Intrauterine hypoxia is the most frequent adverse intrauterine condition that occurs under a variety of circumstances including preeclampsia, placental insufficiency, high-altitude pregnancy, and any inflammatory condition during pregnancy resulting from gestational diabetes or even maternal obesity. However, early diagnosis of intrauterine hypoxia is still a challenge. In this study, we comparatively analyzed the systolic to diastolic ratio (S/D), resistant index (RI), and pulse index (PI) of the umbilical artery (UmA) and middle cerebral artery (MCA) blood flows obtained from 46 pregnant women with intrauterine hypoxia and 80 normal pregnant women at 28-31, 32-36, and 37-41 gestational weeks. Results found that the S/D, RI, and PI of UmA and MCA blood flows at 28-31, 32-36, and 37-41 gestational weeks were all increased in hypoxic fetuses than in normal fetuses (
There has been an increasing death rate of children younger than 5 years occurring in the neonatal period (aged 0-28 days), which has resulted in much attention to neonatal mortality worldwide. The common causes of neonatal mortality refer to intrapartum-related factors such as hypoxic ischemic encephalopathy, preterm birth complications, infections including sepsis, meningitis, and neonatal tetanus, and other conditions including jaundice and congenital infections. Intrauterine hypoxia is the most frequent adverse intrauterine condition that occurs under a variety of circumstances including preeclampsia, placental insufficiency, high-altitude pregnancy, and any inflammatory condition during pregnancy resulting from gestational diabetes or even maternal obesity [
The umbilical cord is a nutrition exchange channel between the fetus and the mother. Evaluation of its blood flow can predict the state of fetal intrauterine hypoxia and the severity of the disease. At present, there is no gold standard for the diagnosis of fetal intrauterine hypoxia. In clinical practice, comprehensive judgment is usually made through a variety of methods, such as fetal heart rate monitoring and fetal movement count, but the accuracy is limited. Although the pathogenesis of intrauterine hypoxia remains unclear and thus management and treatment are limited, it has been reported that fetoplacental blood vessels are compromised upon intrauterine hypoxia. Doppler ultrasound can detect the hemodynamic changes of umbilical artery (UA) and middle cerebral artery (MCA) to judge the abnormal situation of fetal organs, which is the main examination method for clinical noninvasive, timely, and accurate diagnosis of fetal intrauterine hypoxia. The resistance index (RI) and pulsation index (PI) of the fetal arterial blood flow impedance were measured, the peak systolic velocity of the diastolic velocity ratio (S/D) can fully reflect the peripheral circulation impedance and blood perfusion of the supplied vessels. Severe reduction in UmA blood flow as reflected by the absent or reverse end diastolic velocity during pregnancy is related to fetal morbidity and mortality, and early delivery should be contemplated to prevent intrauterine hypoxia-induced disorders [
This retrospective study included 46 pregnant women with intrauterine hypoxia and 80 normal pregnant women who delivered their babies in our hospital from January 2019 to January 2020. The Apgar scores of newborns delivered by normal pregnant women were 8-10 one minute after birth, and those of newborns delivered by pregnant women with intrauterine hypoxia were 0-7. At the same time, the blood gas analysis of the cord blood was carried out immediately after delivery. Fetal intrauterine hypoxia was diagnosed according to the pH value of UmA
The pregnant women with intrauterine hypoxia had age ranging from 33 to 39 years, with an average age of
The normal pregnant women had age ranging from 34 to 39 years, with an average age of
Pregnant women complicated with malignant tumor, severe metabolic diseases, gestational diabetes mellitus and hypertension, fetal congenital malformations, and incomplete clinical data were excluded out of the study.
The pregnant women held their breath, and the fetus was in quiescent condition. Color Doppler Ultrasound (Voluson730, GE Company, USA) was employed to evaluate the systolic to diastolic ratio (S/D), resistant index (RI), and pulse index (PI) of UmA and MCA blood flows at 28-31, 32-36, and 37-41 gestational weeks, with the frequency set at 3.0-4.0 MHz. Each parameter was tested in triplicates to obtain the average. Ultrasound evaluation of UmA and MCA blood flows was evaluated by experienced doctors for many years.
