Intrauterine Fetal Growth Retardation Research Articles

Mechanisms of pregnancy loss in antiphospholipid syndrome.

Antiphospholipid antibodies are associated with intrauterine fetal growth retardation and fetal distress leading to premature birth or fetal death. These complications are caused by uteroplacental insufficiency that is the result of multiple placental thromboses, infarcts, and spiral artery vasculopathy, which are almost certainly provoked by the hypercoagulable state induced by aPL antibodies. Available data indicate that the thrombogenic function of aPL antibodies involves their general effect on platelets, endothelial cells, anticoagulant mechanisms, and fibrinolytic pathways, as well as their local effect on trophoblasts and villi cells, leading to reduction of annexin V (placental anticoagulant protein-I) production and inhibition of its anticoagulant function.

Pregnancy in Women with Epilepsy

The aim of this study was to analyze the outcome of pregnancy and delivery in epileptic women. A retrospective review of the 41 pregnant women with epilepsy who delivered in the Department of Obstetrics and Perinatology of the University School of Medicine in Lublin over 7 years (1993–1999) was carried out. Women with epilepsy had more pregnancy complications including premature labor, anemia, hypertension, vaginal bleeding, urinary tract infection, nausea and vomiting. An increased risk of congenital malformations and intrauterine fetal growth retardation was observed. Women with epilepsy require more extensive pregnancy planning including neurologic and preconceptional care.

Prediction of the development of pregnancy-induced hypertensive disorders in high-risk pregnant women by artificial neural networks.

Pregnancy-induced hypertensive disorders (PIHD) are common complications of pregnancy and are associated with increased maternal and fetal morbidity. In this study, artificial neural networks (aNN) and multivariate logistic regression (MLR) were applied to a set of clinical and laboratory data (urea, creatinine, uric acid, total proteins, hematocrit, iron and ferritin) collected at 16 and 20 weeks of gestation. The efficacy of the two approaches in predicting the development of PIHD in 303 consecutive normotensive pregnant women at high risk of pre-eclampsia and intrauterine fetal growth retardation was then compared. The aNN were trained with a randomly selected set of 187 patient records and evaluated on the remainder (n=116). MLR analysis was done with the same 116 patients. The performance of each model was assessed using receiver operator characteristic (ROC) curves. Pregnancies had a normal physiological course in 227 cases, whereas 76 (25.1%) women developed PIHD during the third trimester. The best aNN at 20 weeks yielded an area under the ROC curve of 0.952, the sensitivity of 86.2%, the specificity of 95.4%, the positive predictive value of 86.2% and the negative predictive value of 95.5% for PIHD. The corresponding values for the MLR at 20 weeks were 0.962, 79.3%, 97.7%, 92% and 93.4%, respectively. The computer-aided integrated use of these conventional tests seems to provide a useful means for and early prediction of PIHD development.

Expression of insulin-like growth factor in the placenta of intrauterine growth-retarded human fetuses

Many cases of intrauterine growth retardation (IUGR) are the result of placental and fetal tissue insufficiency. Insulin-like growth factor-I (IGF-I) is known to play a role in placental and fetal growth. An immunocytochemical study was performed to localize IGF-I peptides in human placenta and umbilical cords of normal (n = 3) and IUGR (n = 3) fetuses. The peripartum fetal conditions were evaluated as well. Immunoreactive IGF-I was detected in the cytotrophoblast, syncytiotrophoblast, amnion, endothelial cells of fetal capillaries and in the decidua in both normal and IUGR placental tissue. A more robust immunostaining and increased numbers of positively stained cells were found in the decidua of IUGR placenta (p < 0.001). Intense immunostaining was also found in endothelial cells, smooth muscle cells and fibroblasts of the umbilical vein. IGF-I immunoreactivity was also present in stroma (Hofbauer cells and/or fibroblasts) of IUGR villi. Our results indicate that expression of IGF-I is high in specific sites in placenta and umbilical cords, which indicates a paracrine and/or endocrine function. The increased expression of IGF-I in placenta of IUGR fetuses indicates its involvement in restoring normal growth by means of a positive feed-back mechanism.

