Morphology of early fetal deaths and their chromosomal characteristics

The morphologic features of a consecutive series of 3,472 singleton spontaneous abortions are described. Of the total, 21% consisted of well-formed fetuses (over 30 mm long), 27.9% had no identifiable fetal tissues, 34.2% consisted of fetal membranes only, and the remainder, 16.8%, consisted of a variety of embryonic types. The rate of focal malformations among embryos over 10 mm in length and among fetuses was 16.4%. The overall rate of chromosome anomalies in the 1,356 karyotyped specimens was 39.8%. The vast majority, 94%, occurred in embryos less than 30 mm, and in specimens whose development had not proceeded beyond differentiation of fetal membranes. The rate of chromosome anomalies among nonmalformed fetuses (greater than 30 mm) was only 1.7%. However, the presence of limited embryonic development was not a good predictor of the presence of a chromosome anomaly. Slightly over half (56%) of all specimens less than 30 mm long had chromosome anomalies; for individual classes of such specimens the rate ranged from 45% to 81%. The morphologic category with the highest rate of karyotypic anomalies had an excess of monosomy X abortuses. A gradient of developmental level could be associated with the degree of intrauterine mortality of each chromosome anomaly; i.e., conceptuses with karyotypes that occur at term had a greater degree of embryonic development than karyotypes that are never seen among term births. Thus, trisomies 13, 18, and 21 were more often associated with fetuses, and less often with tissue fragments than other trisomies. Focal malformations were multiple and severe in abortuses with triploidy, trisomies 13 and 18, and monosomy X and mild in trisomy 21. With the exception of monosomy X the malformations were similar to, and not more severe than those reported from, term births with the same anomaly. The high rate of intrauterine mortality in conceptuses with chromosome anomalies could be ascribed to their failure to develop past the embryonic stages. However, the presence of an equally large fraction of chromosomally normal abortions with the same degree of rudimentary development suggests the existence of early and profound developmental problems that are not associated with anomalies of the chromosome complement.     

Palate development after fetal tongue removal in cortisone-treated mice

Morphological studies of cortisone-induced cleft palate have shown retardation in the rotation of palatine shelves from a sagittal to a transverse plane. Cortisone also reduces fetal muscular movements, which may explain why displacement of the tongue from between the palatine shelves is delayed. Previous work with extrauterine development of control fetuses demonstrated that fetal membranes and tongue were major obstacles to shelf rotation. Thus, removal of these obstacles might permit rotation and fusion of palatine shelves in cortisone-treated fetuses. In the present experiment, fetuses from cortisone-treated strain CD-1 mice were released from uterus and membranes and allowed to develop for eight hours in a fluid medium with the umbilical cord left intact. Compared to 4% fusion in utero, there was palatal fusion in 20% of fetuses released from membranes. When the fetal tongue was removed during extrauterine development, the frequency of fusions increased to 61%. Fusion appeared normal by the criteria applicable through light microscopy. Thus, cortisone induces cleft palate primarily through interference with shelf rotation. The palatine shelves of treated fetuses retain their ability to fuse when they can come in contact during the normal time for palate closure.     

Cytogenetic and histologic analyses of spontaneous abortions

Summary In a study of spontaneous abortions the correlations between karyotype (166 cases), anamnestic data, and macroscopic and histologic findings in placentas (107 cases) and embryos (73 cases) were analyzed. The main results were: 1. The rate of chromosomal aberrations was 39%. Trisomies predominated (60%), followed by monosomy X (20%), triploidies (14%), and structural aberrations (6%). 2. In trisomies a clear prevalence of female sex constitution (2:1) was observed. In normal karyotypes a slight prevalence of females was seen (1.2:1). 3. With increasing maternal age, more trisomies were found in the abortions. 4. Women whose index abortion had a normal karyotype had a history of fewer births but more abortions. 5. Trisomies of acrocentric chromosomes were mainly chorionic sacs with an embryo, while trisomies of the other autosomes resulted in intact empty sacs. 6. The average developmental stage of the embryos was 5 weeks, with a mean gestational age of 14 weeks. Gross malformations were found in 58% of the embryos.     