The UmA blood was collected immediately from after delivery and stored in 2-8°C. After centrifugation at 3500 r/min for 10 min, the upper serum was extracted. The malondialdehyde (MDA) level and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities were measured in the serum by immunoradiometric assays using commercial available kits (Diagnostic Products Corp., Los Angeles, Calif., USA) according to the instructions provided by the manufacture. The activities of NADPH oxidase 2 (Nox2) and NADPH oxidase 4 (Nox4) were measured by enzyme-linked immunosorbent assay (ELISA) according to kit’s instructions (R&D, Minneapolis, MN, USA). The fresh placental tissues were obtained within 30 min after delivery and then rinsed with normal saline followed by removal of calcified tissues and large vessels. The expression level of survivin protein was examined by ELISA according to kit’s instructions (Abcam, Cambridge, UK) and caspase-3, caspase-6, and caspase-9 proteins according to kit’s instructions (R&D, USA). The concentrations of erythropoietin in the UmA blood and amniotic fluid were measured by ELISA using a commercial available kit (R&D, USA).
SPSS 21.0 software (IBM, USA) was employed for data analysis. The measurement data were expressed as the
This retrospective study included 46 pregnant women with intrauterine hypoxia and 80 normal pregnant women. The two groups of pregnant women did not differ in terms of age, gestational age at delivery, BMI, gravidities, and abortion histories (
The S/D, RI, and PI of UmA and MCA blood flows in normal and hypoxic fetuses at 28-31 gestational weeks.
Group | UmA | MCA | |||||
---|---|---|---|---|---|---|---|
S/D | RI | PI | S/D | RI | PI | ||
Normal | 80 | ||||||
Hypoxic | 46 | ||||||
8.81 | 6.44 | 8.44 | 12.37 | 14.86 | 15.94 | ||
<0.001 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 |
Note: UmA: umbilical artery; MCA: middle cerebral artery; S/D: systolic to diastolic ratio; RI: resistant index; PI: pulse index.
The S/D, RI, and PI of UmA and MCA blood flows in normal and hypoxic fetuses at 32-36 gestational weeks.
Group | N | UmA | MCA | ||||
---|---|---|---|---|---|---|---|
S/D | RI | PI | S/D | RI | PI | ||
Normal | 80 | ||||||
Hypoxic | 46 | ||||||
13.31 | 11.46 | 13.38 | 8.29 | 12.04 | 10.32 | ||
<0.001 | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 |
Note: UmA: umbilical artery; MCA: middle cerebral artery; S/D: systolic to diastolic ratio; RI: resistant index; PI: pulse index.
The S/D, RI, and PI of UmA and MCA blood flows in normal and hypoxic fetuses at 37-41 gestational weeks.
Group | N | UA | MCA | ||||
---|---|---|---|---|---|---|---|
S/D | RI | PI | S/D | RI | PI | ||
Normal | 80 | ||||||
Hypoxic | 46 | ||||||
16.46 | 30.26 | 6.64 | 4.22 | 13.54 | 2.192 | ||
<0.001 | <0.001 | <0.001 | <0.001 | <0.001 | 0.03 |
Note: UmA: umbilical artery; MCA: middle cerebral artery; S/D: systolic to diastolic ratio; RI: resistant index; PI: pulse index.
Oxidative stress plays a crucial role in the pathogenesis of diseases related to hypoxia during intrauterine development and postnatal life, which is usually evaluated by expression levels of MDA, SOD, GSH-Px, and CAT. As shown in Figure
The levels of MDA, SOD, GSH-Px, CAT, Nox2, and Nox4 in the UmA blood between pregnant women with intrauterine hypoxia (
The levels of MDA, SOD, GSH-Px, CAT, Nox2, and Nox4 in the UmA blood between pregnant women with intrauterine hypoxia and normal pregnant women.
Marker | Normal ( | Hypoxic ( | ||
---|---|---|---|---|
MDA (U/L) | 22.73 | <0.001 | ||
SOD (U/L) | 11.62 | <0.001 | ||
GSH-Px (U/L) | 68.08 | <0.001 | ||
CAT (U/L) | 9.338 | <0.001 | ||
Nox2 (pg/mL) | 23.19 | <0.001 | ||
Nox4 (pg/mL) | 13.90 | <0.001 |
Note: MDA: malondialdehyde; SOD: superoxide dismutase; GSH-Px: glutathione peroxidase; CAT: catalase; Nox2: NADPH oxidase 2; Nox4: NADPH oxidase 4.
