Caffeine and Pregnancy Outcome

Caffeine is a drug which easily crosses the placental barrier and enters the fetal circulation. To date, most studies that demonstrate caffeine's teratogenic potential have been conducted in animal models. Although no definite relationship in humans has been confirmed, it is suggested that a pregnant woman should limit or discontinue her intake of caffeine.     

Caffeine and pregnancy outcome

Caffeine is a drug which easily crosses the placental barrier and enters the fetal circulation. To date, most studies that demonstrate caffeine's teratogenic potential have been conducted in animal models. Although no definite relationship in humans has been confirmed, it is suggested that a pregnant woman should limit or discontinue her intake of caffeine.     

Human fetal growth and organ development: 50 years of discoveries

Knowledge about human fetal growth and organ development has greatly developed in the last 50 years. Anatomists and physiologists had already described some crucial aspects, for example, the circulation of blood during intrauterine life through the fetal heart, the liver as well as the placenta. However, only in the last century physiologic studies were performed in animal models. In the human fetus, the introduction of ultrasound and Doppler velocimetry has provided data about the growth and development of the fetus and of the circulation through the different fetal districts. Moreover, in the last 2 decades we have learned about fetal oxygenation and fetal nutrient supply caused by the availability of fetal blood samples obtained under relatively steady state conditions. These studies, together with studies using stable isotope methodologies, have clarified some aspects of the supply of the major nutrients for the fetus such as glucose, amino acids, and fatty acids. At the same time, the relevance of placental function has been recognized as a major determinant of fetal diseases leading to intrauterine growth restriction. More recently, the availability of new tools such as 3-dimensional ultrasound and magnetic resonance imaging, have made possible the evaluation of the growth and development of fetal organs. This knowledge in the healthy fetus will improve the ability of clinicians to recognize abnormal phenotypes of the different fetal organs, thus allowing to stage fetal diseases.     

Fetal microchimerism: self and non-self, finally who are we?

For a long time, the conventional view was that the fetus and maternal vascular system are kept separate. In fact there is a two-way traffic of immune cells through the placenta and the transplacental passage of cells is in fact the norm. The fetal cells can persist in a wide range of woman's tissue following a pregnancy or an abortion and she becomes a chimera. Fetal cells have been found in the maternal circulation and they were shown to persist for almost three decades in humans, thus demonstrating long-term engraftment and survival capabilities. Microchimerism is a subject of much interest for a number of reasons. Studies of fetal microchimerism during pregnancy may offer explanations for complications of pregnancy, such as preeclampsia, as well as insights into the pathogenesis of autoimmune disease which usually ameliorates during pregnancy. The impact that the persistence of allogenic cells of fetal origin and the maternal immunological response to them has on the mother's health and whether it is detrimental or beneficial to the mother is still not clear. Although microchimerism has been implicated in some autoimmune diseases, fetal microchimerism is common in healthy individuals. On the beneficial side, it has been proposed that genetically disparate fetal microchimerism provides protection against some cancers, that fetal microchimerism can afford the mother new alleles of protection to some diseases she has not, that fetal microchimerism can enlarge the immunological repertoire of the mother improving her defense against aggressor. Fetal cells are often present at sites of maternal injury and may have an active role in the repair of maternal tissues.     

Echocardiographic evaluation of cardiac function in the fetus

The development of high-resolution ultrasound has allowed detailed examination of the fetal heart. The accuracy of fetal echocardiography in the diagnosis of malformations of the fetal heart has been established in the second trimester and, more recently, at a much earlier stage in gestation (Allan et al., 1980; Allan et al., 1981; Simpson, 2000; Huggon et al., 2002). Confirmation of structural abnormalities has usually been by autopsy or by postnatal investigation. This is certainly sufficient for confirmation of structural malformations, but functional evaluation of the fetal heart is far more difficult to validate. Post-mortem studies, by their very nature give little insight into cardiac function and postnatal studies, whilst permitting functional evaluation of the heart, do so under entirely different conditions compared to the circulation in utero. Prior to the advent of ultrasound, fetal data was drawn from invasive animal studies (Pohlman, 1909; Dawes et al., 1954; Barcroft, 1936; Rudolph, 1985). There have been very few invasive studies in the human fetus including some conducted on exteriorised fetuses undergoing termination by hysterotomy (Nyberg and Westin, 1962; Rudolph et al., 1971). Pressure data has been obtained from the human fetus for normal human hearts and in cardiac disease (Johnson et al., 2000; Johnson et al., 1992; Johnson, 1992). However, the vast majority of cardiac functional data in the human fetus has been obtained by non-invasive means, which has almost exclusively been by echocardiography. This article will review some of the techniques that may be used to evaluate fetal cardiac function and will also emphasise some of the limitations of such techniques.     