Development of the orbicularis oris muscle in normal and cleft lip and palate human fetuses using three-dimensional computer reconstruction

As part of an ongoing study of cleft lip and palate fetal morphology, normal and dysmorphic development of the human fetal orbicularis oris muscle was studied in a cross-sectional sample of 29 human fetuses (20 "normal" and 9 cleft lip and palate) ranging in age from 8 to 21 postmenstrual weeks. The specimens were embedded in celloidin and sectioned at 20 microns, and every tenth section was stained with hematoxylin and eosin. A computer reconstruction technique was applied to produce three-dimensional representations of the orbicularis oris muscle. The orbicularis oris muscle in the normal fetal sample with discernible lip fibers (N = 15) increased symmetrically in both fiber density and complexity from 12 to 21 weeks. Metrically, muscle volume and thickness growth curves were consistent with qualitative observations. In contrast, the unilateral cleft lip and palate fetal specimens with discernible lip fibers (N = 3) exhibited a 3.5-week delay in overall muscle development, asymmetrical fiber distribution, and abnormal fiber insertions. However, quantitatively, no significant (p greater than 0.05) differences were noted in orbicularis oris muscle thickness or volume between the normal and cleft lip and palate fetal specimens through 21 weeks. Findings suggest that orbicularis muscle deficiency, noted clinically in cleft lip and palate neonates, may be a result of perinatal functional dysmorphogenesis rather than congenital mesenchymal reduction or deficiency.     

Microarray analysis of cell-free fetal DNA in amniotic fluid: a prenatal molecular karyotype

Metaphase karyotype analysis of fetal cells obtained by amniocentesis or chorionic villus sampling is the current standard for prenatal cytogenetic diagnosis, particularly for the detection of trisomy 21. We previously demonstrated that large quantities of cell-free fetal DNA (cffDNA) are easily extracted from amniotic fluid (AF). In this study, we explored potential clinical applications of AF cffDNA by testing its ability to hybridize to DNA microarrays for comparative genomic hybridization (CGH) analysis. cffDNA isolated from 11 male fetuses showed significantly increased hybridization signals on SRY and decreased signals on X-chromosome markers, compared with female reference DNA. cffDNA isolated from six female fetuses showed the reverse when compared with male reference DNA. cffDNA from three fetuses with trisomy 21 had increased hybridization signals on the majority of the chromosome 21 markers, and cffDNA from a fetus with monosomy X (Turner syndrome) had decreased hybridization signals on most X-chromosome markers, compared with euploid female reference DNA. These results indicate that cffDNA extracted from AF can be analyzed using CGH microarrays to correctly identify fetal sex and aneuploidy. This technology facilitates rapid screening of samples for whole-chromosome changes and may augment standard karyotyping techniques by providing additional molecular information.     

Improved technique for the expression of fragile-X in cultured amniotic fluid cells

Summary An improved technique for inducing fra(X) expression in cultured cells was obtained by using diazepam for mitotic arrest and 5-fluorodeoxyuridine (FUdR) for the induction of fra(X) expression. The method was developed using cultured fibroblast and urinary cells from fra(X) patients. Prenatal studies were performed on cultured amniotic fluid cells in five pregnancies at risk for fra(X). In two cases the cultured cells showed a 46,XY, fra(X) karyotype. One of the pregnancies was terminated and the diagnosis was confirmed by chromosome studies on several fetal tissues including chorionic villi and by histopathologic changes in the lymphatic vessels of the fetal testes. The fra(X) was also demonstrated in chorionic villi in a case in which amniotic fluid cells were not studied. Chorionic villi were isolated after a spontaneous abortion, the cultured cells had a 45,X karyotype and in addition 5% of the cells were fra(X) positive.     

