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Thirty-four fertilized human ova, good, bad and indifferent, recovered from 210 women of known fertility; a study of biologic wastage in early human pregnancy
Pediatrics
Abstract
From a study of 34 early human ova (24 normal and 10 abnormal) recovered from a series of 107 patients known to be fertile whose conditions for conception were optimal it appears that the maximum fertility rate at implantation is 58%; the maximum normal fertility rate after the twelfth day of ovular development is 42%; the probable maximum fertility rate during the preimplantation stages is from 80 to 90%; the greatest ovular loss is in the preimplantation stage; the next greatest loss is during the week after implantation; the ovular loss after the first missed period may be as great as 28.6%, either with or without clinical signs and is therefore comparable to the clinical abortion rate; these defective human fertilized ova rise because of intrinsic defects rather than from defects of the local or endocrine environment, and, finally, the fertility rates and fate of fertilzed ova are roughly comparable in man and other mammals.
... The existence of a black box' was first documented in the mid and late 1950s when precious information on early embryonic losses became available with the publication by Hertig and his group [10][11][12] of the results of a careful investigation of 34 human embryos aged between 1 and 17 days (8 were considered to be in the preimplantation stage), collected over a period of 17 years. They found that 4 of the 8 preimplantation embryos presented with such severe anomalies that gestation could not have proceeded to term. ...
... Calculations of early embryonic losses have been scrutinized by Jarvis [35], who expressed the opinion that: (i) the hypothesis by Roberts and Lowe [13] has no practical quantitative value; (ii) life-table analyses cannot evaluate losses at very early stages of development; (iii) measurement of hCG can only reveal losses occurring from the second week of gestation; and (iv) calculations by Hertig and his group [10][11][12] are highly imprecise and cast doubt on the validity of their analysis. ...
Today, there is strong and diversified evidence that in humans at least 50% of early embryos do not proceed beyond the pre-implantation period. This evidence comes from clinical investigations, demography, epidemiology, embryology, immunology, and molecular biology. The purpose of this article is to highlight the steps leading to the establishment of pregnancy and placenta formation. These early events document the existence of a clear distinction between embryonic losses during the first two weeks after conception and those occurring during the subsequent months. This review attempts to highlight the nature of the maternal–embryonic dialogue and the major mechanisms active during the pre-implantation period aimed at “selecting” embryos with the ability to proceed to the formation of the placenta and therefore to the completion of pregnancy. This intense molecular cross-talk between the early embryo and the endometrium starts even before the blastocyst reaches the uterine cavity, substantially initiating and conditioning the process of implantation and the formation of the placenta. Today, several factors involved in this dialogue have been identified, although the best-known and overall, the most important, still remains Chorionic Gonadotrophin, indispensable during the first 8 to 10 weeks after fertilization. In addition, there are other substances acting during the first days following fertilization, the Early Pregnancy Factor, believed to be involved in the suppression of the maternal response, thereby allowing the continued viability of the early embryo. The Pre-Implantation Factor, secreted between 2 and 4 days after fertilization. This linear peptide molecule exhibits a self-protective and antitoxic action, is present in maternal blood as early as 7 days after conception, and is absent in the presence of non-viable embryos. The Embryo-Derived Platelet-activating Factor, produced and released by embryos of all mammalian species studied seems to have a role in the ligand-mediated trophic support of the early embryo. The implantation process is also guided by signals from cells in the decidualized endometrium. Various types of cells are involved, among them epithelial, stromal, and trophoblastic, producing a number of cellular molecules, such as cytokines, chemokines, growth factors, and adhesion molecules. Immune cells are also involved, mainly uterine natural killer cells, macrophages, and T cells. In conclusion, events taking place during the first two weeks after fertilization determine whether pregnancy can proceed and therefore whether placenta’s formation can proceed. These events represent the scientific basis for a clear distinction between the first two weeks following fertilization and the rest of gestation. For this reason, we propose that a new nomenclature be adopted specifically separating the two periods. In other words, the period from fertilization and birth should be named “gestation”, whereas that from the completion of the process of implantation leading to the formation of the placenta, and birth should be named “pregnancy”.
