Creatine supplementation during pregnancy: summary of experimental studies suggestion a treatment to improve fetal and neonatal morbidity and reduce mortality in high-risk human pregnancy

While the use of creatine in human pregnancy is yet to be fully evaluated, its long-term use in healthy adults appears to be safe, and its well documented neuroprotective properties have recently been extended by demonstrations that creatine improves cognitive function in normal and elderly people, and motor skills in sleep-deprived subjects. Creatine has many actions likely to benefit the fetus and newborn, because pregnancy is a state of heightened metabolic activity, and the placenta is a key source of free radicals of oxygen and nitrogen. The multiple benefits of supplementary creatine arise from the fact that the creatine-phosphocreatine [PCr] system has physiologically important roles that include maintenance of intracellular ATP and acid–base balance, post-ischaemic recovery of protein synthesis, cerebral vasodilation, antioxidant actions, and stabilisation of lipid membranes. In the brain, creatine not only reduces lipid peroxidation and improves cerebral perfusion, its interaction with the benzodiazepine site of the GABAA receptor is likely to counteract the effects of glutamate excitotoxicity – actions that may protect the preterm and term fetal brain from the effects of birth hypoxia. In this review we discuss the development of creatine synthesis during fetal life, the transfer of creatine from mother to fetus, and propose that creatine supplementation during pregnancy may have benefits for the fetus and neonate whenever oxidative stress or feto-placental hypoxia arise, as in cases of fetal growth restriction, premature birth, or when parturition is delayed or complicated by oxygen deprivation of the newborn

Ventilation Prior to Umbilical Cord Clamping Improves Cardiovascular Stability and Oxygenation in Preterm Lambs After Exposure to Intrauterine Inflammation

Background: Delaying umbilical cord clamping until after aeration of the lung (physiological-based cord clamping; PBCC) maintains cardiac output and oxygenation in preterm lambs at birth, however, its efficacy after intrauterine inflammation is not known. Given the high incidence of chorioamnionitis in preterm infants, we investigated whether PBCC conferred any benefits compared to immediate cord clamping (ICC) in preterm lambs exposed antenatally to 7 days of intrauterine inflammation.Methods: Ultrasound guided intraamniotic injection of 20 mg Lipopolysaccharide (from E. coli:055:B5) was administered to pregnant ewes at 0.8 gestation. Seven days later, ewes were anesthetized, preterm fetuses exteriorised via cesarean section, and instrumented for continuous measurement of pulmonary, systemic and cerebral pressures and flows, and systemic, and cerebral oxygenation. Lambs were then randomized to either PBCC, whereupon ventilation was initiated and maintained for 3 min prior to umbilical cord clamping, or ICC where the umbilical cord was cut and ventilation initiated 30 s later. Ventilation was maintained for 30 min.Results: ICC caused a rapid fall in systemic (by 25%) and cerebral (by 11%) oxygen saturation in ICC lambs, concurrent with a rapid increase in carotid arterial pressure and heart rate. The overshoot in carotid arterial pressure was sustained in ICC lambs for the first 20 min of the study. PBCC maintained cardiac output and prevented the fall in cerebral oxygen delivery at birth. PBCC lambs had lower respiratory compliance and higher respiratory requirements throughout the study.Conclusion: PBCC mitigated the adverse effects of ICC on oxygenation and cardiac output, and therefore could be more beneficial in preterm babies exposed to antenatal inflammation as it maintains cardiac output and oxygen delivery. The increased respiratory requirements require further investigation in this sub-group of preterm infants

Studies on the effectiveness of maternal dietary creatine to protect the fetal musculature from birth asphyxia

