Prenatal alcohol exposure and fetal programming: effects on neuroendocrine and immune function

Alcohol abuse is known to result in clinical abnormalities of endocrine function and neuroendocrine regulation. However, most studies have been conducted on males. Only recently have studies begun to investigate the influence of alcohol on endocrine function in females and, more specifically, endocrine function during pregnancy. Alcohol-induced endocrine imbalances may contribute to the etiology of fetal alcohol syndrome. Alcohol crosses the placenta and can directly affect developing fetal cells and tissues. Alcohol-induced changes in maternal endocrine function can disrupt maternal-fetal hormonal interactions and affect the female's ability to maintain a successful pregnancy, thus indirectly affecting the fetus. In this review, we focus on the adverse effects of prenatal alcohol exposure on neuroendocrine and immune function, with particular emphasis on the hypothalamic-pituitary-adrenal (HPA) axis and the concept of fetal programming. The HPA axis is highly susceptible to programming during fetal development. Early environmental experiences, including exposure to alcohol, can reprogram the HPA axis such that HPA tone is increased throughout life. We present data that demonstrate that maternal alcohol consumption increases HPA activity in both the maternal female and the offspring. Increased exposure to endogenous glucocorticoids throughout the lifespan can alter behavioral and physiologic responsiveness and increase vulnerability to illnesses or disorders later in life. Alterations in immune function may be one of the long-term consequences of fetal HPA programming. We discuss studies that demonstrate the adverse effects of alcohol on immune competence and the increased vulnerability of ethanol-exposed offspring to the immunosuppressive effects of stress. Fetal programming of HPA activity may underlie some of the long-term behavioral, cognitive, and immune deficits that are observed following prenatal alcohol exposure.     

Identifying and treating pregnant patients at risk from alcohol.

Heavy alcohol consumption during pregnancy has been associated with retardation of fetal growth and abnormal fetal development. Pregnant women whose offspring are at risk because of alcohol abuse can be identified and counselled by health professional providing prenatal care. Offspring born to women who had been drinking heavily and subsequently abstained from or reduced their intake of alcohol before the third trimester demonstrated improvements in growth and in regulation of sleep-awake states. The existing health care delivery system can be modified in a cost-effective manner to treat pregnant women who are problem drinkers. Physicians'' attitudes and behaviour are critical for the success of this strategy.     

Moebius syndrome: animal model--human correlations and evidence for a brainstem vascular etiology

The Moebius syndrome consists of congenital seventh nerve palsy associated with other cranial nerve palsies, most often of the sixth, and/or musculoskeletal abnormalities. A retrospective study of the events of pregnancy in 15 cases was undertaken, after a rat animal model showed that abdominal trauma, uterine vessel clamping and handling and hyperthermia caused bilateral brainstem lesions in fetal rats. Eight of the 15 cases surveyed included a possible associated event during pregnancy; hyperthermia, previous uterine surgery, electric shock, failed abortion, prolonged rupture of the membranes, or alcohol abuse. These events can be correlated with animal studies that involve acute uteroplacental vascular insufficiency produced by a variety of methods. The cause of most cases of Moebius syndrome is probably a transient ischemic/hypoxic insult to the fetus.     

Effects of alcohol on the fetus: impact and prevention.

In the spectrum of adverse effects on the fetus or infant associated with maternal drinking during pregnancy the most dramatic is the fetal alcohol syndrome, a pattern of malformation that has been associated with maternal alcohol abuse. Other undesirable outcomes of pregnancy linked to alcohol exposure in utero include growth deficiency, major and minor anomalies, decrements in mental and motor performance, and fetal and perinatal wastage. Alcohol, like other teratogens, does not uniformly affect all those exposed to it. Rather, there seems to be a continuum of effects of alcohol on the fetus with increasingly severe outcomes generally associated with higher intakes of alcohol by the mother. The cost of fetal damage associated with alcohol exposure is very high. A program to decrease the incidence of fetal alcohol effects is therefore imperative. The cornerstone of such a program must be not only education of the public but also careful training of all professionals who provide health care for pregnant women.     

