| Part 1 Catch-up growth of small for gestational age and its influencing factorsObjective:To explore characteristics and related influencing factors of the catch-up growth of small for gestational age(SGA)infants in Langfang in two years after birth.Methods:Infants born in the Langfang Women and Children's Health,Hebei province between January 2012 and January 2013 were enrolled in this retrospective cohort study,who were divided into SGA group,appropriate for gestational age(AGA)group and large for gestational age(LGA)group according to birth weight.Data information about infants and mothers were collected.Statistical analysis was performed to explore characteristics and related influencing factors of the catch-up growth of SGA infants.Results:A total of 661(8.3%)cases of SGA,6,571(82.5%)cases of AGA and 729(9.2%)cases of LGA were enrolled in this study.The rate of short stature at 2 years old was 0.9%in the SGA group,which was similar to that of AGA(0.6%)and LGA(0.3%).At 6 months after birth,the growth rate of body length in the SGA group was 36.17±4.79 cm/year,which was dropped to 17.46±3.53 cm/year at 12 months after birth,significantly higher than those in the AGA group(P<0.001)and LGA group(P<0.001).At 18 months and 24 months after birth,there was no significant difference in the growth rate of body length among the three groups.Correlation analysis sh owed that the growth rate of body length within 1 year of SGA was negatively correlated with birth weight,birth body length,and Apgar score.It was positively correlated with the placental weight(r=0.116,P=0.044)but negatively correlated with fetal/placental weight ratio(F/P)(r=-0.216,P<0.001).Conclusion:Six hundred and fifty-five out of 661(99.1%)SGA infants completed catch-up growth at the age of 2,which mainly occurred within 1 year after birth.The catch-up gowrth of SGA was affected by several factors including birth length,birth weight,and Apgar score.Moreover,catch-up growth was positively correlated with placental weight but negatively correlated with F/P ratio,suggesting that inappropriately heavy placenta was not only involved in the occurrence of SGA but also might be related to the long-term prognosis of SGA,which needed further study.Part 2 Efficacy of growth hormone treatment in small for gestational age and the correlation between growth hormone provocation tests and treatment responseObjective:To retrospectively analyze the effect of recombinant human growth hormone(rhGH)in small for gestational age,and to analyze the results of growth hormone provocation tests and its relationship with the response to rhGH in short stature.Methods:Forty-five cases of SGA,36 cases of isolated growth hormone deficiency(IGHD)and 24 cases of idiopathic short stature(ISS)were enrolled in this retrospective study.Clinical data were collected to analyze the growth of height and weight after rhGH treatment.Patients were divided into the GHD group and the non-GHD group according to the GH provocation tests,and the correlation between GH provocation tests and treatment response was analyzed.Results:(1)The age of starting rhGH treatment in SGA group was 7.6±2.9 years,and the bone age was 5.0±2.9 years,which were lower than those of IGHD group,but similar to those of ISS group.Before rhGH treatment,the height SDS of SGA was-2.7±1.0,which was similar to those of IGHD and ISS patients.(2)The growth rate of height in the three groups increased significantly after rhGH treatment.After six months of treatment,the height SDS of SGA,IGHD and ISS were significantly higher than those before treatment(P<0.05).(3)Sixty-nine short stature patients completed GH provocation tests.Nine patients were SGA,three of who were combined with GHD.Correlation analysis showed that growth rate in the first year of treatment in the GHD group was negatively correlated with the peak value and AUC of GH provocation tests,while this was not found in non-GHD group.