Strain differences between C57BL/6 and SWV mice in time of palate closure and induction of palatal slit and cleft palate

Palatal slit, which occurs spontaneously in C57BL/6 (C57BL) mice, is increased in frequency among C57BL fetuses from dams treated with triamcinolone acetonide, but is not induced in SWV fetuses. On the other hand, C57BL is more resistant than SWV to cleft palate induction by triamcinolone. Using these C57BL and SWV mice, the relation of palate stage and chronological age was examined from 1 P.M. on day 14 to 9 A.M. on day 16 in untreated embryos, and the condition of the palate after triamcinolone treatment on day 12 was examined at 9 A.M. on day 16. In untreated embryos, horizontalization and fusion of the palatal shelves occurred earlier in C57BL than in SWV embryos, but fusion of the primary palate with the secondary palate occurred later. After triamcinolone treatment, the development of the palate was delayed in both C57BL and SWV embryos. These results suggest that the times of normal palate closure are related to the differences between C57BL and SWV mice in their susceptibilities to palatal slit and cleft palate induction and that triamcinolone produces palatal slit and cleft palate by delaying palate closure.     

Genetic aspects of the effects of methylmercury in mice: the incidence of cleft palate and concentrations of adenosine 3':5' cyclic monophosphate in tongue and palatal shelf

Concentrations of adenosine 3':5' cyclic monophosphate (cAMP) were measured in the tongues and palates of 14.5-day-old fetuses from control and methylmercury-treated mothers of four inbred lines of mice which represent the four possible combinations of two H-2 alleles and two residual genetic backgrounds. The incidence of cleft palate in fetuses from control and methylmercury-treated mothers was also examined. The H-2 alleles significantly affected the degree of reduction of cAMP concentration in palates seen in fetuses from mothers treated with methylmercury. Neither the H-2 allele nor the residual genetic background played a role in the effect of methylmercury on cAMP concentrations in fetal tongues. The magnitude of increase in the incidence of cleft palate with methylmercury treatment was approximately the same for all lines. Thus, methylmercury-induced cleft palate may not be mediated by the reduction of cAMP. Finally, fetuses with cleft lip had increased palatal cAMP levels, whether or not they were from control or methylmercury treated mothers.     

Occurrence of cleft palate, palatal slit, and fetal death in mice treated with a glucocorticoid: an embryo transfer experiment

SWV and C57BL/6 (C57BL) mice were treated subcutaneously with triamcinolone acetonide in a single dose of 2.5 mg/kg on day 12 of pregnancy (vaginal plug = day 0), and the palate of their fetuses was examined at term. Cleft palate was seen in some SWV and C57BL fetuses; its frequency was significantly higher in the former. Closer examination revealed palatal slit in some C57BL, but in no SWV fetuses. In addition, fetal mortality was significantly increased in SWV, but not in C57BL, exposed to triamcinolone. These strain differences in cleft palate, palatal slit, and fetal mortality were investigated by embryo transfer. The results showed that, in cleft palate induction, the effects of uterine environment were more important than those of fetal genotype. On the other hand, after transfer, palatal slit still occurred in C57BL but not in SWV fetuses; thus, in palatal slit occurrence, the fetal genotype played a more important role than the uterine environment. Accordingly, it is suggested that the nature of the participation of fetal genotype and uterine environment in palatal slit occurrence is different from that in cleft palate induction. In regard to fetal mortality, embryo transfer procedures influenced it in SWV dams and the effect of triamcinolone could not be detected after embryo transfer.     

Multivariate analysis of second trimester midfacial morphology in normal and cleft lip and palate human fetal specimens.

