Protecting Future Children from In‐Utero Harm

The actions of pregnant women can cause harm to their future children. However, even if the possible harm is serious and likely to occur, the law will generally not intervene. A pregnant woman is an autonomous person who is entitled to make her own decisions. A fetus in‐utero has no legal right to protection. In striking contrast, the child, if born alive, may sue for injury in‐utero; and the child is entitled to be protected by being removed from her parents if necessary for her protection. Indeed, there is a legal obligation for health professionals to report suspected harm, and for authorities to protect the child's wellbeing. We ask whether such contradictory responses are justified. Should the law intervene where a pregnant woman's actions risk serious and preventable fetal injury? The argument for legal intervention to protect a fetus is sometimes linked to the concept of ‘fetal personhood’ and the moral status of the fetus. In this article we will suggest that even if the fetus is not regarded as a separate person, and does not have the legal or moral status of a child, indeed, even if the fetus is regarded as having no legal or moral status, there is an ethical and legal case for intervening to prevent serious harm to a future child. We examine the arguments for and against intervention on behalf of the future child, drawing on the example of excessive maternal alcohol intake.     

Problems posed by prenatal diagnosis of abdominal wall malformations

The authors present 6 observations of in utero detected abdominal wall defect : 2 laparoschisis and 4 omphaloceles. In three cases the diagnosis have been done prior week 20, by systematic AFP assay for amniocentesis performed for cytogenetic or metabolic reasons; the pregnancy was terminated. In three other cases, the pregnancy was complicated by hydramnios after week 30; amniocentesis for AFP and echography were performed to detect fetal malformations after associated with hydramnios. The detected abdominal wall anomaly was not alone: two fetus had an abnormal caryotype (trisomy 18), three other presented a polymalformative syndrome, a Beckwith-Wiedemann syndrome was discussed for the last child. The in utero diagnosis of omphalocele or laparoschisis implicates difficulties for genetic counselling, particularly if the diagnosis is done prior week 20. These anomalies can be treated with surgical management, but frequency of associated malformations must be underlined. it is important for genetic counselling to know the family history, the amniotic fluid cells caryotype, and an ultrasound scanning performed to reveal any other malformations.     

Umbilical artery flow velocity waveform analysis in normal ovine pregnancy and after carunculectomy

Twenty fetal lambs were studied in utero using continuous wave Doppler ultrasound to analyse the fetal umbilical artery flow velocity waveforms. Satisfactory waveforms were obtained. Prepregnancy surgical removal of uterine caruncles was used to produce intrauterine fetal growth retardation in 14 of these ovine pregnancies of whom 8 delivered a small for gestational age fetus. In only one fetus was the umbilical artery flow velocity waveform abnormal with a high systolic diastolic ratio. We conclude that the growth restriction occurring in the ovine fetus following a reduction of placental implantation sites is not related to a restriction in the fetoplacental circulation and this is different from the most frequently observed human fetal growth retardation.     

Fetal immunization of baboons induces a fetal-specific antibody response

Neonates face a high risk of infection because of the immaturity of their immune systems. Although the transplacental transfer of maternal antibodies to the fetus may convey improved postnatal immunity, this transfer occurs late in gestation and may fail to prevent in utero infection. Both fetal immunization and in utero exposure to antigen can result in a state of immunologic tolerance in the neonate. Tolerance induction of fetal and premature infant lymphocytes has become a paradigm for neonatal responsiveness. However, fetal IgM responses have been demonstrated to maternal immunization with tetanus toxoid and to congenital infections such as rubella, toxoplasma, cytomegalovirus and human immunodeficiency virus. Moreover, 1-week-old infants can respond to standard pediatric vaccination, and neonates immunized with polysaccharide antigens do not develop immunologic tolerance. Here, direct immunization of the baboon fetus with recombinant hepatitis B surface antigen produced a specific fetal IgG antibody response. No specific maternal antibody response was detected, eliminating the possibility of vertical antibody transmission to the fetus. Some infants also responded to later vaccinations with hepatitis B surface antigen, indicating that no immunological tolerance was induced by prior fetal immunization. These results characterize the ability of the fetal immune system to respond to in utero vaccination. We demonstrate that active fetal immunization can serve as a safe and efficient vaccination strategy for the fetus and neonate.     