... One of the best preserved human implantation sites is "The Peter's embryo" which was described by several authors. This embryo is estimated to be thirteen days old, was first described by Peters in 1899 [24], later extensively studied by Hertig et al. 1959 [25] and is also part of the classics "The Human Placenta" by Boyd and Hamilton [26]. Boyd and Hamilton also describe the syncytial surface of the Barnes embryo e another remarkable early human implantation site, estimated to be eleven days old e as "adjacent to an endometrial gland which is showing degenerative changes". ...
... One of the best preserved human implantation sites is "The Peter's embryo" which was described by several authors. This embryo is estimated to be thirteen days old, was first described by Peters in 1899 [24], later extensively studied by Hertig et al. 1959 [25] and is also part of the classics "The Human Placenta" by Boyd and Hamilton [26]. Boyd and Hamilton also describe the syncytial surface of the Barnes embryo e another remarkable early human implantation site, estimated to be eleven days old e as "adjacent to an endometrial gland which is showing degenerative changes". ...
Extravillous trophoblast invasion serves to attach the placenta to the uterus and to enable access to nutrients for the embryo throughout pregnancy - secretions of the uterine glands in the first trimester, maternal blood in the second and third trimester. For assessing extravillous trophoblast invasion, histology (in combination with immunohistochemistry) still plays a major role in placental research. This is especially true for the re-assessment of rare archival specimens from early human implantation sites or placenta in utero with the background of recent knowledge which may help to strengthen current hypotheses. This review summarizes the recently expanded picture of extravillous trophoblast invasion, gives an overview about fundamental archival specimens in placental research, presents new images of archival specimens, gives insights into the latest developments in the field of biobanking and provides insight into the current situation on sample usage in the absence of biobanks. Modern techniques allow expanding our hitherto believed concept of extravillous trophoblast invasion, which is not restricted to spiral arteries: Extravillous trophoblasts also invade into uterine glands and uterine veins and thereby connect all these luminal structures with the intervillous space. All biomedical research dramatically depends on the quality of the assessed biological samples. Hence, researchers should be aware that the time between collection of a sample from a body and the beginning of analysis (pre-analytical phase) may have more impact on the outcome of a study than previously assumed.
... Estimates of natural human embryo mortality have been derived using speculative calculations 1 , mathematical modelling 2 , pregnancy surveys 3 , and a unique collection of surgical material 4,5 . Three well-designed studies (henceforth referred to as the Wilcox 6 , Zinaman 7 and Wang 8 studies) have shown that approximately two-thirds of menstrual cycles in which elevated human chorionic gonadotrophin (hCG) is detected approximately 1 week after ovulation proceed to a live birth. ...
... The analysis presented here cannot be satisfactorily completed owing, in part, to a lack of data on fertilisation success rates in vivo 40,41 . Consequently, the range for pre-implantation loss, at approximately 10-40%, is wide, although inclusive of Hertig's pre-implantation loss estimate of 30% 4,5 . Despite the imperfections and weaknesses in the available data, it is apparent that plausible values for embryo mortality are considerably less than some figures published in the scientific literature. ...