Correlation of Confined Placental Mosaicism with Fetal Intrauterine Growth Retardation

Objective: Our purpose was to determine if the frequency of confined placental mosaicism in newborns with unexplained intrauterine growth retardation (IUGR) was higher compared with infants with appropriate growth in utero and the outcome of these pregnancies. Study Design: A total of 20 cases with unexplained IUGR and 20 cases with appropriate growth for gestational age has been studied. Amnion, chorion and villi biopsy specimens were obtained from growth-retarded cases and controls at delivery. Cord blood specimens for 48-hour lymphocyte cultures were obtained from all infants with IUGR. Results: Karyotype analysis revealed confined placental mosaicism in two of 20 (10%) cases with IUGR. In one growth retarded case and one appropriate growth for gestational age case, mosaicism was also confirmed in the amnion. Cytogenetic analysis from peripheral blood of newborns showed normal karyotype in all cases. Three pregnancies in the group of fetuses with IUGR (15%) ended with fetal death compared with normal fetal surveillance of all cases from the control group. Conclusion: Confined placental mosaicism was detected two times more frequently from placentas of growth- retarded infants compared with those of newborns with appropriate growth. The fetal loss was significantly higher in the group of cases with IUGR compared with the control group.

WS15‐05Fetal venous Doppler: is it helpful in timing of delivery of hypoxic fetus?

BackgroundThe aim of this study was to investigate the potential of fetal venous Doppler in detection of fetal hypoxia and timing of the delivery.MethodsThe study group consisted of patients with increased risk for developing fetal hypoxia. These were patients with diagnosed fetal intrauterine growth retardation (IUGR) and patients with pregnancy induced hypertension (PIH), or a combination of both problems. All patients had Doppler assessment of fetal arterial (umbilical artery, aorta, middle cerebral artery) and venous circulation (ductus venosus and umbilical vein), and cardiotocography 24 h before delivery. Collection of postnatal data included pH of umbilical chord blood, admission in neonatal intensive care unit, and perinatal death.ResultsA total of 360 patients were included in the study (IUGR 48%, PIH 20%, IUGR + PIH 32%). Deterioration in fetal venous return developed after fetal arterial circulation had been severely compromised. The decrease in end‐diastolic flow in ductus venosus anticipated development of umbilical vein pulsatile flow. Patients with pulsations in umbilical vein blood flow had high incidence of perinatal acidosis, morbidity, and mortality.ConclusionDelivery should be performed before umbilical vein pulsations develop. Careful monitoring of ductus venosus blood flow is helpful predictor of this event.

Recurrent spontaneous abortion and intrauterine fetal growth retardation as symptoms of coeliac disease

Women having recurrent miscarriages or intrauterine growth retardation could have subclinical coeliac disease, which can be detected by serological screening tests.

Clinical study on effect of Chinese herbal medicine for supplementing kidney and Qi and activating blood circulation in treating intrauterine growth retardation of fetus

To explore the therapeutic effect and its possible mechanism on using Chinese herbal medicine (CHM) for supplementing Kidney and Qi, and activating blood circulation in treating intrauterine growth retardation of fetus (IUGR). Fifty-five cases of IUGR were observed, 30 of them were treated with CHM and 25 treated with amino acid for control. The neonatal birth weight in the CHM group was markedly greater than that in the control group. Not only the maternal fundal height and abdominal circumference, but also the fetal growth parameters, including biparietal diameter, head circumference, abdominal circumference, femur length in the CHM group increased much faster than those in the control group. After CHM treatment, the maternal serum levels of estriol (E3) and human placental lactogen (hPL) were close to the normal pregnancy group, but the levels in the control group were significantly different from the normal range. The umbilical venous plasma concentration of essential amino acids was markedly improved after treatment, however, the improvement in the CHM group was more significant than that in the control group. No adverse effect of CHM was found both in mother and fetus. CHM for supplementing Kidney and Qi, and activating blood circulation was more effective in the improvement of placental function and amino acid transportation than those of amino acid.