Survivin and caspase are two common apoptotic factors, both of which have been recently reported to be associated with oxidative stress. We collected placental tissues from pregnant women within 30 min after delivery. Results of ELISA methods showed that the expression level of survivin was lower but the expression levels of caspase-3, caspase-6, and caspase-9 were higher in the placental tissues of pregnant women with intrauterine hypoxia than those in normal pregnant women (
The expression levels of survivin, caspase-3, caspase-6, and caspase-9 in the placental tissues between pregnant women with intrauterine hypoxia (
In adults and fetuses, erythropoietin is a glycoprotein that regulates erythropoiesis. Its production is mainly stimulated and regulated by tissue hypoxia. Chronic intrauterine hypoxia caused by various stimuli can cause the increase of erythropoietin. It was found by ELISA methods that the concentrations of erythropoietin in the amniotic fluid and UmA blood were increased in pregnant women with intrauterine hypoxia compared with normal pregnant women (
The concentrations of erythropoietin in the amniotic fluid and UmA blood between pregnant women with intrauterine hypoxia (
We studied the correlation between ultrasound parameters of UmA blood flow and oxidative stress in intrauterine hypoxia. It was found that the S/D, RI, and PI of UmA blood flow at 37-41 gestational weeks were positively correlated with the levels of Nox2, Nox4, and MAD and the UmA concentration of erythropoietin but negatively correlated with the activities of SOD, GSH-Px, and CAT
Spearman correlation between ultrasound parameters of UmA blood flow at 37-41 gestational weeks, serum markers of oxidative stress, and concentrations of UmA erythropoietin in intrauterine hypoxia.
Index | S/D | PI | RI | |||
---|---|---|---|---|---|---|
Nox2 | 0.512 | <0.05 | 0.385 | <0.05 | 0.441 | <0.05 |
Nox4 | 0.667 | <0.05 | 0.424 | <0.05 | 0.475 | <0.05 |
CAT | -0.395 | <0.05 | -0.411 | <0.05 | -0.482 | <0.05 |
SOD | -0.221 | <0.05 | -0.377 | <0.05 | -0.398 | <0.05 |
MDA | 0.349 | <0.05 | 0.386 | <0.05 | 0.452 | <0.05 |
GSH-Px | -0.429 | <0.05 | -0.399 | <0.05 | -0.469 | <0.05 |
Erythropoietin | 0.471 | <0.05 | 0.714 | <0.05 | 0.689 | <0.05 |
S/D: systolic to diastolic ratio; RI: resistant index; PI: pulse index; MDA: malondialdehyde; SOD: superoxide dismutase; GSH-Px: glutathione peroxidase; CAT: catalase; Nox2: NADPH oxidase 2; Nox4: NADPH oxidase 4.
Intrauterine hypoxia can induce oxidative stress, which is not conducive to the growth and development of the fetus [
The UmA is the channel of material exchange between the fetus and the mother. The detection of UmA ultrasound parameters may have a reference value for prediction of fetal status [
The Nox protein family, CAT, SOD, and MDA are the main members involved in oxidative stress [
Hypoxia is commonly assigned a role in the placental dysfunction characteristic of preeclampsia and intrauterine growth restriction. Preeclampsia and intrauterine growth restriction are associated with increased apoptosis of placental villous trophoblast [
Previous evidence showed that erythropoietin production is mainly stimulated and regulated by tissue hypoxia. Although the fetal kidneys are the main site of erythropoietin generation under basal conditions, recent experimental data indicate that the placenta is also an important site of erythropoietin generation in the circumstances of hypoxia [
These findings obtained from the present study support the notion that ultrasound parameters of UmA blood flow including S/D, RI, and PI could serve as predictors of intrauterine hypoxia. In the future research, we will further work from the following aspects: increasing the sample size of the study and using multicenter comparative study and exploring the correlation between ultrasound parameters of UmA and MCA blood flows and blood gas.
The data used to support the findings of this study are included within the article.
All authors declare that they have no conflict of interest.
Jiewen Tao and JingWang contributed to the work equally and should be regarded as co-first authors.