Birth asphyxia is a significant problem, responsible for ~1.2 million deaths each year worldwide. Those who survive often suffer from a myriad of health issues including brain damage, manifesting as cerebral palsy (CP), respiratory insufficiency, and cardiovascular collapse. Although the majority of research is directed towards reducing the brain injury that results from birth asphyxia, the multi-organ effects observed in surviving neonates are of equal importance. Furthermore, the motor deficits observed in babies and children with CP, traditionally thought to be neural in origin, may have a muscular component which has not been investigated. Using our spiny mouse model of birth asphyxia, we previously reported damage to the brain and kidney, as well as structural and functional deficits in the diaphragm muscle. These deficits were prevented by supplementing the maternal diet with 5% creatine from mid-pregnancy. However, the effect of this model on the heart, as well as the potential involvement of the skeletal muscle in the motor deficits observed in this model have not been examined. Furthermore, the long-term effects of this exposure on all three muscle types are unknown. In these studies, pregnant spiny mice were fed control or 5% creatine-supplemented diet for the second half of pregnancy, and fetuses were delivered by caesarean section with or without 7.5 min of in-utero asphyxia. Surviving pups were raised by a cross-foster dam for 24 hours or 33±2 days of age when heart, diaphragm and hindlimb skeletal muscle were obtained for ex-vivo functional assessment, and for structural and molecular analyses. The major findings of this study were that, like the diaphragm, the hindlimb skeletal muscle exhibited significant structural changes immediately after birth asphyxia including a reduction in muscle fibre size in all three-muscle fibre types and a reduction in oxidative capacity. There were also significant reductions in fatigue resistance in male offspring, assessed ex-vivo at 24 h of age. We found persistent structural changes in the diaphragm and hindlimb skeletal muscles, including alterations in fibre type proportions, reductions in fibre size and decreased oxidative capacity. These changes corresponded to substantial functional deficits, with birth asphyxia animals exhibiting significantly reduced fatigue resistance in the diaphragm at 1 month of age and reduced aerobic endurance, assessed using the accelerating Rotarod test. Lastly, this model caused no significant short- or long-term molecular, structural or functional changes in the heart. Finally, we report that in the case of the hindlimb and diaphragm muscle, maternal creatine supplementation completely prevented all structural and functional changes observed in the immediate neonatal period and into later life. Furthermore, creatine did not result in any significant changes to normal muscle structure or function, thus highlighting this harmless dietary supplement as a potentially lifesaving preventative treatment for birth asphyxia induced muscular injury, and strengthening the body of evidence supporting the clinical translation of creatine for prevention of birth asphyxia in human pregnancy

Studies on the effectiveness of maternal dietary creatine to protect the fetal musculature from birth asphyxia

Birth asphyxia is a significant problem, responsible for ~1.2 million deaths each year worldwide. Those who survive often suffer from a myriad of health issues including brain damage, manifesting as cerebral palsy (CP), respiratory insufficiency, and cardiovascular collapse. Although the majority of research is directed towards reducing the brain injury that results from birth asphyxia, the multi-organ effects observed in surviving neonates are of equal importance. Furthermore, the motor deficits observed in babies and children with CP, traditionally thought to be neural in origin, may have a muscular component which has not been investigated. Using our spiny mouse model of birth asphyxia, we previously reported damage to the brain and kidney, as well as structural and functional deficits in the diaphragm muscle. These deficits were prevented by supplementing the maternal diet with 5% creatine from mid-pregnancy. However, the effect of this model on the heart, as well as the potential involvement of the skeletal muscle in the motor deficits observed in this model have not been examined. Furthermore, the long-term effects of this exposure on all three muscle types are unknown. In these studies, pregnant spiny mice were fed control or 5% creatine-supplemented diet for the second half of pregnancy, and fetuses were delivered by caesarean section with or without 7.5 min of in-utero asphyxia. Surviving pups were raised by a cross-foster dam for 24 hours or 33±2 days of age when heart, diaphragm and hindlimb skeletal muscle were obtained for ex-vivo functional assessment, and for structural and molecular analyses. The major findings of this study were that, like the diaphragm, the hindlimb skeletal muscle exhibited significant structural changes immediately after birth asphyxia including a reduction in muscle fibre size in all three-muscle fibre types and a reduction in oxidative capacity. There were also significant reductions in fatigue resistance in male offspring, assessed ex-vivo at 24 h of age. We found persistent structural changes in the diaphragm and hindlimb skeletal muscles, including alterations in fibre type proportions, reductions in fibre size and decreased oxidative capacity. These changes corresponded to substantial functional deficits, with birth asphyxia animals exhibiting significantly reduced fatigue resistance in the diaphragm at 1 month of age and reduced aerobic endurance, assessed using the accelerating Rotarod test. Lastly, this model caused no significant short- or long-term molecular, structural or functional changes in the heart. Finally, we report that in the case of the hindlimb and diaphragm muscle, maternal creatine supplementation completely prevented all structural and functional changes observed in the immediate neonatal period and into later life. Furthermore, creatine did not result in any significant changes to normal muscle structure or function, thus highlighting this harmless dietary supplement as a potentially lifesaving preventative treatment for birth asphyxia induced muscular injury, and strengthening the body of evidence supporting the clinical translation of creatine for prevention of birth asphyxia in human pregnancy