High prevalence of subclinical celiac disease among recurrent spontaneous abortion and intrauterine fetal growth retardation

High prevalence of subclinical celiac disease among recurrent spontaneous abortion and intrauterine fetal growth retardation

Association between Helicobacter pylori infection and fetal intrauterine growth retardation (IUGR)

Association between Helicobacter pylori infection and fetal intrauterine growth retardation (IUGR)

Fetal heart rate in relation to its variation in normal and growth retarded fetuses

Objectives: (1) to assess the relationship of basal fetal heart rate (FHR) with both long term (LTV) and short term (STV) FHR variation in low-risk pregnancies, longitudinally from 24 weeks gestation onwards and (2) to investigate the relationship of FHR with LTV and STV in intrauterine growth retarded (IUGR) fetuses. Study design: Computerised FHR recordings were made in twenty-nine uncomplicated pregnancies ( n=224) and in twenty-seven IUGR fetuses who were selected retrospectively from three databases ( n=135). Nomograms of FHR variation with FHR and GA were constructed using multilevel analysis. Results and conclusions: There was a strong negative relationship of FHR with both LTV and STV in the control group ( R 2=53% and 52%, respectively). In the IUGR fetuses, FHR was generally higher than in normal fetuses whereas LTV and STV were lower. The relationship of FHR with LTV and STV in the IUGR group was less strong (for both: R 2=18%). Correction of FHR variation for basal FHR in the IUGR fetuses only resulted in a slight reduction in the number of recordings with a variation below the normal range. As it does not improve the recognition of fetuses being considered at the highest risk, such a correction of FHR variation for basal FHR is therefore not necessary. Intrafetal consistency, known to be present in healthy fetuses, was also present in the IUGR fetuses with a low FHR variation.

Effect of Steroids on Arterial Doppler in Intrauterine Growth Retardation Fetuses

Background: Antenatal steroid administration decreases fetal mortality and morbidity in preterm neonates. However, maternal steroids administration can cause a transient reduction in fetal heart rate variability and can also alter biophysical profile parameters. Other methods to assess fetal well-being in high-risk fetuses are therefore needed, when steroids are given in high-risk pregnancies. Objective: To study the effect of betamethasone and dexamethasone on placental and fetal arterial circulation in 40 growth-retarded fetuses. Methods: Forty fetuses with intrauterine growth retardation were exposed in utero to a single course of betamethasone (n = 25) or dexamethasone (n = 15). Blood flow waveforms were recorded from uterine arteries, umbilical arteries, descending aorta and middle cerebral arteries and analyzed prospectively. Doppler recordings were compared before (baseline), during (24–48 h) and after treatment (4–7 days). Results: No significant changes were found in the pulsatility indices (PI) in any of these vessels during the course and after the treatment was stopped. However, the PI in the middle cerebral arteries showed a trend to decrease 24–48 h and 4–7 days after steroids were given to the mother when compared to pretreatment values. Conclusion: Since antenatal steroids do not seem to affect Doppler measurements, they might be useful to assess well-being in high-risk fetuses during the course. It might allow to differentiate transient iatrogenic changes in fetal heart rate variability from the effect of hypoxemia.

Effect of SOD-Mimetic Fe-Chlorine e6-Na on the Level of Brain Lipid Peroxide of Rat Fetal Brains Exposed to Reactive Oxygen Species Leading to Intrauterine Growth Retardation

The influence of oxidative stress in rat brain and liver on intrauterine growth retardation (IUGR) in rat fetuses was examined. Twenty pregnant Wistar rats were used. On the 15th day of pregnancy, uterine artery and vein were ligated bilaterally using a modified Wigglesworth method. On the 21st day of pregnancy, the fetuses were delivered by hysterotomy. Fetal blood was collected by cardiac puncture. Fetal brain and liver were removed for the analysis of lipid peroxide. Sham surgical operations were performed in the control rats. Within the ligated group, a superoxide dismutase mimicking substance, Fe-chlorine e6-Na (FeCNa), was injected intraperitoneally once a day from day 15 of gestation to day 20. Fetal blood, brain, and liver were stored at –70°C until analysis. Control rats received an equivalent volume of saline. In growth-retarded fetuses, both superoxide released from erythrocytes and brain lipid peroxide showed significantly higher levels, but not superoxide dismutase in erythrocytes and liver lipid peroxide. These changes were alleviated by injection of superoxide dismutase-mimicking substance, FeCNa. Rat fetuses with intrauterine growth retardation suffered from a significant oxidative stress in utero. The increase in reactive oxygen species was alleviated by an injection of FeCNa.