Fetal microchimerism: benevolence or malevolence for the mother?

For a long time, the conventional view was that the fetus and maternal vascular system are kept separate. In fact there is a two way traffic of cells through the placenta and the transplacental passage of cells is in fact the norm. The fetal cells can persist in a wide range of woman's tissues following a pregnancy or an abortion and she becomes a chimera. Fetal cells have been found in the maternal circulation and they were shown to persist for the entire life in humans, thus demonstrating long-term engraftment and survival capabilities. Microchimerism is a subject of much interest for a number of reasons. Studies of fetal microchimerism during pregnancy may offer explanations for complications of pregnancy, such as preeclampsia, as well as insights into the pathogenesis of autoimmune diseases which usually ameliorate during pregnancy. The impact of the persistence of allogenic cells of fetal origin and of the maternal immunological response to them on the mother's health is still not clear. On the beneficial side, it has been proposed that genetically disparate fetal microchimerism provides protection against some cancers, that fetal microchimerism can afford the mother new mechanisms of protection to some diseases, that fetal microchimerism can enlarge the immunological repertoire of the mother improving her defense against aggressor. Fetal cells are often present at sites of maternal injury and may have an active role in the repair of maternal tissues.     

Adult sequelae of intrauterine growth restriction

Fetal intrauterine growth restriction has been associated with adult disease in both human epidemiologic studies and in animal models. In some cases, intrauterine deprivation programs the fetus to develop increased appetite and obesity, hypertension, and diabetes as an adult. Although the mechanisms responsible for fetal programming remain poorly understood, both anatomic and functional (cell signaling) changes have been described in affected individuals. In some animal models, aspects of fetal programming can be reversed postnatally; however, at the present time, the best strategy for avoiding the adult consequences of fetal growth restriction is prevention.     

Can fetal electrocardiography improve the prediction of intrapartum fetal acidosis?

An outline is given of a computer-based system which continuously enhances and measures the waveform of the intrapartum fetal electrocardiogram. This system has been used to examine the behaviour of the ST segment and T wave in a group of 14 fetuses where the outcome was biochemically and clinically normal, and in a group of 10 fetuses which were acidotic at birth. When the mean values in each group were compared, highly significant differences were found for both of these components of the waveform. These differences have also been demonstrated by the analysis of long-term trends in the behaviour of these variables. The highly significant correlation between both a long-term increase in ST segment and T wave height and fetal acidosis, found in this study, reflects earlier work by others in the experimental animal fetus. The findings suggest that continuous monitoring of the waveform of the fetal electrocardiogram in labour may give a much better prediction of fetal acidosis than is currently achieved with the monitoring of heart rate alone.     

Fetal cells in the maternal circulation.

The analysis of fetal cells from the maternal circulation would be the least invasive method of prenatal diagnosis. Potential fetal cell types to enter the maternal circulation are lymphocytes, trophoblast cells and nucleated erythrocytes. With conventional methods, such as cytology and interphase or metaphase cytogenetics, the ratio of fetal to maternal cells was overestimated in the past. Currently most groups use polymerase chain reaction-based Y-sequence analysis for the detection of fetal cells in pregnancies with male fetuses, either with or without prior enrichment of fetal cells. For fetal cell separation, fluorescence-activated cell sorting and immunomagnetic beads have been applied, and recently our group has used discontinuous density gradient centrifugation for this purpose. We have shown that the transferrin receptor antigen alone is not sufficient for enrichment of fetal nucleated erythrocytes. Despite some initial promising results with fluorescence in situ hybridization, the reproducibility and reliability of the techniques are still limited, mainly due to the lack of very specific cell markers and the very low and variable concentrations of fetal cells among numerous maternal cells.     

Importance of venous flow assessment for clinical decision-making.