To better understand the contribution of congenital dysmorphogenesis to postnatal midfacial dysplasia in individuals with complete cleft lip and palate (CLP), a series of studies were undertaken to investigate age related changes in a number of midfacial components for a sample of 20 normal and 9 complete CLP second trimester fetal specimens. Using data from this sample, the present study assessed the complex multivariate relationships among these variables which represent the fetal normal and CLP midface. Ten variables were standardized relative to crown-rump length and used in Canonical Discriminant Function Analysis (CDFA). CDF analysis revealed that five variables best described the midface and accounted for 72% of the overall variance. These included nasal capsule length, nasal airway volume, premaxillary length, premaxillary volume, and tongue volume. Classification using the CDFA coefficients resulted in correct group membership assignment for 26 of 29 total specimens (89.66%), 8 of 9 cleft (88.9%), and 18 of 20 normal specimens (90.0%). These results suggest that by as early as the second trimester CLP fetuses have a significantly distinct set of midfacial morphological relationships. Some or all of these factors may be responsible for postnatal growth dysplasias noted in CLP individuals.     

Prenatal repair of experimentally induced clefts in the secondary palate of the rat

A refined technique of amniotic sac puncturing at day 16.2 (i.e., 16 + 2/10 days) of gestation was employed in order to produce a series of total clefts and rare forms of partial clefts in Sprague-Dawley rat fetuses. From a total of 410 fetuses of a precise, individually determined age, 95 upper jaws were examined in the scanning electron microscope and, in part, in serial Epon sections. All fetal heads were examined macroscopically. Total clefts were found in 48.9% of a total of 184 viable rat fetuses examined at day 17.8 of smear age and in 21.8% of a total of 211 fetuses examined at day 19.3. Partial clefts were observed in 14.1% and 18.5% of fetuses at days 17.8 and 19.3 of smear age, respectively. At day 19.3, 16.1% of the viable fetuses showed a very inconspicuous, small abnormality (with residual clefting and incomplete fusion with the nasal septum) in the region of the palatine foraminae. Morphological observations suggested that under conditions of detained palatal closure (1) fusion of the soft palatal shelves commences independently from and prior to fusion of the hard palate, (2) delayed palatal shelf fusion proceeding in the anterior direction may occur with or without remaining sickle-shaped clefts in the anterior hard palate, and (3) in fetuses with small sickle-shaped clefts, fusion of the palatal shelves with the nasal septum does not occur. The present data imply that an almost total prenatal repair and delayed closure of the secondary palate may occur in rats that, at day 16.2 of multiple analysis age, most certainly had a total palatal cleft resulting from tongue resistance.     

Teratogenic effects of a single oral administration of methylmercuric chloride in mice.

The teratogenic effects of methylmercuric chloride (MMC) given orally as a single dose to pregnant ICR mice on day 10 of gestation were examined. The doses tested were 25, 20, 15 and 10 mg/kg. Controls received distilled water orally. Each group consisted of 20 females. Fetuses were taken on day 18 of gestation for teratological study. The number of resorbed or dead embryos was moderately increased in the 25 mg/kg group. Fetuses from dams given 25, 20 and 15 mg/kg MMC weighed significantly less than those in the control group. Many fetuses with malformations were observed in the treated groups; cleft palate occurred in 100, 58.6 and 28.0% of fetuses from dams given 25, 20 and 15 mg/kg MMC, respectively (statistically significant). Hydronephrosis appeared in 23.8 and 18.5% of fetuses from dams given 25 and 20 mg/kg MMC, respectively (statistically significant). Skeletal variations, incomplete ossification of sternebrae, for example, were also observed in the treated groups. These results indicate that MMC is teratogenic so far as cleft palate is concerned and embryotoxic in ICR mice.     

