Fetal magnetocardiogram recordings and Fourier spectral analysis.

Power spectral analysis of fetal magnetocardiogram (FMCG) data was evaluated in 64 pregnancies, using the non-invasive one channel superconducting quantum interference device (DC-SQUID), in order to investigate the power spectral amplitude distribution in the frequency range between 2 and 3 Hz. In all cases with normal and uncomplicated pregnancies, the data from the fetal heart and specifically the QRS complexes, were identifiable and unaffected by any maternal cardiac activity and furthermore the power spectral amplitudes, which varied between 120 and 350 fT/Hz, were directly related to gestational age.     

Thrombophilia and fetal growth restriction

OBJECTIVE: Genetic thrombophilia may represent a new risk factor for obstetrical complications. The aim of the study was to determine which subgroups may be associated with genetic thrombophilia for small for gestational age infants (SGA). METHODS: A case-control study was performed in three different maternity wards in Normandy. Cases (n=203) were women who had pregnancies complicated by unexplained SGA infants defined as a birth weight below the 3rd centile and control subjects (n=203) were women who had infants with birth weight > or =10th centile. Patients were tested in the immediate postpartum period and 2 months later for factor V Leiden mutation, and prothrombin 20210A mutation. Frequencies of these mutations were observed in different subgroups of SGA infants depending on pregnancy or neonatal outcomes usually associated with intrauterine growth restriction (IUGR), and were then compared with the overall prevalence for these mutations detected in the control group. RESULTS: Prevalences for factor V Leiden mutation (or=2.58; 95% confidence interval: 0.83-8.04), prothrombin 20210A mutation (or=2.03; 95% confidence interval: 0.51-8.01), were comparable between cases and controls (4.9% versus 1.9% and 2.9% versus 1.4%, respectively). Frequencies for these two polymorphisms significantly increased in subgroups of SGA infants with a normal Pourcelot index (13/133 versus 7/203; P=0.04), a gestational age > or =37 weeks of gestation (15/143 versus 7/203; P=0.01), a vaginal delivery (11/117 versus 7/203; P=0.04), a birth weight > or =2000 g (12/121 versus 7/203; P=0.03), no admission to paediatric ward (11/116 versus 7/203; P=0.01), a low Ponderal index <2.5(e) centile (6/45 versus 7/203; P=0.04), and normal head circumference >10th centile (7/53 versus 7/203; P=0.01) in comparison with the control group. CONCLUSIONS: An association was found between polymorphisms for factor V Leiden and prothrombin, and asymmetrical intrauterine growth restriction with immediate favourable neonatal outcomes.     

Placenta and fetal growth restriction

The placenta, as the vector for all maternal-fetal oxygen and nutrient exchange, is a principal influence on birthweight. Placental weight summarizes laterally expanding growth of the chorionic disc, and villous arborization yielding the nutrient exchange surface. These different growth dimensions alter fetoplacental weight ratio and ponderal index, and thus may modify placental functional efficiency. The placenta may show a range of histopathologies, some of which are also associated with fetal growth restriction. Different fetal intrinsic abilities to compensate for gross and histo-pathology may clarify the imperfect relationships between fetal growth and both intrauterine pathology, and the long-term health risks associated with poor fetal growth.     

Stillbirth and fetal growth restriction

Objective: To confirm the role of fetal growth restriction (FGR) as a cause of stillbirth, and to compare diagnostic accuracy of customized fetal growth and population-based standards in identifying FGR within a pathological population of early and late stillbirths. Methods: Retrospective study on a cohort of 189 stillbirths occurred in single pregnancy between January 2006 and September 2011. Unexplained stillbirths, defined by Aberdeen-Wigglesworth and ReCoDe classifications, were evaluated on the basis of fetal birthweight with both Tuscany population and Gardosi customized standards. Unexplained stillbirths have been classified as early or late depending on the gestational age of occurrence. Results: Aberdeen-Wigglesworth classification, applied to the 189 cases of stillbirth, left 94 unexplained cases (49.7%), whereas the ReCoDe classification left only 40 (21%). By applying population standards to the 94 unexplained stillbirths we have identified 31 FGRs (33% of sample), while customized standards identified 54 FGRs (57%). Customised standards identified a larger number of FGRs with respect to population standards during the third trimester (i.e. 51% vs. 25% respectively) than in the second trimester (73% vs. 54% respectively) (p = 0.05). Conclusions: Customized standards have a higher diagnostic accuracy in identifying FGRs especially during the third trimester.     