Maternal creatine supplementation during pregnancy prevents acute and long-term deficits in skeletal muscle after birth asphyxia: a study of structure and function of hind limb muscle in the spiny mouse

BACKGROUND: Maternal antenatal creatine supplementation protects the brain, kidney, and diaphragm against the effects of birth asphyxia in the spiny mouse. In this study, we examined creatine\u27s potential to prevent damage to axial skeletal muscles. METHODS: Pregnant spiny mice were fed a control or creatine-supplemented diet from mid-pregnancy, and 1 d before term (39 d), fetuses were delivered by c-section with or without 7.5 min of birth asphyxia. At 24 h or 33 ± 2 d after birth, gastrocnemius muscles were obtained for ex-vivo study of twitch-tension, muscle fatigue, and structural and histochemical analysis. RESULTS: Birth asphyxia significantly reduced cross-sectional area of all muscle fiber types (P < 0.05), and increased fatigue caused by repeated tetanic contractions at 24 h of age (P < 0.05). There were fewer (P < 0.05) Type I and IIa fibers and more (P < 0.05) Type IIb fibers in male gastrocnemius at 33 d of age. Muscle oxidative capacity was reduced (P < 0.05) in males at 24 h and 33 d and in females at 24 h only. Maternal creatine treatment prevented all asphyxia-induced changes in the gastrocnemius, improved motor performance. CONCLUSION: This study demonstrates that creatine loading before birth protects the muscle from asphyxia-induced damage at birth

Maternal Creatine Supplementation during Pregnancy Prevents Long-Term Changes in Diaphragm Muscle Structure and Function after Birth Asphyxia.

Using a model of birth asphyxia, we previously reported significant structural and functional deficits in the diaphragm muscle in spiny mice, deficits that are prevented by supplementing the maternal diet with 5% creatine from mid-pregnancy. The long-term effects of this exposure are unknown. Pregnant spiny mice were fed control or 5% creatine-supplemented diet for the second half of pregnancy, and fetuses were delivered by caesarean section with or without 7.5 min of in-utero asphyxia. Surviving pups were raised by a cross-foster dam until 33±2 days of age when they were euthanized to obtain the diaphragm muscle for ex-vivo study of twitch tension and muscle fatigue, and for structural and enzymatic analyses. Functional analysis of the diaphragm revealed no differences in single twitch contractile parameters between any groups. However, muscle fatigue, induced by stimulation of diaphragm strips with a train of pulses (330 ms train/sec, 40 Hz) for 300 sec, was significantly greater for asphyxia pups compared with controls (p<0.05), and this did not occur in diaphragms of creatine + asphyxia pups. Birth asphyxia resulted in a significant increase in the proportion of glycolytic, fast-twitch fibres and a reduction in oxidative capacity of Type I and IIb fibres in male offspring, as well as reduced cross-sectional area of all muscle fibre types (Type I, IIa, IIb/d) in both males and females at 33 days of age. None of these changes were observed in creatine + asphyxia animals. Thus, the changes in diaphragm fatigue and structure induced by birth asphyxia persist long-term but are prevented by maternal creatine supplementation

