a pregnancy supplement.

BACKGROUND: Pre-clinical studies suggest maternal dietary creatine supplementation during pregnancy could protect babies against hypoxic intrapartum events, however creatine has not been used as a supplement in pregnancy. The aim of this study was to explore pregnant women and healthcare professional's general knowledge, behaviours, and attitudes toward nutritional supplements, and their thoughts on introducing creatine as a pregnancy supplement. METHODS: Pregnant women (n = 42) and partners (n = 23), attending a tertiary care pregnancy service in Melbourne, Australia, participated in focus groups or semi-structured interviews. Health professionals (n = 100), completed a semi-structured online survey. Descriptive data were analyzed using SPSS 25.0 and qualitative data was managed using NVivo 22.0. RESULTS: Use of branded nutritional supplements in pregnancy was commonplace and acceptable. All primary healthcare respondents discussed supplements with their patients at first consultation. Supplements consumed corresponded closely to those recommended. Women had good general awareness of commonly recommended nutritional supplements, however, were less aware of the rationale for supplement use. This aligned with health professional's perceptions. Women would consider taking creatine if recommended by their health professional. Health professionals would require detailed safety, beneficence, and efficacy information before recommending creatine supplementation. They would also be more likely to recommend a new supplement in higher-risk pregnancies, where benefits may outweigh any perceived side-effects. CONCLUSION: There is high acceptance of current recommended nutritional supplements in pregnancy. Implementing creatine as a new supplement will require substantive empirical evidence and changes to clinical guidelines. Public awareness and education would also be essential to consumer acceptability of creatine.

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.

Recurrence of bacterial vaginosis is significantly associated with posttreatment sexual activities and hormonal contraceptive use.

BACKGROUND: Bacterial vaginosis (BV) recurrence posttreatment is common. Our aim was to determine if behaviors were associated with BV recurrence in women in a randomized controlled trial (RCT). METHODS: Symptomatic 18- to 50-year-old females with BV (≥3 Amsel criteria and Nugent score [NS] = 4-10) were enrolled in a 3-arm randomized double-blind RCT Melbourne Sexual Health Centre, Australia, in 2009-2010. All 450 participants received oral metronidazole (7 days) and were equally randomized to vaginal clindamycin, lactobacillus-vaginal probiotic or vaginal placebo. At 1, 2, 3, and 6 months, participants self-collected vaginal smears and completed questionnaires. Primary endpoint was NS = 7-10. Cox regression was used to estimate hazard ratios (HRs) for risk of BV recurrence associated with baseline and longitudinal characteristics. RESULTS: Four hundred four (90%) women with postrandomization data contributed to analyses. Cumulative 6-month BV recurrence was 28% (95% confidence interval [CI], 24%-33%) and not associated with treatment. After stratifying for treatment and adjusting for age and sex frequency, recurrence was associated with having the same pre-/posttreatment sexual partner (adjusted HR [AHR] = 1.9; 95% CI, 1.2-3.0), inconsistent condom use (AHR = 1.9; 95% CI, 1.0-3.3), and being non-Australian (AHR = 1.5; 95% CI, 1.0-2.1), and halved with use of an estrogen-containing contraceptive (AHR = 0.5; 95% CI, .3-.8). CONCLUSIONS: Risk of BV recurrence was increased with the same pre-/posttreatment sexual partner and inconsistent condom use, and halved with use of estrogen-containing contraceptives. Behavioral and contraceptive practices may modify the effectiveness of BV treatment. CLINICAL TRIALS REGISTRATION: ACTRN12607000350426.

Efficacy of oral metronidazole with vaginal clindamycin or vaginal probiotic for bacterial vaginosis: randomised placebo-controlled double-blind trial.