Fetal breathing and behavior measured through a double-wall Plexiglas window in sheep

The inability to see the fetus makes the assessment of fetal behavior difficult. To circumvent this problem we implanted a Plexiglas window in the left flank of the ewe. Fetuses were instrumented for measurements of sleep, breathing, and swallowing. Ten fetal sheep were studied on 32 occasions. Six fetuses were delivered through the window at term, and postnatal behavior was compared with intrauterine behavior. Fetuses observed during resting conditions alternated between periods of quiet sleep [high-voltage electrocortical activity (ECoG)] and active or rapid-eye-movement sleep (low-voltage ECoG). In quiet sleep, movements were absent except for periodic generalized electromyographic discharges. Eye and breathing movements were rare or absent. Swallowing was also absent. In active sleep, movements were increased with powerful breathing and swallowing activity. Fetal wakefulness defined by open eyes and purposeful movements of the head was never seen in utero but was clearly observed after delivery. We conclude that fetal wakefulness as defined postnatally was not able to be demonstrated in utero.     

Fetal laser surgery in genetic polydactyly mice

The first digital ray of the hindlimb plate in Slc:ICR mouse fetus was irradiated with 2 watts argon laser beam for 0.3 sec after releasing from the abdominal cavity and envelop of uterine myometrium on day 13 of gestation, and then the fetuses were allowed to develop in the abdominal cavity contacting with the uterus via the placenta exo utero until term. ICR mouse fetuses which received fetal laser surgery lost their first digits completely, resulting in 4-digit hindfoot on day 18 of gestation. The homozygous Polydactyly Nagoya (Pdn/Pdn) mice exhibit 1-3 extra digits both in the fore- and hindlimbs preaxially. The extra digital rays in the left hindlimbs of Pdn/Pdn fetuses were irradiated with 2 watts argon laser beam for 0.3 sec on day 13 of gestation exo utero. The left hindlimbs of the Pdn/Pdn fetuses which received fetal laser surgery lost their preaxial extra digits on day 18 of gestation, resulting in 5 digits, though their 1st digit was triphalangia. The combination of a laser instrument with the fetoscope and/or ultrasound scanner may promote the fetal surgery of congenital anomalies in humans.     

Fetal mortality and malformations associated with experimental infections of western equine encephalomyelitis vaccine virus in rhesus monkeys (Macaca mulatta).

Pregnant Rhesus monkeys were infected via installation of Western Equine Encephalomyelitis (WEE) vaccine virus into the amniotic sacs at 50 and 80 days gestation to determine if the resulting infections would produce fetal mortality or fetal malformations, particularly within the central nervous system. Of those receiving virus at 50 days gestation, 13 of 18 fetuses were aborted or dead in utero at time of Caesarean section; 2 of 18 were malformed (hydrocephalus and polyarthrosis); and 3 of 18 were anatomically normal. Of those receiving virus at 80 days gestation four of eight fetuses were aborted or dead in utero at time of Caesarean section, one of eight was malformed (hydrocephalus) and three of eight were anatomically normal. Three of three controls receiving neutralized virus at each gestational age were anatomically normal. Fetal WEE vaccine virus infection significantly increased fetal mortality and resulted in a significant incidence of fetal malformations.     

Exposure in utero to di(n-butyl) phthalate alters the vimentin cytoskeleton of fetal rat Sertoli cells and disrupts Sertoli cell-gonocyte contact

Di(n-butyl) phthalate (DBP) is commonly used in personal care products and as a plasticizer to soften consumer plastic products. Male rats exposed to DBP in utero have malformations of the male reproductive tract and testicular atrophy characterized by degeneration of seminiferous epithelium and decreased sperm production. In the fetal testis, in utero exposure to DBP reportedly resulted in reduced testosterone levels, Leydig cell aggregates, and multinucleated gonocytes (MNG). We investigated whether exposure in utero to DBP affects rat fetal Sertoli cells and compromises interactions between Sertoli and germ cells in the developing testis. Histological examination showed that MNG occurred at low frequency in the normal fetal rat testis. Exposure in utero at the dose level of DBP above estimated environmental or occupational human exposure levels significantly increased the number of these abnormal germ cells. Postnatally, MNG exhibited aberrant mitoses and were detected at the basal lamina. MNG were not apoptotic in the fetal and postnatal rat testes, as indicated by TUNEL. Sertoli cells in DBP-exposed fetal testis had retracted apical processes, altered organization of the vimentin cytoskeleton, and abnormal cell-cell contacts with gonocytes. The effect of DBP on Sertoli cell morphology at the level of light microscopy was reversed after birth and cessation of exposure. Our data indicate that fetal Sertoli cells are targeted by exposure in utero to DBP and suggest that abnormal interactions between Sertoli and germ cells during fetal life play a role in the development of MNG.     