Long-term alcohol exposure prior to conception results in lower fetal body weights

BACKGROUND: It is well known that alcohol consumption during pregnancy can result in lower birth weight babies but many women stop consuming alcohol prior to conception as a part of pregnancy planning. The purpose of this study was to determine whether alcohol consumption prior to conception may also have an effect on fetal development. METHODS: Male and female C57BL/6J mice at 4, 6, or 8 weeks of age received either a single administration of alcohol (3.0 g/kg) via intragastric gavage (IG) each day for at least 60 days, or an isovolumetric IG administration of sterile water. After 60 treatment days, males and females within each age and treatment group were mated overnight. Females continued to receive daily alcohol treatments until conception. Males continued to receive treatments until all females were successfully mated. At conception, females were isolated and left undisturbed. On embryonic day 14, fetus number, size, and weight was determined. RESULTS: Maternal food consumption, body weight at conception, and delay to conception onset did not differ between the two treatment groups or among the three age groups. Fetal body weights did not differ among the three age groups. Fetuses from females treated with alcohol had lower body weights compared to those treated with water. Male treatments did not seem to affect fetal body weight. CONCLUSIONS: Fetal growth and development can be affected by alcohol consumption prior to the time of conception. Alcohol consumption prior to conception is a potential risk factor to fetal outcome and an important consideration for those females planning to have children.     

A case of fetal carbamazepine syndrome with right hemihypoplasia of the entire body

Anticonvulsant drugs taken by pregnant women to prevent seizures are among the most common causes of potential harm to the fetus. It has been suggested that carbamazepine was less teratogenic than the other drugs. Here, we report a case of fetal carbamazepine syndrome presenting with facial dysmorphism, congenital heart defect, skeletal abnormalities, renal agenesis, ambiguous genitalia, anal atresia, and right hemihypoplasia of the entire body. To the best of our knowledge this is the most severe case of fetal carbamazepine syndrome in the literature. This case can provide useful data about teratogenicity of carbamazepine therapy during the pregnancy.     

Fetal alcohol spectrum disorders: an overview with emphasis on changes in brain and behavior

Fetal alcohol spectrum disorders constitute a major public health problem. This article presents an overview of important issues that surround these disorders and emphasizes the structural and neurobehavioral consequences associated with prenatal exposure to alcohol. Diagnostic criteria are discussed, and possible moderating factors for the range of outcomes are mentioned. In addition, the prevalence of fetal alcohol spectrum disorders is described, and estimates of the financial impact of these disorders are given. Heavy prenatal alcohol exposure can severely affect the physical and neurobehavioral development of a child. Autopsy and brain imaging studies indicate reductions and abnormalities in overall brain size and shape, specifically in structures such as the cerebellum, basal ganglia, and corpus callosum. A wide range of neuropsychological deficits have been found in children prenatally exposed to alcohol, including deficits in visuospatial functioning, verbal and nonverbal learning, attention, and executive functioning. These children also exhibit a variety of behavioral problems that can further affect their daily functioning. Children exposed to alcohol prenatally, with and without the physical features of fetal alcohol syndrome, display qualitatively similar deficits. Determining the behavioral phenotypes that result from heavy prenatal alcohol exposure is critical, because the identification of these children is crucial for early interventions. In addition, knowing which brain areas are involved might enable the development of better intervention strategies. However, intervention needs to go beyond the affected individual to prevent future cases. As evidenced by the staggering financial impact these disorders have on society, prevention efforts need to be aimed at high-risk groups, and this issue needs to be made a high priority in terms of public health.     

Vascular effects of maternal alcohol consumption

Maternal alcohol consumption during pregnancy is a significant field of scientific exploration primarily because of its negative effects on the developing fetus, which is specifically defined as fetal alcohol spectrum disorders. Though the effects on the mother are less explored compared with those on the fetus, alcohol produces multiple effects on the maternal vascular system. Alcohol has major effects on systemic hemodynamic variables, endocrine axes, and paracrine factors regulating vascular resistance, as well as vascular reactivity. Alcohol is also reported to have significant effects on the reproductive vasculature including alterations in blood flow, vessel remodeling, and angiogenesis. Data presented in this review will illustrate the importance of the maternal vasculature in the pathogenesis of fetal alcohol spectrum disorders and that more studies are warranted in this field.     

