Helicobacter pylori's virulence and infection persistence define pre-eclampsia complicated by fetal growth retardation

AIM: To better understand the pathogenic role of Helicobacter pylori (H. pylori) in pre-eclampsia (PE), and whether it is associated or not with fetal growth retardation (FGR). METHODS: Maternal blood samples were collected from 62 consecutive pregnant women with a diagnosis of PE and/or FGR, and from 49 women with uneventful pregnancies (controls). Serum samples were evaluated by immunoblot assay for presence of specific antibodies against H. pylori antigens [virulence: cytotoxin-associated antigen A (CagA); ureases; heat shock protein B; flagellin A; persistence: vacuolating cytotoxin A (VacA)]. Maternal complete blood count and liver enzymes levels were assessed at delivery by an automated analyzer. RESULTS: A significantly higher percentage of H. pyloriseropositive women were found among PE cases (85.7%) compared to controls (42.9%, P < 0.001). There were no differences between pregnancies complicated by FGR without maternal hypertension (46.2%) and controls. Importantly, persistent and virulent infections (VacA/ CagA seropositive patients, intermediate leukocyte blood count and aspartate aminotransferase levels) were exclusively associated with pre-eclampsia complicated by FGR, while virulent but acute infections (CagA positive/ VacA negative patients, highest leukocyte blood count and aspartate aminotransferase levels) specifically correlated with PE without FGR. CONCLUSION: Our data strongly indicate that persistent and virulent H. pylori infections cause or contribute to PE complicated by FGR, but not to PE without feto-placental compromise.

The Predictive Value of Plasma Fibronectin Concentration on Fetal Growth Retardation at Earlier Stage of the Third Trimester

In order to evaluate the predictive value of maternal plasma fibronectin (FN) concentration at 24-34 weeks on fetal intrauterine growth retardation (IUGR), a prospective double-blinded study was performed. The maternal plasma FN concentrations were measured by using a rate nephelometric procedure in the 130 initial normal nulliparous pregnant woman at 24-34 gestational weeks. The outcome of pregnancies and birth weight of their infants were followed up. IUGR was defined as that the birth weight was less than the 10th percentile for gestational age. The receiver operating characteristic curves and predictive values of FN predicting on outcome of pregnancy with IUGR were analyzed. The results showed that: (1) In a cohort of 130 initially normal nulliparous pregnant women, IUGR occurred in 14 cases during the follow-up; (2) The plasma FN levels in the women with IUGR (467.58±104.43 mg/L) were significantly higher than in the normal control group (299.44±105.55 mg/L, P<0.01). However, there was no significant difference in the mean maternal age, gravidity, sampling gestational ages, delivering gestational ages between the two groups (P>0.05); (3) The areas under ROC curve for predicting the outcome of pregnancy in IUGR was 0.893; (4) At the cut point of 475 mg/L FN level, the sensitivity, specificity, positive predictive value, negative predictive value and Kappa index for predicting the outcomes of pregnancy in IUGR were 57.14 %, 95.69 %, 61.54 %, 94.87 %, 0.5455 respectively. It was concluded that the maternal plasma FN might be used as an earlier predictor for screening of IUGR.

Perinatal Morbidity, Mortality, and Neurodevelopmental Outcomes of Neonates with Fetal Growth Restriction

Objective: This study aimed to assess perinatal morbidity, mortality rates, and neurodevelopmental outcomes in the management of fetal growth restriction (FGR) at a single tertiary institute. Methods: Among 2465 deliveries between 2013 and 2019, 109 cases of FGR were reviewed retrospectively for causes, indications for pregnancy termination, perinatal death, overall neonatal outcomes, and long-term prognosis. Results: Excluding FGR due to congenital anomalies (n = 17), the mortality rate was 3.3% (3/92). One neonate delivered at 23 weeks developed cerebral palsy (1.1%). Retinopathy of prematurity occurred in four neonates (4.3%). Neurodevelopmental disorders were present in six neonates (6.5%), all of whom were delivered at 32 - 38 weeks. Significantly lower gestational age at delivery, lower birth weight, and higher umbilical artery resistance indices were observed in neonates with neurodevelopmental disorders. Conclusions: Intact survival before 27 weeks of gestation at delivery with FGR is uncommon. Neurodevelopmental disorders may still develop after delivery at 32 - 38 weeks;consideration should be given to the timing of delivery usingfetal ductus venosus Doppler waveforms measurements to reduce neurodevelopmental disorders.