In recent years Doppler ultrasound examinations of fetal venous circulation has given new insight into fetal hemodynamics. Blood flow in the systemic circulation has a pulsating pattern which reflects fetal central venous pressure. Characteristic changes in the blood velocity waveform have been described in different clinical conditions like congestive heart failure, imminent fetal asphyxia and arrhythmias. Recording fetal venous blood flow by Doppler ultrasound can thus give important clinical information and has with time gained a place as one of the most valuable tools for fetal surveillance in high-risk pregnancies.     

Gestational programming of offspring obesity/hypertension

The intrauterine milieu impacts fetal growth directly during gestation. It is now clear, however, that postnatal phenotype is also influenced by prenatal conditions. A variety of disorders in the adult have been linked to fetal size at birth; these include glucose intolerance, cardiovascular disease, and the subjects of this review, obesity and hypertension. We will review recent data regarding these associations and the pathophysiologic mechanisms underlying them in humans as well as in animal models.     

Gestational programming of offspring obesity/hypertension.

The intrauterine milieu impacts fetal growth directly during gestation. It is now clear, however, that postnatal phenotype is also influenced by prenatal conditions. A variety of disorders in the adult have been linked to fetal size at birth; these include glucose intolerance, cardiovascular disease, and the subjects of this review, obesity and hypertension. We will review recent data regarding these associations and the pathophysiologic mechanisms underlying them in humans as well as in animal models.     

Can fetal electrocardiography improve the prediction of intraparturn fetal acidosis?

Summary. An outline is given of a computer-based system which continuously enhances and measures the waveform of the intrapartum fetal electrocardiogram. This system has been used to examine the behaviour of the ST segment and T wave in a group of 14 fetuses where the outcome was biochemically and clinically normal, and in a group of 10 fetuses which were acidotic at birth. When the mean values in each group were compared, highly significant differences were found for both of these components of the waveform. These differences have also been demonstrated by the analysis of long-term trends in the behaviour of these variables. The highly significant correlation between both a long-term increase in ST segment and T wave height and fetal acidosis, found in this study, reflects earlier work by others in the experimental animal fetus. The findings suggest that continuous monitoring of the waveform of the fetal electrocardiogram in labour may give a much better prediction of fetal acidosis than is currently achieved with the monitoring of heart rate alone.     

Tissue heating effect of pulsed Doppler ultrasound in the live fetal lamb brain.

A series of experiments in fetal lambs investigated the heating effects of pulsed Doppler ultrasound on fetal brain tissue. In dead lamb brain, tissue heating was observed at the skull bone-to-brain interface. Minimal or no temperature rise was found in the live lamb, suggesting that the intact circulation conducts away any potential heating. The choice of animal model and the state of the circulation influence the results obtained. This will of course have implications for clinical practice.     

Acute versus chronic conditions for studies of fetal nutrient requirements: applicability to the human

In order to validate results obtained in 'acute' versus 'chronic' experimental conditions, two fetal sheep nutrients, lactate and glucose, have been determined in 'acute' conditions and compared with the 'chronic' data in the literature. Maternal and fetal blood glucose in 'acute' conditions was in the range of published 'chronic' data. Fetal blood lactate was similar in 'acute' and during 'chronic' conditions. Maternal and fetal veno-arterial (VA) differences were in the same direction in 'acute' and in 'chronic' conditions for both lactate and glucose and of the same magnitude for lactate. For glucose, a good relationship was observed between umbilical VA differences and maternal arterial concentrations for all 'acute' and 'chronic' values. Thus no fundamental differences appear in the results obtained in 'acute' or during 'chronic' conditions. The applicability of such animal results to the human and the use of acute conditions to study fetal nutrition in the human are discussed.     

Continuous variability of fetal PO2 in the chronically catheterized fetal sheep.

A method of continuous monitoring of fetal intravascular PO2 at various sites in the circulation in the chronically catheterized fetal sheep for up to 41 days (mean 11.1 days) has been compared with values obtained in blood samples measured extracorporeally in a standard blood gas analyzer. A double-blind comparison of the two methods showed that there was no bias between the two methods and correlation was 0.94. The stability of the electrodes was superior to that of a conventional blood gas analyzer. In every animal there was continuous variability of fetal vascular PO2. In the period from 105 to 126 days' gestation we noted the presence of slow increases in basal uterine tone that we have called "contractures". The frequency of these contractures was very regular at approximately one per hour. The frequency of these contracutres was very regular at approximately one per hour. There is a statistically significant related fall in fetal vascular PO2 in relation to these contractures. Well-coordinated uterine contractions during labor also produced a fall in fetal vascular PO2 that was related to the uterine activity.     