胎儿生长受限与印痕现象研究进展

胎儿生长受限(FGR)是围生期主要并发症之一,发生原因与妊娠妇女、胎儿及胎盘三种因素有关.研究表明.FGR儿在成人期易患冠心病、高血压、中风、糖尿病、肥胖等疾病,表明很多成年期疾病可能在胎儿发育期就已被编程,这种现象称为印痕现象.胎儿发育时期营养改变能直接或间接影响胎儿各器官系统生长和成熟;胎儿营养改变和宫内糖皮质激素暴露二者可能通过类似途径引起机体内环境长期变化,导致成年疾病风险增加.节俭表型假说、预言适应性反应假说及胎儿胰岛素假说有助于理解印痕现象.瘦素、儿茶酚胺、葡萄糖转运蛋白、胰岛素样生长因子-1、脂联素等可能是印痕现象发生的重要因子.对印痕现象的理解有助于对某些成年期疾病发生的认识,对FGR儿早期临床干预对降低其特定疾病风险系数有重要意义.     

Origins of fetal growth restriction

Regulation of growth of the fetus and its placenta begins before pregnancy. Early in pregnancy the mother sets the rate of growth of the fetus on a trajectory, which may be modified by events later in pregnancy.Low maternal weight for height, history of previous small babies, maternal undernutrition, pregnancy disorders, e.g. pre-eclampsia, are associated with low birthweight. Maternal smoking is a major factor in developed countries; infections and undernutrition in developing countries.Recently, there has been emphasis on adverse long-term outcomes including ischaemic heart disease, hypertension and diabetes associated with poor fetal growth. Experimental studies in animals show that some of these outcomes can readily be induced by restriction of fetal growth.Progress in determining successful treatments to improve the growth of the fetus has lagged behind these epidemiological and experimental findings. However, nutrient supplements improve growth in undernourished women and smoking cessation also improves fetal size and outcome.     

Models of fetal growth restriction

The growth of the fetus is determined by substrate supply mostly for mass accretion and energy gain, and by control systems. Experiments with whole animal models will face the following problems: (1) The fetus, like a three compartmental "Russian doll", is at the end of a long supply chain. There are interactions (e.g. hormones) and partitioning of substrates between the compartments. (2) The fetal organism is growing and differentiating at the same time and not in a steady-state. Experimental results thus depend on gestational age. (3) About 75% of animal experiments on fetal growth restriction have been performed in rats and mice. The possible experimental methods and the results depend on the species which include sheep, pigs, rabbits, guinea pigs, horses and non-human primates. Many experiments have clearly shown that restriction of substrate supply will usually impair fetal growth. Less is known about growth control mechanisms but recent studies in gene mutant mice have opened a new approach to study the effects of systemic and local controlling factors. It appears that insulin-like growth factors and their binding proteins may play an important role for fetal growth.     

Placental pathology in fetal growth restriction

Objectives

One of the causes of intrauterine fetal growth restriction (FGR) can be pathology of the placenta. The aim of this study was to compare macroscopic and microscopic changes of the placentas from intrauterine growth restricted fetuses with those from normally developed fetuses, in order to test the hypothesis that vascular damage due to decreased maternal vascular perfusion may be responsible for FGR.

Study design

Between May 2007 and December 2008 we performed detailed macroscopic and histological examination of singleton placentas of 50 consecutive neonates with fetal growth restriction (FGR group) and compared them to 50 normal fetuses, born next to an FGR case, as a control group.