Natural human embryonic mortality is generally considered to be high. Values of 70% and higher are widely cited. However, it is difficult to determine accurately owing to an absence of direct data quantifying embryo loss between fertilisation and implantation. The best available data for quantifying pregnancy loss come from three published prospective studies (Wilcox, Zinaman and Wang) with daily cycle by cycle monitoring of human chorionic gonadotrophin (hCG) in women attempting to conceive. Declining conception rates cycle by cycle in these studies indicate that a proportion of the study participants were sub-fertile. Hence, estimates of fecundability and pre-implantation embryo mortality obtained from the whole study cohort will inevitably be biased. This new re-analysis of aggregate data from these studies confirms the impression that discrete fertile and sub-fertile sub-cohorts were present. The proportion of sub-fertile women in the three studies was estimated as 28.1% (Wilcox), 22.8% (Zinaman) and 6.0% (Wang). The probability of conceiving an CG pregnancy (indicating embryo implantation) was, respectively, 43.2%, 38.1% and 46.2% among normally fertile women, and 7.6%, 2.5% and 4.7% among sub-fertile women. Pre-implantation loss is impossible to calculate directly from available data although plausible limits can be estimated. Based on this new analysis and a model for evaluating reproductive success and failure it is proposed that a plausible range for normal human embryo and fetal mortality from fertilisation to birth is 40-60%.
... 1,2 In 1959, results were published of a study of 210 fertile women who had undergone hysterectomy within three weeks after the estimated day of ovulation. 3 In the examination of the uteri, a total of 26 implanted blastocysts were identified. Two blastocysts were identified as being recently implanted (well attached but still on the surface of the endometrium) in uteri and removed seven to eight days after the estimated day of ovulation. ...
Background Implantation of the conceptus is a key step in pregnancy, but little is known about the time of implantation or the relation between the time of implantation and the outcome of pregnancy. Methods We collected daily urine samples for up to six months from 221 women attempting to conceive after ceasing to use contraception. Ovulation was identified on the basis of the ratio of urinary estrogen metabolites to progesterone metabolites, which changes rapidly with luteinization of the ovarian follicle. The time of implantation was defined by the appearance of chorionic gonadotropin in maternal urine. Results There were 199 conceptions, for 95 percent of which (189) we had sufficient data for analysis. Of these 189 pregnancies, 141 (75 percent) lasted at least six weeks past the last menstrual period, and the remaining 48 pregnancies (25 percent) ended in early loss. Among the pregnancies that lasted 6 weeks or more, the first appearance of chorionic gonadotropin occurred 6 to 12 days after ovulation; 118 women (84 percent) had implantation on day 8, 9, or 10. The risk of early pregnancy loss increased with later implantatio n (P<0.001). Among the 102 concep- tuses that implanted by the ninth day, 13 percent ended in early loss. This proportion rose to 26 percent with implantation on day 10, to 52 percent on day 11, and to 82 percent after day 11. Conclusions In most successful human pregnancies, the conceptus implants 8 to 10 days after ovulation. The risk of early pregnancy loss increases with later implantation
... Endometrial receptivity is closely related to the development of many diseases. Clinical data estimates indicate that one-third of implantation failures are due to the embryo itself, and another two-thirds are due to poor endometrial respectability and inconsistent dialogue between the embryo and the endometrium [2][3][4]. Glycosylation is a significant factor affecting endometrial receptivity. Therefore, understanding how glycosylation N-glycan is covalently attached to proteins on asparagine (Asn) residues via N-glycosidic bonds, which is called the N-linked glycosylation modification of proteins. ...
The endometrium is an important part of women’s bodies for menstruation and pregnancy. Various proteins are widely expressed on the surface of endometrial cells, and glycosylation is an important post-translational modification of proteins. Glycosylation modification is closely related not only to endometrial receptivity but also to common diseases related to endometrial receptivity. Glycosylation can improve endometrial receptivity, promote embryo localization and trophoblast cell adhesion and invasion, and contribute to successful implantation. Two diseases related to endometrial receptivity include endometriosis and endometrial cancer. As a common benign disease in women, endometriosis is often accompanied by an increased menstrual volume, prolonged menstrual periods, progressive and aggravated dysmenorrhea, and may be accompanied by infertility. Protein glycosylation modification of the endometrial surface indicates the severity of the disease and may be an important pathogenesis of endometriosis. In cancer, glycosylation modifications on the surface of tumor cells can be a marker to distinguish the type and severity of endometrial cancer. This review highlights the role of protein glycosylation in embryo–maternal endometrial dialogue and explores its potential mechanisms in diseases related to endometrial receptivity, which could provide a new clinical approach for their diagnosis and treatment.