Vascular Doppler techniques

Doppler ultrasound used for the assessment of the fetal umbilical circulation in the human pregnancy has been reported in the scientific literature since the early 1980s and has been rigorously evaluated by randomized, controlled trials. The consensus of the reviewers of these trials is that there do appear to be grounds for including umbilical artery Doppler ultrasound studies in the management of high-risk pregnancies. There is no apparent benefit for low-risk pregnancies or later gestation. Other fetal vascular beds are currently undergoing prospective studies and some limited randomized, controlled trials have been reported; but to date they are not at a point of development to be considered part of clinical management.     

Detection of maternal deoxyribonucleic acid in peripheral blood of premature and mature newborn infants

BACKGROUND: Over the past decade, a lot of attention has been directed towards the fetomaternal and maternofetal transfer of nucleated cells and plasma DNA. In some autoimmune diseases, the fetal DNA is suspected to play an important role in the etiology of the disease. In the same way, the presence of maternal cells and free plasma DNA in fetal/newborn circulation gives rise to interesting questions. The aim of our study was to detect maternal deoxyribonucleic acid in the peripheral blood of premature and mature newborn infants. METHODS: In the case of eight RhD-positive mothers-RhD-negative newborn pairs, peripheral blood samples were collected from the newborn infants within 35-120 min after birth. The maternal origin DNA was determined by real-time PCR amplification of the exon 7 of the RhD-positive allele. RESULT: In all eight cases, the RhD exon 7 was amplified during the PCR reaction. CONCLUSION: The result of our study demonstrates that maternal DNA is present in the fetal peripheral circulation. The presence of maternally derived cells/DNA in the blood of newborn infants might have a role in the immunization of the newborn infants and also could be a possible explanation for 'grandmother effect' in the case of Rh-negative nulligravida patients.     

细胞游离胎儿DNA产前诊断胎儿非整倍体异常

细胞游离胎儿DNA（cffDNA）已被成功在妊娠妇女血循环中检测到。与母体血循环中胎儿细胞不同,cffDNA最早可在妊娠4周检测出,并能在产后迅速消失。cffDNA可能源于胎盘部位的滋养细胞等并通过凋亡机制释放进入母体血循环中。通过检测cffDNA可产前诊断胎儿非整倍体异常,但因其在妊娠妇女血中含量较少,检测具有挑战性。目前已有多种新检测方法用于非整倍体异常的产前诊断,尚需不断完善。     

Review: Nutrient sulfate supply from mother to fetus: Placental adaptive responses during human and animal gestation

Nutrient sulfate has numerous roles in mammalian physiology and is essential for healthy fetal growth and development. The fetus has limited capacity to generate sulfate and relies on sulfate supplied from the maternal circulation via placental sulfate transporters. The placenta also has a high sulfate requirement for numerous molecular and cellular functions, including sulfate conjugation (sulfonation) to estrogen and thyroid hormone which leads to their inactivation. Accordingly, the ratio of sulfonated (inactive) to unconjugated (active) hormones modulates endocrine function in fetal, placental and maternal tissues. During pregnancy, there is a marked increase in the expression of genes involved in transport and generation of sulfate in the mouse placenta, in line with increasing fetal and placental demands for sulfate. The maternal circulation also provides a vital reservoir of sulfate for the placenta and fetus, with maternal circulating sulfate levels increasing by 2-fold from mid-gestation. However, despite evidence from animal studies showing the requirement of maternal sulfate supply for placental and fetal physiology, there are no routine clinical measurements of sulfate or consideration of dietary sulfate intake in pregnant women. This is also relevant to certain xenobiotics or pharmacological drugs which when taken by the mother use significant quantities of circulating sulfate for detoxification and clearance, and thereby have the potential to decrease sulfonation capacity in the placenta and fetus. This article will review the physiological adaptations of the placenta for maintaining sulfate homeostasis in the fetus and placenta, with a focus on pathophysiological outcomes in animal models of disturbed sulfate homeostasis.