Upper limb hemimelia in a twin pregnancy which was obtained by an ICSI and PGD in a woman with mosaic Turner's syndrome and the prognosis

Turner's syndrome (TS) is depicted as a total or partial absence of X chromosome, and occurs in approximately 1/2200 of live born females. Generally, mosaic patients are diagnosed following karyotype analysis due to recurrent pregnancy loss, repeated in vitro fertilization (IVF) failure, and a history of malformed babies. The purpose of this case report is to show that even a selection of normal karyotype embryos can result in abnormalities for those with mosaic TS. A 32-year old patient who underwent IVF after ICSI-PGD, and was diagnosed with 45X/46XX karyotype. At the 12-week scan, one of the fetuses had an upper limb hemimelia in one arm, and feticide was applied to that fetus. The patient delivered a healthy, 2980 g female baby at the thirty-eighth week. In mosaic TS pregnancies (even those obtained by ICSI-PGD), fetal anomaly risk is high. Therefore, careful prenatal scanning is needed for these pregnancies.     

The fetal cleft palate: II. Scarless healing after in utero repair of a congenital model.

The role of fetal surgery in the treatment of non-life-threatening congenital anomalies remains a source of much debate. Before such undertakings can be justified, models must be established that closely resemble the respective human anomalies, and the feasibility and safety of these in utero procedures must be demonstrated. The authors recently described and characterized a congenital model of cleft palate in the goat. The present work demonstrates the methodology they developed to successfully repair these congenital cleft palates in utero, and it shows palatal healing and development after repair. A surgically created cleft model was developed for comparative purposes. Palatal shelf closure normally occurs at approximately day 38 of gestation in the caprine species. Six pregnant goats were gavaged twice daily during gestational days 32 to 41 (term, 145 days) with a plant slurry of Nicotiana glauca containing the piperidine alkaloid anabasine; the 12 fetuses had complete congenital clefts of the secondary palate. Repair of the congenital clefts was performed at 85 days of gestation using a modified von Langenbeck technique employing lateral relaxing incisions with elevation and midline approximation of full-thickness, bilateral, mucoperiosteal palatal flaps followed by single-layer closure. Six congenitally clefted fetuses underwent in utero repair, six remained as unrepaired controls. Twelve normal fetuses underwent surgical cleft creation by excision of a 20 x 3 mm full-thickness midline section of the secondary palate extending from the alveolus to the uvula, at 85 days of gestation. Six surgically clefted fetuses underwent concurrent repair of the cleft at that time; six clefted fetuses remained as unrepaired controls. At 2 weeks of age, no congenitally or surgically created clefts repaired in utero demonstrated gross or histologic evidence of scar formation. A slight indentation at the site of repair was the only remaining evidence of a cleft. At 6 months of age, normal palatal architecture, including that of mucosal, muscular, and glandular elements, was seen grossly and histologically. Cross-section through the mid-portion of the repaired congenitally clefted palates demonstrated reconstitution of a bilaminar palate, with distinct oral and nasal mucosal layers, after single-layer repair. In utero cleft palate repair is technically feasible and results in scarless healing of the mucoperiosteum and velum. The present work represents the first in utero repair of a congenital cleft palate model in any species. The use of a congenital cleft palate model that can be consistently reproduced with high predictability and little variation represents the ideal experimental situation. It provides an opportunity to manipulate specific variables, assess the influence of each change on the outcome and, subsequently, extrapolate such findings to the clinical arena with a greater degree of relevance.     

Experimental study of umbilical cord length as a marker of fetal alcohol syndrome

Umbilical cord length has long been investigated as a potential marker of intrauterine events that may place the neonate at risk for future adverse developmental sequelae. Experimentally, significantly shortened cords have been reported in association with prenatal exposure to common drugs of abuse. This study in rats reports the time course of effects on umbilical cord length of a daily maternal ethanol gavage (3,200 mg/kg) from gestational day 6 through termination of pregnancy at either day 17, 18, 19, or 20. A total of 786 fetuses derived from 60 litters were examined. Control fetuses demonstrated a linear increase in umbilical cord length and body weight gain during late gestation, findings that support previous studies. The body weights of the ethanol-exposed fetuses were reduced significantly on all gestational days examined, indicating intrauterine growth retardation, a characteristic of fetal alcohol syndrome. Similarly, acute fetal akinesia as well as long-term sequelae stemming from impaired neurological development would result from the elevated blood ethanol levels achieved in this study. The umbilical cords of ethanol-exposed fetuses were significantly shorter on gestational days 19 and 20 in comparison to their controls, while cord lengths on days 17 and 18 were not shortened significantly. A stretch hypothesis has been proposed suggesting that the degree of fetal activity is the main determinant of umbilical cord length. In rats, there is a physiologic diminution of the volume of amniotic fluid (oligohydramnios) in late gestation (day 19 to term), which restricts fetal movements but does not appear to alter the linear relationships between gestational age and cord length in controls, thus arguing against the stretch hypothesis. However, cord lengths in the ethanol-exposed fetuses plateaued in late gestation, suggesting possible adherence to a stretch hypothesis. This dichotomy is discussed emphasizing fetal growth and activity as well as intrauterine space.     