Correlation of maternal and pup NK-like activity and TNF responses against cytomegalovirus to pregnancy outcome in inbred guinea pigs

Immunologic causes for poor outcome of pregnancy complicated by primary cytomegalovirus (CMV) infection are only partially understood. Maternal and pup tumor necrosis factor (TNF) and natural killer cell (NK)-like activity associated with primary gestational CMV infection initiated in either the first or third trimester equivalent in the inbred guinea pig model were investigated. Poor pregnancy outcome defined as fetal resorptions, premature delivery, stillbirths, and intrauterine growth retardation occurred with infection at either gestational time. Induction of TNF and NK activity by CMV infection during pregnancy correlated with resorptions in early pregnancy infection and with premature labor in late pregnancy infection. Stillbirths occurred with CMV infection at either time. Regardless of the gestational time of CMV acquisition, poor outcome correlated with higher maternal NK and TNF responses during the first weeks after maternal virus acquisition. Furthermore, CMV infected dams with loss of >/= 50% of conceptus had higher TNF responses than infected dams with < 50% conceptus loss. Likewise, pups born in litters from CMV-infected dams with resorptions and/or premature labor also had enhanced NK activity and TNF response to CMV compared with pups born to dams not having resorptions or premature labor. TNF responses in the delivered pups of infected dams were higher than from pups of uninfected dams regardless of litter outcome, whereas pup NK responses were enhanced only in pups from litters of dams with premature labor or resorptions. Enhanced NK and TNF activity appear to be associated with premature delivery and other poor outcomes of pregnancy.

Correlation of maternal and pup NK-like activity and TNF responses against cytomegalovirus to pregnancy outcome in inbred guinea pigsPresented in part at the 33rd Infectious Diseases Society of America Meeting, San Francisco, CA, September 1995

Immunologic causes for poor outcome of pregnancy complicated by primary cytomegalovirus (CMV) infection are only partially understood. Maternal and pup tumor necrosis factor (TNF) and natural killer cell (NK)-like activity associated with primary gestational CMV infection initiated in either the first or third trimester equivalent in the inbred guinea pig model were investigated. Poor pregnancy outcome defined as fetal resorptions, premature delivery, stillbirths, and intrauterine growth retardation occurred with infection at either gestational time. Induction of TNF and NK activity by CMV infection during pregnancy correlated with resorptions in early pregnancy infection and with premature labor in late pregnancy infection. Stillbirths occurred with CMV infection at either time. Regardless of the gestational time of CMV acquisition, poor outcome correlated with higher maternal NK and TNF responses during the first weeks after maternal virus acquisition. Furthermore, CMV infected dams with loss of ≥ 50% of conceptus had higher TNF responses than infected dams with < 50% conceptus loss. Likewise, pups born in litters from CMV-infected dams with resorptions and/or premature labor also had enhanced NK activity and TNF response to CMV compared with pups born to dams not having resorptions or premature labor. TNF responses in the delivered pups of infected dams were higher than from pups of uninfected dams regardless of litter outcome, whereas pup NK responses were enhanced only in pups from litters of dams with premature labor or resorptions. Enhanced NK and TNF activity appear to be associated with premature delivery and other poor outcomes of pregnancy. J. Med. Virol. 60:230–236, 2000. © 2000 Wiley-Liss, Inc.

Uteroplacental hemostasis in intrauterine fetal growth retardation.