Role of intergenic interactions among folate cycle genes in the development of fetal growth retardation

Objective:Metabolic disturbances in the folate cycle in mothers can lead to fetal growth retardation(FGR).This study was to analyze the role of intergenic interactions among maternal folate cycle genes in the development of FGR.Methods:This case-control study recruited 365 women in the third trimester of pregnancy,including 122 FGR patients and 243 controls.The women were genotyped for 5 polymorphisms of the 4 folate cycle genes:MTR(rs1805087),MTRR(rs1801394),serine hydroxymethyl transferase(SHMT1;rs1979277),and TYMS(rs699517 and rs2790).The SNP×SNP interactions in the two-,three-,and four-locus models were analyzed using the multifactor dimensionality reduction method and a modification of it(the model-based multifactor dimensionality reduction method).Results:Four loci of maternal folate cycle genes(rs1805087 MTR,rs2790 TYMS,rs1801394 MTRR,and rs1979277 SHMT1)were associated with FGR in 3 significant models of single nucleotide polymorphism(SNP)×SNP interactions(two-,three-,and four-locus models)(P<0.05).The highest contribution to FGR was made by polymorphic loci rs1979277 SHMT1(1.70%of entropy),rs1805087 MTR(0.96%),and interactions between rs1979277 SHMT1×rs1805087 MTR(-1.11%)and rs1801394 MTRR×rs1979277 SHMT1(-0.64%).The four-locus maternal genotype combination AG rs1801394 MTRR×AA rs1805087 MTR×CT rs1979277 SHMT1×AG rs2790 TYMS was associated with an increased risk of FGR(β=2.69,P=0.012).FGR-associated SNPs were correlated with the expression of 16 genes(MTR,MTRR,SHMT1,ALKBH5,CTD-2303H24.2,ENOSF1,FAM106A,FOXO3B,LGALS9C,LLGL1,MIEF2,NOS2P2,RP11-806L2.6,SMCR8,TOP3A,and USP32P2)in various tissues and organs related to FGR pathophysiology.Conclusion:SNP×SNP interactions of maternal folate cycle genes(MTR,MTRR,SHMT1,and TYMS)are associated with the development of FGR.

Color Doppler Monitoring of Changes ofUtero-placental-fetal Circulation in Normal Pregnancy and Intrauterine Growth Retardation

The utero-placental-fetal circulation (UPFC) of 150 subjects duringsecond and third trimester was examined by using color DOppler. Of them 89 were normal woman and 58 were patients with intrauterine growth retardation (IUGR). Our results showed that UPFC was increased gradually during normal pregnant period. In IUGR patients it was revealed that TAV and Q of UmA,UmV and UtA decreased at 20th week of gestation, especially after 30th week.PI, RI and S/D ratio of UmA were increased, but TAV, Q of UmA and UmV were markly reduced, so was UtA. Pl were increased, but the changes of RI,S/D ratio in UtA were not significant. HemodynamicaI findings of UmA,UmV and UtA were abnormal in 92. 53 % of IUGR patients,Only 81. 03% present abnormal S/D ratio of UmA (P<0. 01) and the difference was statistically significant.Maternal serum E,, HPL level in IUGR were significantly lower than that of thenormal. 6KP level was reduced, TXB,/6KP ratio was significantly increased.TXB2/6KP ratio was markedIy related with TAV, Q of UmA, UmV and UtA.Our results suggested that using color doppler ultrasound for examination of hemodynamical changes of UmA, UmV and UtA could revealed UPFC function directly. It is one of the best methods for monitoring IUGR and might be used forearly diagnosis of IUGR. The main pathophysiological changes of IUGR were UPFC obstruction and placental disfunction.

Placental Isoferritin Action in Pathogenesis of Pre-eclampsia and/or Intrauterine Growth Retardation and Its Earlier Predictive Value