Dietary creatine supplementation during pregnancy: a study on the effects of creatine supplementation on creatine homeostasis and renal excretory function in spiny mice

Recent evidence obtained from a rodent model of birth asphyxia shows that supplementation of the maternal diet with creatine during pregnancy protects the neonate from multi-organ damage. However, the effect of increasing creatine intake on creatine homeostasis and biosynthesis in females, particularly during pregnancy, is unknown. This study assessed the impact of creatine supplementation on creatine homeostasis, body composition, capacity for de novo creatine synthesis and renal excretory function in non-pregnant and pregnant spiny mice. Mid-gestation pregnant and virgin spiny mice were fed normal chow or chow supplemented with 5&nbsp;% w/w creatine for 18&nbsp;days. Weight gain, urinary creatine and electrolyte excretion were assessed during supplementation. At post mortem, body composition was assessed by Dual-energy X-ray absorptiometry, or tissues were collected to assess creatine content and mRNA expression of the creatine synthesising enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) and the creatine transporter (CrT1). Protein expression of AGAT and GAMT was also assessed by Western blot. Key findings of this study include no changes in body weight or composition with creatine supplementation; increased urinary creatine excretion in supplemented spiny mice, with increased sodium (P&nbsp;&lt;&nbsp;0.001) and chloride (P&nbsp;&lt;&nbsp;0.05) excretion in pregnant dams after 3&nbsp;days of supplementation; lowered renal AGAT mRNA (P&nbsp;&lt;&nbsp;0.001) and protein (P&nbsp;&lt;&nbsp;0.001) expressions, and lowered CrT1 mRNA expression in the kidney (P&nbsp;&lt;&nbsp;0.01) and brain (P&nbsp;&lt;&nbsp;0.001). Creatine supplementation had minimal impact on creatine homeostasis in either non-pregnant or pregnant spiny mice. Increasing maternal dietary creatine consumption could be a useful treatment for birth asphyxia

Renal dysfunction in early adulthood following birth asphyxia in male spiny mice, and its amelioration by maternal creatine supplementation during pregnancy

BACKGROUND: Acute Kidney Injury (AKI) affects ~70% of asphyxiated newborns, and increases their risk of developing chronic kidney disease (CKD) later in life. AKI is driven by renal oxygen deprivation during asphyxia, thus we hypothesized that creatine administered antenatally would protect the kidney from the long-term effects of birth asphyxia. METHODS: Pregnant spiny mice were fed standard chow or chow supplemented with 5% creatine from 20-days gestation (mid-getstation). One day prior to term (37-days gestation), pups were delivered by caesarean or subjected to intrauterine asphyxia. Litters were allocated to one of two time-points. Kidneys were collected at one month of age to estimate nephron number (stereology). Renal function (excretory profile and GFR) was measured at three months of age, and kidneys then collected for assessment of glomerulosclerosis. RESULTS: Compared to controls, at one month of age male (but not female) birth-asphyxia offspring had 20% fewer nephrons (P&lt;0.05). At three months of age male birth-asphyxia offspring had 31% lower GFR (P&lt;0.05) and greater glomerular collagen IV content (P&lt;0.01). Antenatal creatine prevented these renal injuries arising from birth asphyxia. CONCLUSION: Maternal creatine supplementation during pregnancy may be an effective prophylactic to prevent birth asphyxia induced AKI and the emergence of CKD.Pediatric Research (2016); doi:10.1038/pr.2016.268

E<i>x-vivo</i> diaphragm muscle function at 31–33 days of age.

<p>2-Way ANOVA found no significant differences for peak twitch tension, time to peak twitch tension or time to ½ relaxation tension (p>0.05) between the four treatment groups. No effect of sex was observed for any of the above parameters (p>0.05). Values are means ± SEM; n = 5/group.</p