During pregnancy, extensive hemostatic changes occur in the uteroplacental circulation. Invading endovascular trophoblast cells induce physiological adaptations of uterine spiral arteries, required to accommodate the increased maternal blood flow to the intervillous space of the placenta as pregnancy advances. Much of the vascular endothelium and the underlying medial smooth muscle is replaced by trophoblasts, and fibrin or fibrinoid forms a major morphological feature of the arterial walls. Compared with endothelial cells, the trophoblast lining decidual spiral arteries have a reduced capacity to lyse fibrin, and recent studies have shown this to be caused by high levels of plasminogen activator inhibitors (PAI-1 and PAI-2). In pregnancies complicated by intrauterine fetal growth retardation (IUGR), with or without superimposed preeclampsia, a restricted physiological adaptation of uteroplacental spiral arteries is coupled with vascular lesions containing increased fibrin deposition. Significantly higher levels of PAI-1 are found in blood from the uterine vein at delivery and in tissue extracts of the placenta in these pregnancies than are found in normal pregnancy. Recent tissue culture studies have provided new information on the role of trophoblast cells in maintaining hemostatic control in the uteroplacental circulation in pregnancy. Cytotrophoblast cells isolated from the placenta and placental bed from IUGR pregnancies express significantly higher levels of PAI-1, coupled with a significant decrease in plasminogen activator activity, compared with trophoblast cells from normal pregnancy maintained in culture. This localized increased production of PAI-1 may play an important part in restricting endovascular trophoblast invasion in early pregnancy and increasing fibrin deposition and reducing uteroplacental blood flow in pregnancies complicated by IUGR.

Administration of growth hormone or IGF-I to pregnant rats on a reduced diet throughout pregnancy does not prevent fetal intrauterine growth retardation and elevated blood pressure in adult offspring.

Increasing evidence from human epidemiological studies suggests that poor growth before birth is associated with postnatal growth retardation and the development of cardiovascular disease in adulthood. We have shown previously that nutritional deprivation in the pregnant rat leads to intrauterine growth retardation (IUGR), postnatal growth failure, changes in the endocrine parameters of the somatotrophic axis, and to increased blood pressure in later life. In the present study, we investigated whether administration of insulin-like growth factor-I (IGF-I) or bovine growth hormone (GH) during pregnancy could prevent IUGR and/or alter long-term outcome. Dams from day 1 of pregnancy throughout gestation received a diet of ad libitum available food or a restricted dietary intake of 30% of ad libitum fed dams. From day 10 of gestation, dams were treated for 10 days with three times daily subcutaneous injections of saline (100 microl), IGF-I (2 micrograms/g body weight) or GH (2 micrograms/g body weight). Maternal weight gain was significantly increased (P<0.001) in ad libitum fed dams treated with GH, (98.9+/-4.73 g) compared with the IGF-I (80.5+/-2.17 g) and saline-treated (70.7+/-2.65 g) groups. There was a small increase in maternal weight gain (P<0.06) in 30% ad libitum fed dams following GH (16.3+/-2.47 g) and IGF-I (15.8+/-1.97 g) treatment compared with saline (9.2+/-1.96 g). Whole spleen, kidney and carcass weights were significantly (P<0.05) increased in ad libitum fed and 30% ad libitum fed dams with GH treatment. Circulating IGF-I was significantly increased (P<0.001) in ad libitum fed dams with both IGF-I (369.6+/-32.33 ng/ml) and GH (457.9+/-33.32 ng/ml) compared with saline treatment (211.7+/-14.02 ng/ml), and with GH (223.4+/-23.72 ng/ml) compared with saline treatment (112.0+/-7.33 ng/ml) in 30% ad libitum fed dams. Circulating GH binding protein (GHBP) levels were significantly reduced (P<0.05) in GH-treated (299.1+/-51.54 ng/ml) compared with saline-treated (503.9+/-62.43 ng/ml) ad libitum fed dams, but were not altered in 30% ad libitum fed dams. There was no significant effect of either IGF-I or GH treatment on fetal weight, placental weight, fetal organ weights or circulating IGF-I levels in both ad libitum fed and 30% ad libitum fed fetuses. Offspring of 30% ad libitum fed dams remained significantly growth retarded postnatally and showed elevated blood pressure in later life. The increased maternal weight gain following IGF-I or GH administration, without an effect on fetal and placental weights, suggests a modification in the mode of maternal nutrient repartitioning during mid to late pregnancy at the expense of the fetus.