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.     

Fetal surgery.

While most prenatally diagnosed malformations are best managed by appropriate medical and surgical therapy after birth, a few may require or benefit from correction before birth. Extensive experimental work in animals and innovative technologic developments have made fetal surgery a viable approach to perinatal care. Managing preterm labor continues to be a vexing problem. At present, only a few life-threatening malformations have been successfully corrected. Additional research into the abnormal function of some malformations, the development of less interventional techniques, and fetal stem cell transplantation should lead to successful treatment of more fetal disorders.     

Cytologic findings in a fetal intracranial teratoma. A case report

BACKGROUND: Fetal neoplasms are very rare. Recently we had the opportunity to examine the fine needle aspiration (FNA) biopsy of a fetal intracranial teratoma. CASE: The tumor was found in a 30-week-gestation fetus; the mother was 32 years old, gravida 4, para 1. She presented with a rapid increase in abdominal girth over a two-week period. An ultrasound scan showed severe fetal hydrocephalus and a massive intracranial tumor thought to be a teratoma because of variations in echogenicity and spotty calcification. An FNA biopsy was performed under ultrasound guidance. It showed mainly neuroepithelial cells, so a differential diagnosis of malignant neuroepithelial tumor was considered. At autopsy, several other tissue types were found in the tumor, consistent with a teratoma. CONCLUSION: Advances in diagnosis of fetal anomalies by ultrasound have been associated with an increase in the use of fetal interventions performed in utero. This includes the availability of fetal surgery in some centers. FNA biopsy of fetal lesions does not appear to be well described. Increased experience with this technique is necessary if its full potential is to be realized.     

Murine Fetal Echocardiography

Transgenic mice displaying abnormalities in cardiac development and function represent a powerful tool for the understanding the molecular mechanisms underlying both normal cardiovascular function and the pathophysiological basis of human cardiovascular disease. Fetal and perinatal death is a common feature when studying genetic alterations affecting cardiac development ^1-3. In order to study the role of genetic or pharmacologic alterations in the early development of cardiac function, ultrasound imaging of the live fetus has become an important tool for early recognition of abnormalities and longitudinal follow-up. Noninvasive ultrasound imaging is an ideal method for detecting and studying congenital malformations and the impact on cardiac function prior to death ⁴. It allows early recognition of abnormalities in the living fetus and the progression of disease can be followed in utero with longitudinal studies ^5,6. Until recently, imaging of fetal mouse hearts frequently involved invasive methods. The fetus had to be sacrificed to perform magnetic resonance microscopy and electron microscopy or surgically delivered for transillumination microscopy. An application of high-frequency probes with conventional 2-D and pulsed-wave Doppler imaging has been shown to provide measurements of cardiac contraction and heart rates during embryonic development with databases of normal developmental changes now available ^6-10. M-mode imaging further provides important functional data, although, the proper imaging planes are often difficult to obtain. High-frequency ultrasound imaging of the fetus has improved 2-D resolution and can provide excellent information on the early development of cardiac structures ¹¹.     

When hormone defects cannot explain it: Malformative disorders of sex development

The birth of a baby with malformations of the genitalia urges medical action. Even in cases where the condition is not life‐threatening, the identification of the external genitalia as male or female is emotionally essential for the family, and genital malformations represent one of the most stressful situations around a newborn. The female or male configuration of the genitalia normally evolves during fetal life according to the genetic, gonadal, and hormonal sex. Disorders of sex development occur when male hormone (androgens and anti‐Müllerian hormone) secretion or action is insufficient in the 46,XY fetus or when there is an androgen excess in the 46,XX fetus. However, sex hormone defects during fetal development cannot explain all congenital malformations of the reproductive tract. This review is focused on those congenital conditions in which gonadal function and sex hormone target organ sensitivity are normal and, therefore, not responsible for the genital malformation. Furthermore, because the reproductive and urinary systems share many common pathways in embryo‐fetal development, conditions associating urogenital malformations are discussed. Birth Defects Research (Part C) 102:359–373, 2014. © 2014 Wiley Periodicals, Inc.     