BACKGROUND: To determine if oral metronidazole (MTZ-400 mg bid) with 2% vaginal clindamycin-cream (Clind) or a Lactobacillus acidophilus vaginal-probiotic containing oestriol (Prob) reduces 6-month bacterial vaginosis (BV) recurrence. METHODS: Double-blind placebo-controlled parallel-group single-site study with balanced randomization (1:1:1) conducted at Melbourne Sexual Health Centre, Australia. Participants with symptomatic BV [Nugent Score (NS) = 7-10 or ≥3 Amsel's criteria and NS = 4-10], were randomly allocated to MTZ-Clind, MTZ-Prob or MTZ-Placebo and assessed at 1,2,3 and 6 months. MTZ and Clind were administered for 7 days and Prob and Placebo for 12 days. Primary outcome was BV recurrence (NS of 7-10) on self-collected vaginal-swabs over 6-months. Cumulative BV recurrence rates were compared between groups by Chi-squared statistics. Kaplan-Meier, log rank and Cox regression analyses were used to compare time until and risk of BV recurrence between groups. RESULTS: 450 18-50 year old females were randomized and 408 (91%), equally distributed between groups, provided ≥1 NS post-randomization and were included in analyses; 42 (9%) participants with no post-randomization data were excluded. Six-month retention rates were 78% (n = 351). One-month BV recurrence (NS 7-10) rates were 3.6% (5/140), 6.8% (9/133) and 9.6% (13/135) in the MTZ-Clind, MTZ-Prob and MTZ-Placebo groups respectively, p = 0.13. Hazard ratios (HR) for BV recurrence at one-month, adjusted for adherence to vaginal therapy, were 0.43 (95%CI 0.15-1.22) and 0.75 (95% CI 0.32-1.76) in the MTZ-Clind and MTZ-Prob groups compared to MTZ-Plac respectively. Cumulative 6-month BV recurrence was 28.2%; (95%CI 24.0-32.7%) with no difference between groups, p = 0.82; HRs for 6-month BV recurrence for MTZ-Clind and MTZ-Prob compared to MTZ-Plac, adjusted for adherence to vaginal therapy were 1.09(95% CI = 0.70-1.70) and 1.03(95% CI = 0.65-1.63), respectively. No serious adverse events occurred. CONCLUSION: Combining the recommended first line therapies of oral metronidazole and vaginal clindamycin, or oral metronidazole with an extended-course of a commercially available vaginal-L.acidophilus probiotic, does not reduce BV recurrence. TRIAL REGISTRATION: ANZCTR.org.au ACTRN12607000350426.

Young pregnant women's views on the acceptability of screening for chlamydia as part of routine antenatal care.

BACKGROUND: In pregnancy, untreated chlamydia infection has been associated with adverse outcomes for both mother and infant. Like most women, pregnant women infected with chlamydia do not report genital symptoms, and are therefore unlikely to be aware of their infection. The aim of this study was to determine the acceptability of screening pregnant women aged 16-25 years for chlamydia as part of routine antenatal care. METHODS: As part of a larger prospective, cross-sectional study of pregnant women aged 16-25 years attending antenatal services across Melbourne, Australia, 100 women were invited to participate in a face-to-face, semi structured interview on the acceptability of screening for chlamydia during pregnancy. Women infected with chlamydia were oversampled (n = 31). RESULTS: Women had low levels of awareness of chlamydia before the test, retained relatively little knowledge after the test and commonly had misconceptions around chlamydia transmission, testing and sequelae. Women indicated a high level of acceptance and support for chlamydia screening, expressing their willingness to undertake whatever care was necessary to ensure the health of their baby. There was a strong preference for urine testing over other methods of specimen collection. Women questioned why testing was not already conducted alongside other antenatal STI screening tests, particularly in view of the risks chlamydia poses to the baby. Women who tested positive for chlamydia had mixed reactions, however, most felt relief and gratitude at having had chlamydia detected and reported high levels of partner support. CONCLUSIONS: Chlamydia screening as part of routine antenatal care was considered highly acceptable among young pregnant women who recognized the benefits of screening and strongly supported its implementation as part of routine antenatal care. The acceptability of screening is important to the uptake of chlamydia screening in future antenatal screening strategies.