Combined effects of radiation and caffeine on embryonic development in mice

The combined effect of radiation and caffeine has been studied in mouse embryos. Radiation and/or caffeine were administered to ICR mice on Day 11 of gestation. Intrauterine death, gross malformation, and fetal body weight were selected as indicators of effects. Doses of whole-body gamma irradiation were 0.5 to 2.5 Gy and those of caffeine were 100 and 250 mg/kg maternal body wt. Intrauterine mortality increased with increasing radiation dose; this trend was more remarkable in combination with caffeine. Gross malformations such as cleft palate and defects of forelegs and hindlegs appeared frequently in the fetuses treated with both radiation and caffeine. Decreased fetal weight was observed even in mice treated with 0.5 Gy of radiation or 100 mg/kg caffeine. There was a linear relationship between dose and reduction of fetal weight. The fetal weight was a sensitive, precise, and easy-to-handle indicator for the effects of growth retardation. Intrauterine mortality and frequencies of cleft palate and defects of forelegs and hindlegs were higher than the sum of those induced by radiation and by caffeine separately. The results indicated that the combined action of radiation and caffeine on intrauterine death and malformations was synergistic.     

Development of the lung in mice with bromodeoxyuridine-induced cleft palate

Clinical and laboratory observations show that denial of free communication between the amniotic fluid and lung fluid results in pulmonary hypoplasia. Thus, cleft palate resulting from tongue obstruction to palatal shelf elevation might be associated with disturbed lung development. This association exists in the Pena-Shokeir phenotype. The goal of these experiments was to see what effect bromodeoxyuridine (BUdR)-induced cleft palate had on lung development. LACA mice were injected with 500 mg/kg BUdR on E11 or E11 and E12 of gestation, a treatment known to produce a 25% and 50% incidence of cleft palate, respectively. BUdR had a direct retarding effect on lung growth but, when cleft palate occurred as well, the lungs were more severely affected. Morphometry showed that lungs from fetuses with cleft palate had only one-half the saccular volume of controls or of treated fetuses with normal palates. Although hypoplastic, lungs associated with cleft palate had type I and type II pneumocytes, and the latter were shown by electron microscopy to be capable of producing surfactant. Hence, cellular differentiation had not been affected by the treatment. Fetuses with cleft palate had less amniotic fluid than controls but significantly more than those with normal palates after treatment. Thus, the pattern of abnormalities in this animal model bears some resemblance to that of the human Pena-Shokeir phenotype.     

Effects of the Ay gene on susceptibility to hydrocortisone fetotoxicity and teratogenicity in mice