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.     

Citrullinemia: prenatal diagnosis of an affected fetus.

We monitored a pregnancy in a family at risk for citrullinemia due to argininosuccinic acid (ASA) synthetase deficiency. ASA synthetase activity in cultured epithelioid amniotic fluid cells from the fetus at risk was less than 2% of control epithelioid amniotic fluid cell activity. An increased concentration of citrulline was found in the at-risk amniotic fluid (0.14 mumol/ml) as compared with fluid from six controls and one at-risk but unaffected pregnancy (trace). The pregnancy was terminated, and the in utero diagnosis was confirmed by assay of ASA synthetase activity in cultured fetal skin fibroblasts (4.4% of control activity). In addition, all five fetal tissues studied had significant accumulation of citrulline, whereas control fetal tissues had none. These data provide evidence that, if precise control is maintained over tissue culture variables, citrullinemia can be diagnosed successfully in utero by microassay of ASA synthetase activity in cultured amniotic fluid cells. They also suggest that amniotic fluid citrulline concentrations provide strong adjunctive evidence for this prenatal diagnosis.     

The use of CD 34(+) mobilized peripheral blood as a donor cell source does not improve chimerism after in utero hematopoietic stem cell transplantation in non-human primates

In utero hematopoietic stem cell transplantation is a therapeutic procedure that could potentially cure many developmental diseases affecting the immune and hematopoietic systems. In most clinical and experimental settings of fetal hematopoietic transplantation the level of donor cell engraftment has been low, suggesting that even in the fetus there are significant barriers to donor cell engraftment. In postnatal hematopoietic transplantation donor cells obtained from mobilized peripheral blood engraft more rapidly than cells derived from marrow. We tested the hypothesis that use of donor hematopoietic/stem cells obtained from mobilized peripheral blood would improve engraftment and the level of chimerism after in utero transplantation in non-human primates. Despite the potential competitive advantage from the use of CD 34(+) from mobilized peripheral blood, the level of chimerism was not appreciably different from a group of animals receiving marrow-derived CD 34(+) donor cells. Based on these results, it is unlikely that this single change in cell source will influence the clinical outcome of fetal hematopoietic transplantation.     

Stage-specific induction of sister-chromatid exchanges in utero

In order to correlate the induction of sister-chromatid exchanges (SCE) to biological endpoints, and elucidate aspects of this relationships, 7,12-dimethylbenz[a]anthracene (DMBA) and methyl methanesulfonate (MMS), chemicals with different biological actions at different stages in development, have been evaluated for their ability to induce SCE at different gestational ages in the Sprague-Dawley rat. Transplacental exposure to these agents was accomplished by a recently developed intraperitoneal infusion technique to replenish metabolically degraded 5-bromo-2'-deoxyuridine used for SCE visualization. Maternal bone marrow and whole fetal tissue, fetal liver and fetal brain were compared. Day-9 embryo was found to be very sensitive to the effects of both agents, with the ability to induce SCE declining in development in whole fetus and fetal organs. The embryotoxic effects of the agents seem to be ones best correlated with the capacity of the agents to induce SCE. Also, fetal liver is more sensitive than fetal brain to the effects of DMBA compared with MMS, suggesting fetal metabolic activation may have occurred. Measurement of the amount of radiolabelled DMBA reaching the fetal tissue used to estimate SCE indicates that the amount of chemical reaching the fetus does not account for the increased sensitivity, especially at Day 9. Some factor(s) in development, such as differentiation stage, rather than the fetal accessibility to chemical, seem to be important in the induction of SCE in utero.     