Principles of teratogenicity

An agent is now considered a teratogen if its administration to the pregnant mother causes, directly or indirectly, structural or functional abnormalities in the fetus, or in the child after birth, which may not be apparent until later life. A teratogen can induce chromosomal abnormalities, prevent implantation of the conceptus, and cause abortion of the early embryo, late fetal death, congenital malformations, or intrauterine growth retardation. In the neonate there may be functional impairment, e.g. deafness. Behavioural abnormalities and mental retardation may also occur. Little is known about specific teratogenic mechanisms but some general principles have been formulated. Susceptibility to teratogens is genetically determined. Teratogenic agents may be beneficial or harmless to the mother but harmful or lethal to the embryo or the fetus. Most drugs and chemicals will cross the placenta. The timing of the exposure is critically important and determines the type of fetal toxicity that might occur, e.g. malformation or functional impairment. Teratogenicity is usually dose-dependent, and there is evidence that the teratogenicity of a drug may be enhanced by co-administration of a second drug.

Localization and quantification of glucose transporters in liver of growth-retarded fetal and neonatal rats.

To determine whether altered transport of glucose into the hepatocyte may be an important factor contributing to abnormal hepatic glucose metabolism in the intrauterine growth-retarded (IUGR) fetus and newborn, we measured glucose transport (glucose uptake, GLUT protein, and mRNA) and localization of GLUT protein in liver of control (sham operated) and IUGR fetal (day 20) and postnatal (1, 4, 14, and 21 days) rats. GLUT-1 and -2 proteins were localized to the hepatocyte. Glucose uptake and GLUT-1 protein and mRNA levels were increased in IUGR fetal and neonatal liver. GLUT-2 protein and mRNA levels were low in IUGR and control fetal liver. After birth, GLUT-2 abundance did not differ from controls. Run-on experiments showed that the rate of transcription of GLUT-1 and -2 did not differ between IUGR and control rats. However, the transcription rate of GLUT-1 decreased with age, and the GLUT-2 transcription rate increased with age. These studies indicate that the metabolic and physiological factors that cause IUGR also alter glucose transporter expression in fetal liver.

Placental Insufficiency Alters Cerebral Bcl-2 but not P-53 and Bax Gene Expression in Asymmetrical Intrauterine Growth Retarded (IUGR) Fetal Rats• 268

Asymmetric IUGR infants are at significant risk for perinatal ischemic neurological damage as well as neurodevelopmental delay despite sparing of brain growth. A primary source of this ischemic damage is mitochondrial free radical production which leads to subsequent lipid peroxidation (LP). Bcl-2 and P-53 response protein Bax are mitochondrial associated proteins which are linked to increased free radical production and prevent or facilitate cellular apoptosis respectively. We therefore hypothesized that cerebral gene expression of Bcl-2, P-53, and Bax would be altered and LP would be increased in term fetal rats made IUGR by maternal uterine artery ligation (a well characterized model of uteroplacental insufficiency and asymmetrical IUGR). We performed sham surgery (C) and bilateral uterine artery ligation (IUGR) on pregnant rats on day 19 of gestation (term-21d). 48 hours after surgery, a caserean section was performed and cerebral tissue RNA and protein were extracted for RT-PCR (utilizing an internal control) and western blotting. To assess levels of lipid peroxidation present in the cerebral tissue, malondialdehyde levels were quantitated. RESULTS: Cerebral Bcl-2 mRNA levels(C=1.0, IUGR Bcl-2=0.29±0.03; p < 0.05) and protein levels (C=1.0, IUGR Bcl-2= 0.40±0.05; p< 0.05) were significantly decreased in IUGR pups. In contrast, mRNA levels of P53 and Bax were not significantly different between control and IUGR fetal animals (C=1.0, IUGR P53=0.95±0.12, IUGR Bax=1.1±0.20); moreover, cerebral protein levels of P53 were not significantly different between control and IUGR pups (C=1.0, IUGR P53=1.2±0.16). Malondialdehyde levels were increased(IUGR-4.44±0.83 vs C-3.53±0.66 nmol/g tissue) though not significantly. We conclude that the intrauterine milieu associated with placental insufficiency decreases gene expression of the mitochondrial associated apoptosis protein Bcl-2, but does not significantly alter gene expression of P-53 or P-53 response protein Bax. The decreased expression of Bcl-2 is intriguing because Bcl-2 prevents apoptosis by blocking the release of Cytochrome c from the mitochondria. Cytosolic cytochrome c is necessary for the initiation of the apoptosis program. We speculate that decreased gene expression of Bcl-2 may leave the IUGR fetus susceptible to hypoxic-ischemic insults.