In order to investigate the role of placental isoferritin (PLF) in pathogenesis of pre-eclampsia and/or intrauterine growth retardation (IUGR) and its earlier predictive value, a prospective double-blinded study was performed. In 120 initial normal pregnant women at earlier third trimester (from 24 to 34 weeks), plasma placental isoferritin and nitric oxide (NO) metabolites (nitrite/nitrate) (NO 2 -/NO 3 -) were examined by using ELISA and Criess assay respectively. The outcome of pregnancies and birth weight of their infants were followed up. The receiver operating characteristic curves (ROC) and predictive values of PLF predicting the outcome of pregnancy with IUGR, pre-eclampsia were analyzed. Results showed that in 120 initial normal pregnant women, IUGR occurred in 15 pregnant women (IUGR group) and pre-eclampsia in 19 (pre-eclampsia group), and the remaining 86 had normal pregnancy (normal group). The levels of plasma placental isoferritin were significantly decreased in IUGR group (260.01±58.95) μg/ml and pre-eclampsia group (285.31±53.73) μg/ml as compared with those in normal group (775.62±89.32) μg/ml at earlier third trimester (both P<0.01). The levels of plasma NO were significantly increased in IUGR group (61.57±46.22) μmol/L and pre-eclampsia group (58.37±30.52) μmol/L as compared with those in the normal group (35.29±24.46) μmol/L (both P<0.01). There was no significant difference in plasma placental isoferritin and NO levels between IUGR group and pre-eclampsic group (both P>0 05). The plasma placental isoferritin was negatively correlated with NO levels (r=0.329,P<0 01). The areas under ROC of PLF predicting IUGR and pre-eclampsia were 0.977 and 0.905 respectively. At the cut point of 400 μg/ml PLF level, the sensitivity, specificity, positive predictive value, negative predictive value and Kappa index of PLF levels predicting the outcome of pregnancy with pre-eclampsia were 100 %, 85.15 %, 55.88 %, 100 % and 0.645 respectively. At the cut point of 390 μg/ml PLF level, the sensitivity, specificity, positive predictive value, negative predictive value and Kappa index of PLF levels predicting the outcome of pregnancy with IUGR were 100 %, 81.9 %, 44.12 %, 100 % and 0.663 respectively. It was concluded that the decrease of plasma placental isoferritin levels at earlier third trimester was associated with IUGR and/or pre-eclampsia, and the endothelial cell damage may be one of its mechanisms. The plasma PLF level can be used as an earlier predictor for screening of IUGR and/or pre-eclampsia.

Acupuncture on intrauterine growth restriction associated brain injury:case study including use of magnetic resonance imaging

Brain injury due to intrauterine growth restriction(IUGR) is a thorny clinical problem that often leads to permanent neurological deficits such as cerebral palsy.Few practical therapies can treat an IUGR-associated brain injury.We employed acupuncture to treat a 6-month-old male patient with severe hypoxic-ischemic encephalopathy(HIE) due to IUGR,as confirmed by magnetic resonance imaging(MRI).Three courses of acupuncture treatment significantly improved some of the patient’s clinical characteristics,such as his insensitive responsiveness and motor deficits,with remarkably reversed HIE features on MRI at 1-year of age.This case suggests that acupuncture is a potential treatment option for an IUGRassociated brain injury and warrants further investigation.

Low Expression of FGF23 and Its Effect on Rats with Intrauterine Growth Retardation

Objective:To explore the levels of fibroblast growth factor 23(FGF23)during pregnancy and its relationship with intrauterine growth restriction(IUGR).Methods:Pregnant rats were classified into an ad libitum rat chow group(ad libitum rat chow,AD group,n=25)and an undernutrition group(50%of their daily food requirement,UN group,n=25).The levels of maternal serum FGF23,tissue homogenate FGF23,and bone gla protein in fetal rats,and placental FGF23 mRNA and protein expression were examined by enzyme-linked immunosorbent assay,real-time qPCR analysis respectively.Finally,the effect of recombinant FGF23 on the viability of MG-63 cells was determined by cell proliferation assay.Data were analyzed with independent two-tailed t test and one-way analysis of variance.Spearman rank-order correlation coefficients(continuous variables)was performed to determine the relationship of results.Results:The diet restriction induced IUGR in rat offsprings,and the UN group exhibited a significantly lower FGF23 level(P<0.05,n=5).The FGF23 level was increased and peaked in maternal serum on gestation day(GD)15,but peaked in fetal and placenta on GD20.Moreover,the tissue homogenate levels of FGF23 and bone gla protein in fetal rats in both groups were positively correlated(r=0.923,P<0.05;r=0.925,P<0.05,respectively,n=15),FGF23 was localized to both decidual and labyrinth zones,with remarkably higher expression on GD20,P<0.05,n=5.In vitro,recombinant human FGF23 enhanced MG-63 cell viability,P<0.05,n=5.Conclusion:Prenatal undernutrition could decrease the FGF23 expression in fetal rats caused by the mother through the placenta,and induced the IUGR and hindered the ossification.And the FGF23 levels are peaked on GD15 mother but peaked on GD20 placenta and fetuses,these might be associated with the over compensation of maternal placenta on GD20.