彩色多普勒超声检查对胎儿颅内畸形筛查的应用价值及染色体异常分析

摘要 目的：探讨彩色多普勒超声检查对胎儿颅内畸形筛查的应用价值,并进行染色体异常分析。方法：选择2016年2月至2019年5月本院收治的进行胎儿颅内畸形筛查的高危孕妇120例,所有孕妇都给予彩色多普勒二维超声与三维超声筛查,对超声筛查异常者进行染色体异常分析,记录预后情况。结果：在120例孕妇中,二维超声诊断为胎儿颅内畸形12例,三维超声诊断为13例(预后都确诊为胎儿颅内畸形)。染色体核型筛查检出胎儿颅内畸形12例,其中21-三体综合征8例,18-三体综合征3例,13-三体综合征1例。确诊为胎儿颅内畸形的孕妇超声NT值都显著高于非胎儿颅内畸形孕妇,差异都有统计学意义(P<0.05)。孕妇选择终止妊娠10例,选择继续妊娠3例,继续妊娠3例胎儿都最终死亡。结论：产前彩色多普勒超声结合染色体核型在胎儿颅内畸形筛查中具有很高的价值,两者可互相补充,共同发挥诊断与预后评估价值。     

双胎妊娠一胎宫内死亡18 例临床分析

目的:探讨双胎妊娠中一胎宫内死亡的原因、对母亲和存活胎儿的影响及临床处理方法。方法:对2001年1月至2011年10月分娩的双胎妊娠之一胎宫内死亡的18例产妇临床资料进行回顾性分析。结果:双胎妊娠一胎宫内死胎的发生率占双胎的1.08%,其中单绒毛膜双羊膜囊双胎(monochorionic-diamniotic twin,MCDA)11例(61.11%),双绒毛膜双羊膜囊双胎(dichorionic-diamniotic twin,DCDA)7例(38.89%)。胎儿死因:胎盘脐带因素3例(16.67%),胎儿畸形1例(5.56%),妊娠并发症3例(16.67%),双胎输血综合征(twin-twin transfusion syndrome,TTTs)3例(16.67%),宫内感染3例(16.67%),不明原因5例(27.78%)。另一胎选择剖宫产者13例,阴道分娩3例。双胎一胎死亡后对母体的凝血功能影响不大(P>0.05)。结论:单绒毛膜双胎较双绒毛膜双胎母儿结局存在差别;双胎一胎宫内死亡对母体及存活儿有一定影响。对于孕周小,胎儿尚不成熟的病例,可严密监测存活胎儿宫内情况,行期待治疗延长孕龄至足月再分娩。     

The immunostimulatory effect of T cells and T cell lymphokines on murine fetally derived placental cells

Evidence for maternal immune recognition of the fetus can be found during pregnancy, yet the conceptus remains unharmed. Indeed, in some cases immunizing the mother with cells sharing histocompatibility antigens with the fetus is beneficial to fetal survival. This could be due to the effect of maternally derived lymphokines on placental growth and function, according to the immunostimulation hypothesis. We demonstrate here that placental cells in culture proliferate upon the addition of T cell-derived lymphokines. The lymphokine activity has been separated from IL 2 and B cell growth factor, and copurified with IL 3 and granulocyte-macrophage colony-stimulating factor (CSF-GM). Recombinant CSF-GM and recombinant IL 3 showed a similar effect. The placental cells that proliferate in culture are of fetal origin and are characterized by strong adherence, phagocytosis, nonspecific esterase staining, and response to the macrophage-specific colony-stimulating factor CSF-1. In addition, treatment of pregnant females with anti-thymocyte serum as well as anti-Ly-2.1 monoclonal antibody, at gestational times before Ly-2 antigen appearance in the fetus, leads to a reduction of the proliferative and phagocytic capacity of day 12 placentae. These results clearly demonstrate that maternal T cells act upon fetally derived placental cells to improve their proliferative and phagocytic potential, and thus provide evidence for the immunostimulatory role of these cells during pregnancy.     