A method to reduce the invasiveness of fetal catheterization in the cow

Surgical intervention in general anesthesia (GA) of the cow in late gestation is a stressful condition for both mother and fetus, potentially leading to premature delivery or fetal death. The present study hypothesized that fetal catheterization at days 246–253 (90% of gestation) is done with less physical and metabolic stress for the mother and fetus, when the surgery is performed on a standing cow and local anesthesia (LA) rather than on a recumbent cow in general anesthesia. Fetal and uterine maternal intra-vascular catheters were implanted during general anesthesia (GA, n=24) or local analgesia (LA, n=7). Blood gases and metabolite levels in the fetal calves and their mothers were measured during surgery and for 5 days post-operatively. During surgery, venous blood pH was higher (7.44±0.01 versus 7.39±0.01, P<0.05) and hemoglobin and oxygen contents lower in LA cows compared with GA cows (9.3±0.3 mg/dl versus 11.8±0.2 mg/dl, P<0.001 and 10.1±0.3 ml/dl versus 12.6±0.6 ml/dl, P<0.05). The differences between the two groups of fetuses reflected those of their dams in that LA fetuses showed lower arterial oxygen pressure (18.3±1.4 mmHg versus 24.8±1.4 mmHg, P<0.05) and hemoglobin (7.81±0.30 mg/dl versus 9.22±0.21 mg/dl P<0.01) and furthermore, they also showed higher blood glucose (2.4±0.2 mM versus 1.4±0.1 mM, P<0.01). During the 5 days post-surgery, 10 GA fetuses (42%) and 1 LA fetus (14%) died in utero. Bacterial contamination was implicated in six of the GA deaths and in the one LA death. In the dams with surviving calves, differences in hemoglobin (9.49±0.21 mg/dl versus 11.17±0.23 mg/dl P<0.001) and O₂ct (10.9±0.3 ml/dl versus 12.5±0.5 ml/dl, P<0.05) were still present, and in addition, blood glucose was higher in LA versus GA cows (4.3±0.2 mM versus 3.8±0.1 mM, P<0.05). The choice of surgical method did not affect post-surgery blood chemistry in the surviving fetuses, except that the higher blood glucose in the LA fetuses at surgery tended to be maintained also post-operatively (2.0±0.2 mM versus 1.5±0.1 mM, P=0.07). The observed differences in blood chemistry parameters between the two methods of surgery and possibly in the fetal death may be explained by differences in catheterization method and the associated differences in physical and metabolic stress during and after surgery. Thus, surgery upon a standing cow in local anesthesia should be considered as an alternative to surgery in universal anesthesia for fetal catheterization in the cow in late gestation.     

Hormonal regulation of fetal growth

Fetal growth is a complex process depending on the genetics of the fetus, the availability of nutrients and oxygen to the fetus, maternal nutrition and various growth factors and hormones of maternal, fetal and placental origin. Hormones play a central role in regulating fetal growth and development. They act as maturational and nutritional signals in utero and control tissue development and differentiation according to the prevailing environmental conditions in the fetus. The insulin-like growth factor (IGF) system, and IGF-I and IGF-II in particular, plays a critical role in fetal and placental growth throughout gestation. Disruption of the IGF1, IGF2 or IGF1R gene retards fetal growth, whereas disruption of IGF2R or overexpression of IGF2 enhances fetal growth. IGF-I stimulates fetal growth when nutrients are available, thereby ensuring that fetal growth is appropriate for the nutrient supply. The production of IGF-I is particularly sensitive to undernutrition. IGF-II plays a key role in placental growth and nutrient transfer. Several key hormone genes involved in embryonic and fetal growth are imprinted. Disruption of this imprinting causes disorders involving growth defects, such as Beckwith-Wiedemann syndrome, which is associated with fetal overgrowth, or Silver-Russell syndrome, which is associated with intrauterine growth retardation. Optimal fetal growth is essential for perinatal survival and has long-term consequences extending into adulthood. Given the high incidence of intrauterine growth retardation and the high risk of metabolic and cardiovascular complications in later life, further clinical and basic research is needed to develop accurate early diagnosis of aberrant fetal growth and novel therapeutic strategies.     

Fetal breathing and development of control of breathing

Technical advances during the last several decades have greatly facilitated research into fetal physiology and behavior, specifically fetal breathing (FB). Breathing movements have been demonstrated in the fetuses of every mammalian species investigated and appear to be part of normal fetal development. In this review we focus on the methods of measuring FB and on some of the problems associated with these measurements and their interpretation. We also review fetal behavior, the role of the peripheral and central chemoreceptors in spontaneous FB, the fetal respiratory response to hypercapnia and hypoxia, and the transition to continuous breathing at birth. It is clear that in many ways the control of breathing movements in utero differs from that after birth. In particular, inhibitory influences are much more prominent before than after birth. Possibly this is due to the unique fetal situation, in which conservation of energy may be more important than any advantage breathing activity imparts to the fetus.