Results

Gestational age, birth weight, spontaneous delivery rate, mean weight of the placenta and the fetal-placental weight ratio were all lower in the FGR group than in the control group (p < 0.05). Thickening of the villous trophoblastic basal membrane, incidence of villous infarction, presence of thrombi or haematomas and the incidence of villitis were more common in the FGR group than in the controls (p < 0.05). There were, however, no significant differences in perivillous fibrin deposition, stromal fibrosis and cytotrophoblast proliferation between the groups. In FGR women who smoked, intervillous haematomas and villous infarction were more common (p < 0.05) than in controls.

Conclusions

All macroscopic and microscopic pathological changes associated with FGR were directly linked to reduction of placental blood flow. As smoking is a main risk factor for these placental abnormalities these results emphasize the need to persuade women to quit smoking not only during pregnancy, but even better long before pregnancy.     

Perinatal mortality and fetal growth restriction

Stillbirths are the largest component of perinatal mortality. Most are currently classified as 'unexplained', which is not helpful for counselling and individual care or for setting priorities for maternity services. The new ReCoDe classification reduces the number of stillbirths categorized as 'unexplained' from 66 to 14%. Both stillbirths and neonatal deaths are strongly associated with fetal growth restriction, and increased awareness of intrauterine growth is essential for any strategies which seek to avoid adverse perinatal outcome.     

Screening for fetal growth restriction

Since antenatal detection of fetal growth restriction, defined as birth weight <10% for gestational age, can reduce perinatal morbidity with antepartum testing and use of Doppler, it is imperative that there be a greater effort to detect the growth abnormality. According to a well-conducted randomized clinical trial, all uncomplicated pregnancies should have sonographic assessment of birth weight at 30-32 weeks and at 36-37 weeks. An increased awareness not only of the risk factors but also of the associated probability of abnormal growth can identify the cohorts that would benefit from uterine artery Doppler in 2nd trimester. Among patients at risk for suboptimal growth, Doppler of the umbilical artery improves the detection rate.     

Clustering and classical analysis of clinical and placental phenotypes in fetal growth restriction and constitutional fetal smallness

This study aims to determine whether placental examination can be used to distinguish between pathologic fetal growth restriction (FGR) and constitutional fetal smallness. Data were extracted from a clinicoplacental database of high risk pregnancies during the period 1994–2013. These data were used to compare the 590 consecutive cases having birth weights below the 10th percentile with the 5201 remaining cases having gestational ages ≥20 weeks. The authors analyzed 20 clinical and 46 placental phenotypes using classical statistics, clustering analysis, and multidimensional scaling. Of the low-birth-weight babies, the following types of cases were compared:

• •246 cases with the clinical risk factors most discriminative for FGR were compared with 344 cases without these risk factors (gestational hypertension or severe preeclampsia, maternal substance abuse and/or smoking, oligohydramnios, and abnormal umbilical artery Dopplers), and
• •196 early-onset cases were compared with 394 late-onset cases.

Four categories of placental phenotypes (those with features of poor uteroplacental perfusion, postuterine placental pathology, chronic inflammation, and a mixed category) better defined the presumably true FGR than did the clinical phenotypes. Maternal smoking and oligohydramnios were associated with fewer abnormal placental phenotypes than were maternal hypertensive diseases and abnormal Dopplers. Early-onset cases of fetal smallness clustered with placental features of poor uteroplacental perfusion, whereas late onset cases did not. Placental examination helps to retrospectively distinguish constitutionally small fetuses from those that are pathologically growth restricted. The latter correlate best with the clinical risk for FGR and with early-onset FGR. This correlation may have prognostic significance for the child and for future pregnancies, since hypoxic placental lesions can occur without clinical risk factors but with a tendency to recur in future pregnancies.     