... It is well established that errors in mitosis and meiosis are very common among all women. It has been estimated that 50% of oocytes are aneuploid [34] and 30% of conceptuses are lost already before missed menstruation [35]. However, in a subset of RPL cases, an extremely increased rate of impaired chromosome segregation may point to systematic errors in the meiotic process. ...
... It is quite important to know what levels of substances (antibiotics, contraceptives, antibodies, etc.) administered to the mother are obtained in uterine and blastocyst fluids and for how long, since the early developmental stages seem to be more susceptible to chemical damage than later fetal stages (Gottschewski, 1964;Clegg, 1971). Such information may also shed light on the maximum reproductive loss, which surrounds implantation (Brambell, 1948;Frazer, 1955;Hertig, Rock, Adams & Menkin, 1959). ...
Dutch belted rabbits were given single intravenous injections of 100 or 200 mg/kg doses of bovine serum albumin (BSA). BSA in serum and uterine fluid at various times after injection was estimated by a quantitative radial immunodiffusion test, which could measure a minimum of 40 ng. The presence of BSA in uterine fluid was confirmed by immunoelectrophoresis and double diffusion in agar.
BSA passes readily into uterine fluid of non-pregnant rabbits, reaching a peak at 12 h after injection, when its concentration is 7–15% of that in serum. About 72 h seems to be required for equilibration of BSA between serum and uterine fluid, at which time the concentration in the former is about 5 times that in the latter. The kinetics of the process is discussed. Compared to the above, passage of BSA into uterine fluid of pregnant rabbits (5–7 days post coitum) is restricted in the following ways. Significant amounts of BSA appear in the fluid only after a maternal dose of 200 mg/kg. BSA in uterine fluid reaches a peak at 24 h after injection, when it is only 4·5% of the serum level. The permeability rate seems to decrease with early gestation.
Approximate rates of entry of BSA into uterine lumen of non-pregnant and pregnant rabbits are 0·4 and 0·25 μg/h. BSA seems to be treated like rabbit albumin in its passage across the uterine epithelium. There is no evidence of selection between these proteins.
... 5 Later, Hertig and co-workers in their study on hysterectomy specimens of women with proven fertility found that 4 among 8 preimplantation embryos and 9 among 26 implanted embryos were morphologically abnormal. 6,7 According to RCOG, recurrent miscarriages are loss of three or more consecutive pregnancies before the period of viability. 8 There is a lack of consensus regarding a universal definition for recurrent miscarriages ever since the concept was first introduced. ...
Background: Recurrent miscarriages have different underlying aetiologies due to which single common treatment protocol is not possible. Thus evaluation of couples for underlying pathologies for recurrent miscarriages is essential to make appropriate treatment plan. Objectives: The aim of this study was to find out common causes of recurrent miscarriages in North Indian population. Material and methods: This was an observational study conducted in a tertiary care hospital in North India. A total of 53 couples presenting with history of three or more recurrent miscarriages were recruited in the study. Relevant history, examination findings and baseline investigations were noted. Specific investigations were done according to findings. Cases were stratified on the basis of maternal age, number of miscarriages and type of aborters (primary/secondary). Results: A probable cause of recurrent miscarriages could be found in 60.4% of cases. In 13.2% cases co-existing aetiologies were found. Among known causes, most frequent finding was infections contributing to 20.76% cases, with CMV being the most prevalent (11.32%). Autoimmune pathology was found in 18.86%, with 15.1% cases with primary antiphospholipid syndrome and 3.8% with systemic lupus erythematosus. Uterine abnormalities were found in 11.3% with majority having cervical incompetence (5.66%) followed by bicornuate uterus (3.8%). Infections and endocrine abnormalities were more common in early miscarriages (14weeks) and mostly among secondary aborters. Diabetes was detected in 3.8%, luteal phase defect in 9.43%, thyroid abnormality in 1.9%, parental chromosomal abnormalities in 3.8% of cases. Conclusion: In our population, prevalence of infections is higher and contribution of autoimmune, anatomic and endocrine factors is also significant. This can help us formulate local cost-effective protocols for evaluation and treatment of recurrent miscarriages.