Effects of the Ay gene, a coat color gene, on susceptibility to hydrocortisone fetotoxicity and teratogenicity were investigated by using the congenic strain of C57BL/6-Ay (Ay/a) which had been maintained by repeated back-crosses of the Ay gene to the C57BL/6 (a/a) background. Matings were conducted as follows (female x male): group I, a/a; group II, a/a x Ay/a; and group III, Ay/a x a/a. Pregnant females were subcutaneously given daily doses of 0, 12.5, 25, or 50 mg/kg of hydrocortisone on days 10-13 of pregnancy. On day 18 of pregnancy, fetuses were sexed, weighed, and examined for external abnormalities. In group I, the mean fetal weight was significantly decreased at a dose of 25 mg/kg or more. The incidences of cleft palate were 3.2 and 22.7% at 25 and 50 mg/kg, respectively. In group II, in which half of the fetuses were expected to carry the Ay gene, the mean fetal weight was decreased significantly at 12.5 mg/kg or more. The incidence of cleft palate in group II at 50 mg/kg was 44.2%, which was significantly higher than that in group I. In group III, in which maternal mice as well as half of their fetuses carried the Ay gene, a decrease in the mean fetal weight was greater than in group II. In addition, the mean percentage of fetal resorptions was significantly increased at 50 mg/kg. The incidence of cleft palate in group III was significantly increased at 25 mg/kg (10.5%) when compared with those in groups I and II. These results indicate that the Ay gene may be associated with susceptibility to hydrocortisone fetotoxicity and teratogenicity in mice.     

Holoprosencephaly in a fetal macaque (Macaca nemestrina) following weekly exposure to ethanol

Previous studies in rodents have indicated that the facial changes of fetal alcohol syndrome (FAS) closely resemble those of a mild form of holoprosencephaly. In order to examine this relationship in non-human primates, we evaluated a 133-day gestation macaque (Macaca nemestrina) with holoprosencephaly, median cleft lip and palate, and encephalocele. The mother had been given ethanol once per week (1.8 g/kg body weight) from weeks 2 to 19 postconception. Diagnosis of holoprosencephaly was made following ultrasound evaluation for polyhydramnios and delivery of the female fetus by caesarean section. Another fetus of identical age was delivered by caesarean section for use as a control. Both fetuses were studied by anthropometric, gross, radiographic, and histologic techniques. In the fetus exposed to alcohol, no extracranial anomalies were identified and the karyotype was normal. The brain was micrencephalic, with absent olfactory bulbs, tracts, optic nerves and chiasma, fused frontal lobes, and a single, dilated lateral ventricle; a parietooccipital encephalocele consisted of thin, dysplastic cortex bordering the ventricle; the cerebellum was dysplastic and superiorly displaced. Within the craniofacial complex, anophthalmia was bilateral; premaxillary components were absent, palatal shelves separate, the maxillae closeset, and the ethmoid bone small and deformed. Most of these defects are similar to those encountered in humans with holoprosencephaly and support the hypothesis of shared etiologic and pathogenetic relations between the facial anomalies of fetal alcohol syndrome and holoprosencephaly.     

The natural history of cytogenetically abnormal fetuses detected at midtrimester amniocentesis which are not terminated electively: new data and estimates of the excess and relative risk of late fetal death associated with 47,+21 and some other abnormal karyotypes.

We report the results of an ongoing survey of rates of spontaneous death of fetuses with chromosome abnormalities detected at second-trimester amniocentesis in which the mother did not elect abortion. Estimated excess risks (and conservative 90% confidence intervals) of spontaneous fetal death for various cytogenetic abnormalities are as follows: 47,+21, 25.6% (18.0%-34.0%); 47,+18, 63.8% (49.3%-79.8%); 47,+13, 36.5% (11%-69.7%); 45,X, 65.3% (41.0%-84.2%); and mosaic 45,X/46,XX, 10.8% (1.0%-26.8%). There is little evidence for an excess risk of fetal death, at least following amniocentesis, for 47,XXX, 47,XXY, or 47,XYY. The excess risks of fetal death were adjusted for the likelihood that a fetus of normal karyotype would undergo spontaneous fetal death in a population of older maternal age similar to that in which prenatal cytogenetic diagnosis is undertaken. The absolute fetal death rates when this factor is ignored are about 3.5% higher (i.e., may be derived by adding 3.5% to the values given). The excess risks are those which are most appropriate for use in estimating the contribution of chromosome abnormalities to spontaneous fetal death.