Construction of Vapor Chambers Used to Expose Mice to Alcohol During the Equivalent of all Three Trimesters of Human Development

Exposure to alcohol during development can result in a constellation of morphological and behavioral abnormalities that are collectively known as Fetal Alcohol Spectrum Disorders (FASDs). At the most severe end of the spectrum is Fetal Alcohol Syndrome (FAS), characterized by growth retardation, craniofacial dysmorphology, and neurobehavioral deficits. Studies with animal models, including rodents, have elucidated many molecular and cellular mechanisms involved in the pathophysiology of FASDs. Ethanol administration to pregnant rodents has been used to model human exposure during the first and second trimesters of pregnancy. Third trimester ethanol consumption in humans has been modeled using neonatal rodents. However, few rodent studies have characterized the effect of ethanol exposure during the equivalent to all three trimesters of human pregnancy, a pattern of exposure that is common in pregnant women. Here, we show how to build vapor chambers from readily obtainable materials that can each accommodate up to six standard mouse cages. We describe a vapor chamber paradigm that can be used to model exposure to ethanol, with minimal handling, during all three trimesters. Our studies demonstrate that pregnant dams developed significant metabolic tolerance to ethanol. However, neonatal mice did not develop metabolic tolerance and the number of fetuses, fetus weight, placenta weight, number of pups/litter, number of dead pups/litter, and pup weight were not significantly affected by ethanol exposure. An important advantage of this paradigm is its applicability to studies with genetically-modified mice. Additionally, this paradigm minimizes handling of animals, a major confound in fetal alcohol research.     

Fetal DNA in maternal serum: does it persist after pregnancy?

Fetal DNA and cells present in maternal blood have previously been used for non-invasive prenatal diagnosis. However, some fetal cells can persist in maternal blood after a previous pregnancy. Fetal rhesus status and sex determination have been performed by using amplification by real-time polymerase chain reaction (PCR) of fetal DNA sequences present in maternal circulation; no false-positive results related to persistent fetal DNA from a previous pregnancy have been reported. This idea has recently been challenged. An SRY real-time PCR assay was performed on the serum of 67 pregnant women carrying a female fetus but having previously given birth to at least one boy and on the serum of 30 healthy non-pregnant women with a past male pregnancy. In all cases, serum was negative for the SRY gene. These data suggest that fetal DNA from a previous pregnancy cannot be detected in maternal serum, even by using a highly sensitive technique. Therefore, non-invasive prenatal diagnosis by fetal sex determination for women at risk of producing children with X-linked disorders, and fetal RHD genotyping is reliable and secure as previously demonstrated.     

Risk for congenital anomalies associated with different sporadic and daily doses of alcohol consumption during pregnancy: a case-control study

BACKGROUND: The classic clinical criteria for the diagnosis of fetal alcohol syndrome (FAS) include a "characteristic" facial appearance, pre- and postnatal growth deficiency, microcephaly, mental retardation, and occasional major malformations. However, diagnostic constraints, especially in the newborn period, lead to an underestimate of their prevalence. We report an epidemiological study of the potential risk of congenital defects in the offspring of mothers who ingested different sporadic and daily amounts of alcohol during pregnancy. METHODS: The study was based on the data from the ECEMC hospital-based case-control study and surveillance system, with a methodology aimed not only at the surveillance of congenital anomalies, but also at investigating their characteristics, clustering, and causes. For the purposes of this study, we considered as exposed those infants whose mothers reported the ingestion of any amount of alcohol during gestation (4705 mothers of cases and 4329 mothers of controls), and classified them into five groups according to their levels of alcohol consumption. Two groups consisted of mothers who consumed increasing sporadic levels and the other three consisted of mothers who consumed increasing daily levels of alcohol. RESULTS: Our study showed that even low sporadic doses of alcohol consumption during pregnancy may increase the risk of congenital anomalies in the offspring and that this risk increases with increasing levels of alcohol exposure. CONCLUSIONS: The results of our study suggest that it is necessary to generalize the preventive norm and recommend complete abstinence from alcohol during gestation. Birth Defects Research (Part A), 2004.     