... Secondly, many human embryos fail at the blastocyst stage, being incapable of completing full blastocyst development, hatching from a glycoprotein shell called the zona pellucida and/or implanting into the maternal uterine endometrium (Hertig et al., 1959;Hardy et al., 1989;Cohen et al., 1990;Boomsma et al., 2009;Koot et al., 2012). Even of embryos that successfully implant, only ~47.7% of those pregnancies continue past the third month of gestation (Boomsma et al., 2009). ...
In preimplantation development, the pluripotent epiblast is the precursor of all foetal tissues and of human embryonic stem cells (hESCs). Investigating the regulatory mechanisms that underpin human pluripotency is therefore vital to understand human embryogenesis and to improve in vitro models of human pluripotency. However, our current knowledge of the transcriptional regulation of human pluripotency is incomplete. In particular, various regulators identified through studies in the mouse display non-conserved expression or function in the human embryo. To explore how such proteins might be involved in the regulation of human pluripotency, I identified a number of transcription factors that are enriched in the human epiblast and expressed specifically in hESCs cultured under naïve, but not primed, pluripotency conditions. Through analysis of expression in both naïve hESCs and the developing human blastocyst, I determined that KLF17 is a promising candidate pluripotency regulator. I therefore performed gain- and loss-of-function analyses to elucidate the function of KLF17 in hESCs. Through ectopic expression of KLF17, I found that it is sufficient to upregulate the expression of a number of naïve hESC-associated genes in primed conditions and to drive transgene-mediated resetting of primed to naïve pluripotency under appropriate culture conditions. However, a CRISPR-Cas9-mediated null mutation of KLF17 revealed that it is not required for naïve pluripotency acquisition or maintenance in vitro. By transcriptome analysis of KLF17-null mutant hESCs during resetting, I identified possible compensatory mechanisms including upregulated expression of paralogous genes and the impact of exogenous WNT inhibition. In all, this work shows a role for KLF17 in establishing naïve pluripotency, but that it is not strictly necessary for generating naïve hESCs. I therefore suggest that the function of KLF17 is to promote a naïve pluripotent phenotype but that under standard conditions, parallel mechanisms exist and are able to compensate in the absence of KLF17.
... Calculations show that about 15% of the eggs of healthy fertile women are lost before fertilisation. Hertig et al (1959) in their analysis of 34 fertilised ova recovered from 211 hysterectomy specimens, estimated the probability of conception to be 85%. Of these fertilised ova 15% would degenerate before implantation and a further 30% after implantation. ...
There is no prospective data available on the incidence of sporadic and recurrent spontaneous abortion which the clinician can use to assess a woman's risk of recurrence, the factors predisposing to abortion and the benefits of treatment. The incidence of spontaneous abortion in 412 women, recruited prospectively from the general population, was 12%. The risk of abortion was influenced by the previous reproductive history, the most important predictive factor being a previous history of abortion. The possibility that an immunological cause might account for these findings was investigated by determining the incidence and natural history of anti-paternal cytotoxic antibody (APCA) in 306 of these pregnancies. The presence of APCA in the serum prior to pregnancy did not confer protection from spontaneous abortion. The development of a positive APCA test during pregnancy occurred in a minority of the patients, being rarely demonstrable before 28 weeks gestation and usually disappearing between pregnancies. These findings suggest that the absence of serum APCA are unlikely to be causally related to recurrent spontaneous abortion. The incidence of abortion among 200 couples with a history of recurrent abortion was 34%. In this population, immunisation treatment with paternal white cells did not improve pregnancy outcome. However, these patients demonstrated several characteristics which distinguished them from patients with sporadic abortion. A history of relative infertility and a delay in conception prior to the studied pregnancy were associated with a particularly poor pregnancy outcome. This association was further investigated by measuring luteinising hormone (LH) concentrations in 193 women before pregnancy. High follicular phase LH levels (>10iu/l) were a significant risk factor for spontaneous abortion. These data indicate that follicular phase LH estimations might be a useful test to assess the prognosis for a pregnancy. The results presented in this thesis demonstrate that pregnancy outcome can be predicted by a woman's reproductive history and her pre-pregnancy LH concentration. It is possible that these two factors are causally related and that many cases of spontaneous abortion are mediated by an endocrine abnormality of the ovary which is potentially remediable.