(4)The weight SDS of SGA at the third month of rhGH treatment was-1.5±0.9,which was significantly higher than that before treatment(-1.8±0.9),P=0.014.However,no significant differences were noted in BMI or BMI SDS of SGA group during rhGH treatment.Conclusions:The height SDS of SGA children was significantly improved after rhGH treatment.Some SGA patients might be combined with GHD,and GH provocation test could be helpful for screening GHD.The results of provocation tests could predict the therapeutic effect of rhGH in GHD children.The body weight of SGA children increased significantly during rhGH treatment.The long-term metabolic implications of GH treatment in SGA and specific physiological regulation mechanism need to be further studied.Part 3 The implications on serum metabolomics and gut microbiome of growth hormone treatment in small for gestational ageObjectiveTo study the effects of growth hormone(GH)treatment on metabolism and gut microbiome in SGA and GHD patients,and to explore the role of the gut microbiome in metabolic regulation in SGA and GHD patients during GH treatment.MethodsThis study was a prospective observational study that enrolled 12 short stature patients,including 8 cases of SGA and 4 cases of GHD.Patients were followed up once every 3 months until the sixth month of growth hormone treatment.Height,weight,laboratory examinations and other clinical data,serum samples and stool samples were collected before and during treatment.Serum samples were used for metabolomics analysis by UPLC-MS/MS,and gut microbiome was sequenced using 16sDNA sequencing technology.Results(1)The weight of SGA and GHD patients increased after GH treatment,and the weight SDS was-2.52(-3.25,-1.53),-1.42(-1.86,-0.79)and-1.52(-1.88,-0.85),respectively,before treatment,at the third month and the sixth month,P<0.01.But no significant difference was noted in BMI and BMI SDS before and during treatment.(2)The levels of fasting insulin,HOMA-IR and HbA1c were significantly higher at the third month of treatment than before treatment.Lipoprotein(a)was significantly increased in the third month,and decreased in the sixth month,but still significantly higher than before treatment The concentration of free fatty acid(FFA)showed a upward trend.At the sixth month,HDL-C was significantly lower than that before treatment.No significant difference was noted in TC,TQ and LDL-C before and during the treatment of rhGH.(3)Although no statistical difference was noted in serum metabolites after 3 months of GH treatment,in the sixth month,the intensity of five dipeptides significantly increased,including prolyl-hydroxyproline and isoleucyl-hydroxyproline.Meanwhile,the intensity of 7 kinds of fatty and fatty acyls significantly reduced,including arachidonic acid metabolites prostaglandin D2(PGD2)and 8-isoprostaglandin E1(8-iso-PGE1).Moreover,the intensity of other 14 kinds of metabolites such as estradiol-17alpha 3-D-glucuronoside also decreased significantly.(4)Before and in the sixth month of GH treatment,the gut microbiome of SGA and GHD children were mainly composed of g_Firmicutes,g_Bacteroidetes,g Proteobacteria,and g Actinobacteria,and the Firmicutes/Bacteroidetes ratio were 1.51,1.40 and 1.28,respectively,before treatment,in the third month and the sixth month.No significant difference was noted in Alpha diversity before and after GH treatment,but there was a significant difference in Beta diversity in the sixth month compared with that before treatment.T-test showed that there were 52 OTUs in level of genus with significant changes in the sixth month of treatment compared with before treatment,including 24 genara of p Firmicutes,3 genara of g Bacteroidetes,12 genara of p_Proteobacteria,and 9 genara of g_Actinobacteria.LEfSe results showed that after GH treatment for 6 months,10 OTUs including g_Hungatella increased significantly,and 40 OTUs including g Blautia and g_Anaerostipes decreased significantly.(5)g_Blautia in the p Firmicutes decreased gradually during GH treatment,with an average rate of 6.8%before treatment,5.6%in the third month and 3.2%in the sixth month.Spearman correlation analysis showed that the changes of HbA1C and FFA were negatively correlated with the change of g_Blautia,and the change of FFA was still negatively correlated with the change of g Blautia after adjusting for IGF-1,r=-0.892,P=0.042.ConclusionsSix months after the treatment of GH in SGA and GHD children,significant changes in carbohydrate,lipid and protein metabolism occurred.A variety of lipid and lipid-like metabolites were significantly reduced,including arachidonic acid metabolites PGD2 and 8-iso-PGE1.Five dipeptide metabolites including prolyl-hydroxyproline and isoleucyl-hydroxyproline were significantly increased.After GH treatment for 6 months,there was no significant change in Alpha diversity index of gut microbiome,but there was a significant difference in Beta diversity index.The change of FFA was negatively correlated with that of g Blautia. |
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