Even if the fetus is not a person,abortion is immoral: The impairment argument

Much of the debate about the ethics of abortion has centered on whether the fetus is a person. In an attempt to sidestep this complex issue, I argue that, even if the fetus is not a person, abortion is immoral. To arrive at this conclusion, I argue that giving a fetus fetal alcohol syndrome is immoral, and that if this is so, then killing the fetus is immoral. Roughly, this is because killing the fetus impairs it more than giving it fetal alcohol syndrome. Since abortion (in most cases) amounts to killing the fetus, this means that abortion (in most cases) is immoral. I defend the premises of this argument against a plethora of objections, concluding that they either do not work, or commit their proponent to a controversial position.     

EGF-R and erbB-2 in murine tooth development after ethanol exposure

BACKGROUND: Alcohol consumption during pregnancy can frequently lead to a congenital disorder known as fetal alcohol syndrome (FAS); however, not all children born to alcoholic women develop FAS. Alcohol consumption may affect diverse organs and systems during embryonic development, including craniofacial structures. Small teeth, enamel alterations, and delayed eruption have been observed after ethanol exposure. Epidermal growth factor receptors (EGF-Rs) participate in dental proliferation and differentiation, and changes in these receptors were considered here to be a likely mechanism associated to the dental anomalies observed in this syndrome. Epidermal growth factor receptor type 1 (EGF-R) and epidermal growth factor receptor type 2 (erbB-2) immunoexpression during the lower first molar morphogenesis was investigated in mouse fetuses exposed to ethanol during gestation. METHODS: Pregnant female mice were divided into groups, consuming either 5, 10, 15, 20, or 25% ethanol solutions, or water (control group). Heads were obtained from 16.5- and 18.5-day fetuses. Immunohistochemistry was applied to EGF-R and erbB-2. RESULTS: At days 16.5 and 18.5, fetuses from 15%, 20%, and 25% ethanol groups showed delayed differentiation, degenerative changes in dental epithelial tissues and reduced dental size; additionally, they displayed an enhanced immunoreactivity to EGF-R and erbB-2. CONCLUSIONS: Our results suggest that ethanol consumption during pregnancy affects the expression of EGF receptors and induces a delay in murine fetal dental morphogenesis. Dental development is a process that involves a number of growth factors; hence we consider that further research is required to show whether the changes in glycosylation and growth-factor signaling pathways observed in other cells are also involved in the alterations observed in this study.     

Some teratogenic properties of ethanol and acetaldehyde in C57BL/6J mice: implications for the study of the fetal alcohol syndrome

To investigate the teratogenic effect of acute alcohol exposure, pregnant C57BL/6J mice were exposed to 25% ethanol (either two doses of 2.9g/kg or one dose 5.8g/kg) during the organogenic period either by intraperitoneal injections or by intubation. The incidence of malformations varied according to (1) the stage of embryonic development at the time of exposure, (2) the route of administration of the alcohol, and (3) the amount of alcohol given and the time period over which it was administered. Oral doses of alcohol were teratogenic although less so than the same dose given intraperitoneally, and two intraperitoneal doses four hours apart produced significantly more malformation than the same two doses six hours apart. The primary metabolite of alcohol, acetaldehyde, was also investigated for its teratogenicity. It was found that one or two doses of four percent acetaldehyde (0.32g/kg), administered intraperitoneally were teratogenic. A further attempt was made to raise blood acetaldehyde levels by exposing mice to disulfiram, an inhibitor of acetaldehyde dehydrogenase, prior to administration of alcohol. The disulfiram pretreatment did not increase the malformation rate. Treatment with alcohol on day 7 or 8 caused a variety of facial abnormalities, some of which were comparable to those seen in children with fetal alcohol syndrome. Exposure on day 9 or 10 resulted in limb defects. The results suggest that one or more episodes of heavy maternal drinking at critical periods in pregnancy may severely damage the embryo and may produce many features of the fetal alcohol syndrome.     