Development and mechanisms of fetal hypoxia in severe fetal growth restriction

Severe fetal growth restriction (FGR) is often associated with hypoxia. We studied FGR hypoxia in an experimental model which is produced by exposing pregnant ewes to a hyperthermic environment. The study utilized simultaneous measurements of several relevant factors, e.g., uterine and umbilical blood flows and O(2) uptakes. Sixteen ewes were divided equally into control (C) and hyperthermic (HT) groups. Hyperthermia (40 degrees C for 12h/35 degrees C for 12h; approximately 35% relative humidity, RH) was maintained for 80 days commencing at approximately 38 days gestational age (dGA term 147+/-3 days). All ewes were then placed in a control environment ( approximately 21 degrees C, 24h; approximately 30% RH) and studied at approximately 134 dGA. Mean HT placental and fetal weights were 39% and 45% of C, respectively (p<0.0001), umbilical O(2) uptake/kg fetus was 76% of C (p<0.01) and umbilical venous PO(2) was reduced (20.2 vs. 29.7 Torr, p<0.001). Contrary to the hypothesis that FGR hypoxia is due to maternal placental hypoperfusion, uterine flow was not reduced in relation to O(2) uptake. The uterine-umbilical venous PO(2) difference was enlarged (38 vs. 23 Torr, p<0.0001). This difference is the expression of a balance between developmental changes in placental structure and oxidative metabolism, which have opposite effects in terms of fetal oxygenation. We postulate that FGR hypoxia results from disproportionate underdevelopment of those changes which allow for a progressive increase in umbilical O(2) uptake.     

Sonographic diagnosis of fetal growth restriction

Though a number of ultrasonic methods of diagnosing intrauterine growth restriction (IUGR) exist, the combined use of Doppler velocity wave form analysis of fetal vessels and the ultrasonic estimation of fetal weight (or abdominal circumference) appears to be the best method of both identification and evaluation of IUGR. Once identified, the IUGR fetus should undergo serial evaluation every two weeks or on a weekly schedule (or more frequent interval if the clinical situation warrants) with both Doppler velocity wave form studies and biophysical testing. Determination of the optimal time of delivery depends not only on the results of the antenatal testing, but also on the individual clinical situation. Fetal venous Doppler studies may give additional information about the time frame and significance of the IUGR.     

Adult consequences of fetal growth restriction

Low birthweight in relation to the length of gestation, is now known to be associated with increased rates of coronary heart disease and the related disorders stroke, hypertension and type 2 diabetes. These associations extend across the whole range of birthweight, which implies that normal variations in nutrient delivery to the fetus have profound long-term effects. The associations are thought to reflect the body's plasticity during development, by which its structure and function can be permanently changed by the intra uterine and early post natal environment. Slow growth during infancy and rapid weight gain after the age of two years exacerbate the effect of slow fetal growth. Cardiovascular disease and type 2 diabetes arise through a series of interactions between environmental influences and the pathways of development that precede them.     

Prevention of recurrent fetal growth restriction

Fetal growth restriction is associated with multiple short- and long-term consequences for the infant. A woman with a prior gestation complicated by fetal growth restriction has nearly a 20% risk of recurrence. Strategies to predict and prevent the recurrence are critical in obstetric management. Effective interventions for prevention of recurrent fetal growth restriction include the following: a reproductive plan because spacing of pregnancies impacts their outcome, optimization of maternal medical conditions, smoking cessation, accurate dating by first-trimester sonography and monitoring of fetal growth with serial sonograms, and low-dose aspirin (80-160 mg) started before 20 weeks. In women with nutritional deficiencies, optimizing caloric intake with low-protein (less than 25%) supplementation of 500-1,000 calories may prevent recurrent fetal growth restriction. In women living in areas endemic for malaria, antimalarial prophylaxis diminishes risk of recurrent fetal growth restriction.     

Integrated testing and management in fetal growth restriction

Growth-restricted fetuses are at higher risk for poor perinatal and long-term outcome than those who are appropriately grown. Multiple antenatal testing modalities can help document the sequence of fetal deterioration. The full extent of this compromise is best identified by a combination of fetal biometry, biophysical profile scoring, and arterial and venous Doppler. In the preterm growth-restricted fetus, timing of delivery is critically determined by the balance of fetal versus neonatal risks. In the near-term fetus, accurate diagnosis continues to be a challenge as unrecognized growth restriction contributes to a significant proportion of unexplained stillbirths. In this review, we present an integrated diagnostic and surveillance approach that accounts for these factors.