The Association Of Maternal Sleep During Periconceptional Period With Congenital Heart Disease In Offspring

Background & ObjectiveIn 1992,the World Health Organization proposed that good nutrition,a tobacco-alcohol-free lifestyle,regular physical exercise and supportive environments are four cornerstones of health in Victoria Declaration.With the development of medicine,more and more scholars believe that good sleep is the fifth cornerstone of health.Recent studies pointed to a role for maternal sleep in pregnancy complications and fetal growth.Moreover,maternal sleep during periconceptional period has been found to be asscociated with birth defects.Latest studies suggested that maternal sleep may be involved in the regulation of embryonic heart development through melatonin.Taking this as the breakthrough point,the present study explored the association between periconceptional sleep and the risk of congenital heart disease(CHD)from an epidemiological perspective by the case-control study design.Further,we also observed combined effects of maternal diets,exercises and psychology with sleep on CHD in offspring.Meanwhile,this study used melatonin to interfere H9C2 cell,intending to answer the potential mechanism of maternal sleep involved in embryonic heart development.MethodsThis study was conducted in Shanghai Children's Medical Center,in which,a total of 524 cases(262 simple CHD vs.262 complex CHD),and 262 controls without CHD and other birth defects,were recruited through June,2016 to December,2017.All the children were younger than 2 years.Information on sociodemographic characteristics and maternal environmental-behavioral exposure was retrospectively collected through the unified questionnaire.Meanwhile,we also observe the effect of melatonin on cell cycle in H9C2 cell.RNA-seq was conducted to detect the change of expression of mRNA and signaling pathway and Realtime-PCR was conducted to validate the results.Results(1)Maternal sleep during periconception and CHD in offspring: poor sleep could increase the risk of both simple CHD(OR=2.486,95% CI=1.619-3.818)and complex CHD(OR=1.950,95% CI=1.269-2.997),while routine daytime nap could decrease the risk of simple CHD(OR=0.634,95% CI=0.435-0.923).In the stratification and logistic regression,routine daytime nap could significantly weaken the risk of simple CHD caused by poor sleep(OR=3.183,95% CI: 1.830-5.537 decreased to OR=2.236,95% CI: 1.200-4.165).(2)Combined effects of diets/exercises and sleep on CHD: vegetable-fruit pattern,animal food pattern,aquatic product pattern could significantly weaken the risk of CHD caused by poor sleep,especially for aquatic product pattern(simple CHD: OR=4.215,95% CI=2.149-8.268 decreased to OR=2.456,95% CI=1.422-4.242;complex CHD: OR=3.633,95% CI=1.873-7.049 decreased to OR=2.037,95% CI=1.142-3.636).High sodium and high fat pattern could significantly increase the risk in simple CHD caused by poor sleep(OR=1.780,95% CI=1.002-3.162 increased to OR= 2.356,95% CI=1.162-4.776).Exercising ? 2 times/week could significantly weaken the risk of simple CHD and complex CHD(simple CHD: OR=3.306,95% CI=1.733-6.307 decreased to OR= 1.908,95% CI=1.809-3.341;complex CHD: OR=2.129,95% CI=1.136-3.922 decreased to OR= 1.429,95% CI=0.803-2.542).(3)Combined effects of stress and sleep on CHD: stressful life events could increase the risk of simple CHD and complex CHD caused by poor sleep(simple CHD: OR=2.205,95% CI=1.254-3.878 increased to OR=4.037,95% CI=2.184-7.462;complex CHD: OR=2.169,95% CI=1.242-3.787 increased to OR=2.896,95% CI=1.532-5.474).High social supports could significantly weaken the risk of simple CHD and complex CHD caused by poor sleep(simple CHD: OR=3.706,95% CI=1.859-7.387 decreased to OR=2.288,95% CI=1.371-3.820;complex CHD: OR=2.308,95% CI=1.152-4.624 decreased to OR=1.997,95% CI=1.187-3.357).(4)Studies on mechanism in vitro: treating H9C2 with 10 ?mol/l melatonin after 48 hours could make cell cycle redistribution and block the process from G1 to S phase,thus DNA synthesis and cell proliferation were inhibited.The results of RNA-seq showed that the gene Jun was the hub gene of differential genes and Hippo signaling pathway was significantly enriched(P<0.05).The results of Realtime-PCR were consistent with RNA-seq.ConclusionPoor maternal sleep around periconceptional period seems to be an independent risk factor for CHD.The possible mechanism was that poor sleep during periconceptional period could cause abnormal secretion of melatonin,which interfered with Hippo signaling pathway and the expression of Jun,then blocking cell cycle from G1 to S phase and inhibiting cell proliferation.The concurrence with daytime nap,dietary patterns that were enrich in vegetables,fruits,milk,eggs,meat and aquatic products,high social supports and exercising ? 2 times/week could to some extent reduce the risk of CHD caused by poor sleep.The concurrence with dietary patterns that were enrich in high sodium and high fat and stressful life events could further increase the risk of CHD caused by poor sleep.