Polymicrogyria in fetal alcohol syndrome

BACKGROUND: Intrauterine exposure to alcohol may result in a distinct pattern of craniofacial abnormalities and central nervous system dysfunction, designated fetal alcohol syndrome (FAS). The spectrum of malformations of the brain associated with maternal alcohol abuse during pregnancy is much broader than the relatively uniform clinical phenotype of FAS. Among these malformations the most striking abnormalities involve the impairment of neuronal cell migration. However, polymicrogyria (PMG) has so far been reported only once in a human autopsy study of a child with FAS. CASE: A 16‐year‐old girl with confirmed maternal alcohol consumption during pregnancy and full phenotype of FAS presented after two generalized epileptic seizures for neurologic assessment. Cranial magnetic resonance imaging revealed bilateral PMG in the superior frontal gyrus with asymmetric distribution. History, clinical features, and genetic investigations provided no evidence for any of the known genetic or acquired causes of PMG. Therefore, we propose that prenatal alcohol exposure is the cause of PMG in this patient rather than a mere coincidence. CONCLUSION: Our observation represents only the second patient of PMG in FAS and confirms the phenotypic variability of cerebral malformations associated with maternal alcohol abuse during pregnancy. In patients with clinical features of FAS and neurologic deficits or seizures neuroimaging is recommended. Furthermore, FAS should be considered as a differential diagnosis for PMG. Birth Defects Research (Part A), 2010. © 2009 Wiley‐Liss, Inc.     

Risk factors for dystocia in pigtailed macaques (Macaca nemestrina)

Dystocia (difficult labor) is an important component of the management of nonhuman primates and results in significant fetal and maternal morbidity and increased use of veterinary resources. Dystocias can arise from abnormalities of the maternal pelvis or fetus or uncoordinated uterine activity. Although risk factors for stillbirths have been established in nonhuman primates, risk factors for dystocias have not. The objective of this study was to determine maternal and fetal risk factors for dystocia in macaques. Retrospective data were collected from 83 pigtailed macaques (Macaca nemestrina) diagnosed with dystocia. The diagnosis of dystocia was made based on clinical or pathologic evidence. Maternal records of age, reproductive history, experimental history, clinical records, and fetal birth weight and any applicable fetal necropsy reports were reviewed. The gestational age of the fetus, the infant's birth weight, total previous births by the dam, and the proportions of both viable delivery (inverse effect) and surgical pregnancy interventions (direct effect) in the dam's history generated a model that maximized the experimental variance for predicting dystocia in the current pregnancy and explained 24% of the dystocia deliveries. The number of total previous births and proportion of previous cesarean sections accounted for the greatest effect. This model can identify individual dams within a colony that are at risk for dystocias and allow for changes in breeding colony management, more intense monitoring of dams at risk, or allocation of additional resources.     

Correlations between pregnancy pathology, study of the placenta, antenatal echography and examination of the product of conception in a series of 175 congenital malformations

In order to verify the hypothesis that during pregnancy in a woman without peculiar history, signs could be discovered when the fetus is malformed we have reviewed the files of 175 women who had a malformed child and of 300 controls. All of these women had at least one clinical examination and one ultrasonographic examination during pregnancy. Two clinical symptoms were more often discovered in the mother of the malformed fetus (p less than 0.001): decrease of fetal movements and small for date fetus. The placenta is never abnormal in the mother with normal fetus. Placenta is abnormal in 31% of the mother with malformed fetus but the abnormalities are not specific. Ultrasonographic examinations allowed more often the discovery of a malformation when hydramnios (p less than 0.001) or fetal hypotrophy (p less than 0.01) or an anomaly of the morphology of the fetus is discovered. Accuracy of prenatal diagnostic is considered for the different categories of congenital malformations.