... McLean distinguishes between different categories of study on embryo loss: those that, in principle, provide information on embryo loss before implantation cc , and those that provide information on loss only after implantation has commenced dd . In the first category, McLean discusses in some detail the unique studies of Hertig previously mentioned 10 In paragraphs 23-25 of WSJM1, he considers two putative biological markers, early pregnancy factor (EPF) and embryo-derived platelet activating factor (EDPAF), that had been proposed to be released within 24 hours of fertilisation. He discusses the possibility that detection of EDPAF might provide insight into the fate of embryos in the first week jj ; however, he offers no quantitative estimates from such investigations. ...
In 2002, in a judgment relating to the use of the morning-after pill, Mr Justice Munby held that pregnancy begins with the implantation of an embryo into the uterus of a woman. The case involved a large body of expert witness evidence including medical and physiological details of human reproduction. Munby J. emphasised one particular aspect of this evidence: namely, the developmental failure rate of human embryos after fertilisation. Under natural conditions, embryo loss is approximately 10-40% before implantation, and total loss from fertilisation to birth is 40-60% (Jarvis, 2016). By contrast, and based on expert witness testimony, Munby J. stated that not much more than 25% of successfully fertilised eggs reach the implantation stage, and that fewer than 15% of fertilised eggs result in a birth, figures that do not accurately represent scientific knowledge regarding human embryo mortality and pregnancy loss under natural conditions. Rather, these figures were derived from experimental laboratory data and clinical outcomes from in vitro fertilisation treatment. Testimony provided by other expert witnesses directly contradicted these specific numerical claims. In emphasising these figures, Munby J. gave the impression that human embryo mortality is substantially higher than available scientific evidence indicated. In this critique, all the scientific expert witness evidence is presented and reviewed, and an explanation provided for why the emphasised figures are wrong. Whether there are implications of Munby J.’s scientific misjudgment on the legal outcome is for others to consider.
... The m ost likely explanation for early pregnancy loss is embryonic morphological abnormalities secondary to genetic factors (Simpson 1991). There is some evidence that a high proportion of embryos conceived in vivo exhibit m orphological abnormalities (Hertig, et al. 1956;Hertig, et al. 1959 Tan, Royston, et al. 1992), even w hen embryos that have survived as far as the blastocyst stage in vitro are transferred (Bolton, et al. 1991). The chance of achieving a pregnancy through IVF is often enhanced by transferring m ore than one embryo at a time. ...