Puerarin affects bone biomarkers in the serum of rats with intrauterine growth restriction

OBJECTIVE:To investigate serum bone biomarkers in rats with intrauterine growth restriction(IUGR)in order to determine the effects of puerarin on bone metabolism.METHODS:A rat model of IUGR was induced using a low protein diet during pregnancy.The offspring were given puerarin or an identical volume of saline via subcutaneous abdominal injection.All rats were studied at 1,3,and 8 weeks of age.Serum biomarkers of bone formation,including insulin-like growth factor-1(IGF-1),bone-specific alkaline phosphatase(BALP),osteocalcin(OC),osteoprotegerin(OPG),receptor-activator of nuclear factor-κB ligand(RANKL),as well as blood levels of calcium and phosphorus were measured.RESULTS:Serum BALP,OPG,IGF-1,and OC levels,as well as the OPG/RANKL ratio,were lower in the IUGR group compared with the control group at 1week of age(P=0.024,0.011,0.014,0.004,and0.002,respectively).At 3 weeks of age,the serum BALP and OC levels were higher in the protein-re-stricted group compared with the control group(P=0.003 and 0.001,respectively).A comparison between the IUGR plus puerarin intervention group and the IUGR group revealed differences in the levels of BALP and IGF-1 at 3 weeks of age(P=0.008 and 0.003,respectively).In addition,serum OPG and OC levels and the OPG/RANKL ratio were higher at 8 weeks of age(P=0.044,0.007,and0.016,respectively).No differences in serum calcium and phosphorus levels were observed among the three groups.CONCLUSION:Our study demonstrates that the bone microenvironment of the fetus can be altered by a low protein maternal diet and that puerarin can reverse these effects.These results indicate that the nutritional environment plays an important role in early skeletal development and that the bone turnover of IUGR rats can be altered by puerarin treatment.

Postnatal development of fetuses with a single umbilical artery:differences between malformed and non-malformed infants

Background:The presence of a single umbilical artery(SUA)is a fetal soft marker of congenital abnormalities.Among the most common related malformations,there are cardiological,nephrourological and digestive anomalies,most of which are considered to have a vascular etiology.There is an association between increased incidence of intrauterine growth retardation and adverse perinatal indicators,but whether this association is due to related anomalies or isolated SUA(SUA)is controvisal.Methods:We reviewed 96 cases of iSUA and non-isolated SUA(niSUA),diagnosed in a period of two years in a referral hospital for high-risk pregnancies.Data on prenatal explorations,including fetal ultrasonography and karyotyping,were obtained.niSUA was diagnosed when no malformations were found prenatally or in postnatal evaluation.Results:Sixty-six newborns(68.8%)had no other anomalies and 30(31.3%)presented with a variety of malformations including heart diseases,urophaties,digestive,nervous and musculoskeletal disorders,genetic abnormalities and complex malformations.Cardiological and nephrourological abnormalities were found to be the most frequent association with a SUA(both in 23.8%of malformed SUA newborns).Intrauterine growth restriction was not higher in iSUA newborns than in a normal population.Utrasound allowed optimal prenatal diagnosis in most cases.Conclusions:The prognosis of the fetus with a SUA is determined by the presence of other malformations observed by an expert sonographer.If no other findings are made,only a routine physical examination should be performed in newborns,but no other complementary examinations are required.

Prior Preterm Birth and Birthweight Below the 5 th Percentile are Independent Risk Factors for Recurrence of a Small for Gestational Age Neonate

Objective::This study aimed to determine:(1)whether recurrent deliveries of a small for gestational age(SGA)neonate are associated with increased obstetrical or neonatal complications;(2)whether the risk factors that can predict small for gestational age(SGA)recurrence.Methods::This study was based on Soroka Medical Center's Obstetrics electronic database.The database consisted of 109022 women who had 320932 deliveries between the year 1988-2014.The study cohort included 6.8%(7368/109022)of these patients who gave birth to a singleton SGA neonate on their first delivery and had more than one delivery.The study population was divided into two groups according to the outcome of the subsequent delivery:(1)women with sporadic SGA who delivered a non-SGA neonate(n=5416);(2)women with recurrent SGA(n=1952).SGA defined as birthweight<10 th percentile.Maternal and neonatal complications were compared between the two groups.Logistic regression was used to determine independent risk factors for SGA recurrence.Results::The prevalence of birthweight<5 th percentile was higher among the recurrent SGA group in the first delivery(P<0.001).Bedouin ethnicity was more prevalent in the recurrent SGA group(P<0.001).The rate of preterm delivery was higher in the first delivery of the recurrent SGA group(P=0.015).The sporadic SGA group had a higher rate of perinatal mortality during the first pregnancy(P=0.017).The rate of severe hypertension(P=0.005),polyhydramnios,meconium-stained amniotic fluid,nonreassuring fetal heart rate and total perinatal mortality(P<0.001)were higher in the second delivery of the recurrent SGA group.In a logistic regression model,preterm delivery and birthweight<5 th percentile at the first delivery was found to be independent risk factors for recurrence of an SGA neonate in the subsequent birth(relative risks:1.530,confidence interval:1.249-1.875;relative risks:1.826,confidence interval:1.641-2.030,respectively).Conclusion::Women with recurrent SGA neonates have specific clinical characteristics.Among women who deliver an SGA neonate,preterm delivery,and birthweight<5 th percentile are independent predictors for its recurrence.