Research involving the use of human embryos has resulted in the development of assisted conception techniques and has also facilitated the development of other potential uses of IVF such as preimplantation diagnosis of genetic disease. However, it also provokes intense ethical debate and, with increasing numbers of assisted conception units offering cryopreservation, the number of embryos available for research is likely to decline. The proposal under investigation was that human parthenogenetic embryos may provide a useful alternative source of material for embryo research. The historical background to the development of in vitro fertilisation, embryonic development, the problems of performing embryo research and alternative models for such research are reviewed. A series of experiments are presented which examine how closely the development of human parthenogenetically activated oocytes and their ability to synthesise DNA and proteins conform to those observed in fertilised embryos. Blastomeres obtained from parthenogenetic embryos were used as a template for DNA amplification using the polymerase chain reaction (PCR) in order to test whether there might be a practical application for these embryos. It was possible to induce parthenogenetic development in 69% oocytes exposed to the calcium ionophore A23187 and activation rates were found to be related to culture media, patients age and previous obstetric history, oocyte grade and age of oocyte at activation. Cleavage is possible in the absence of the paternal genome and parthenote embryos appear similar morphologically to normally fertilised embryos. However, most of the parthenogenetic embryos showed developmental arrest at the 2-4 cell stage, the possible reasons for which are discussed. DNA content measurement confirmed the assumption that single proncleate oocytes have a DNA content compatible with a haploid chromosome complement while those with 2 pronuclei are diploid, and showed that parthenogenetically activated oocytes are capable of replicating their DNA. Attempts to characterise the protein synthetic patterns of parthenogenetic embryos were beset with problems which are discussed. Signals were obtained for the two loci amplified by PCR, although the amplification efficiency appears to be lower than that observed for fertilised embryos, the reasons for which are considered. It was concluded that the developmental arrest observed is likely to be the biggest obstacle to the extensive use of human parthenogenetic embryos in research, and presents an interesting challenge to overcome. Nevertheless, it may be possible to use parthenogenetically activated oocytes as a model for the early stages of human development, at a time when fertilised embryos are rarely available.
... La frecuencia del aborto espontáneo fluctúa entre el 10 y el 18% aproximadamente (1,2,3) . Dentro de este grupo de mujeres existen aquellas que abortan espontáneamente 3 o más embarazos consecutivos; son las I lamadas abortadoras habituales que constituyen el 0.4% de todas las gestaciones y en las cuales las probabilidades de fracaso en un siguiente embarazo son mayores del 47% (4) . ...
El aborto espontáneo ocupa el primer lugar entre las causas de fracaso de la gestación. Dentro de este grupo de mujeres se encuentran las pacientes abortadoras habituales por deficiencia del cuerpo lúteo, para quienes se carecía de una terapia efectiva hasta la fecha. Intentos previos para corregir la deficiencia endógena de progesterona administrando por vía exógena esta hormona, no habían sido exitosos.
En el presente trabajo se intenta corregir esa deficiencia por medio de gonadotropina coriónica l. M ., la cual provocará la liberación endógena de progesterona.
Es así como se seleccionaron dos grupos: uno constituido por 13 embarazadas normales y el segundo por 13 embarazadas con antecedente de 3 o más abortos espontáneos y sin patología detectable. Las pacientes con aborto habitual tuvieron niveles bajos de progestinas plasmáticas al compararlos con las embarazadas normales. Sin embargo, después de administrar gonadotropina coriónica humana a las pacientes abartadoras habituales, los niveles de progestinas se hicieron sensiblemente iguales en ambos grupos y las 26 pacientes finalizaron exitosamente su gestación.
Sobre la base de los anteriores resultados se sugiere la administración periódica de cantidades conocidas de gonadotropina coriónica humana en la prevención del aborto en pacientes abortadoras habituales, por deficiencia de progesterona.
... The extent of preimplantation loss in humans has been a subject of speculation for decades. Hertig and Rock's extraordinary 1959 study of uteri surgically removed from fertile women provided the first evidence of extensive early pregnancy loss in humans-although with too few observations to quantitate that extent (Hertig et al., 1959). Since then, there have been many estimates of preimplantation loss, widely varying and mostly based on thin assumptions or scant data (Chard, 1991;Weinberg and Wilcox, 1995;Kennedy, Figure 3 Continuous relationship of fertilization rate and estimated preimplantation loss. ...
Study question:
What proportion of fertilized human ova are lost before implantation?
Summary answer:
An estimated 40 to 50% of fertilized ova fail to implant.
What is known already:
Preimplantation loss is not detectable with current technology. Published estimates of preimplantation loss range from 10 to 70%.
Study design, size, duration:
We combine data from epidemiologic, demographic, laboratory and in vitro fertilization studies to construct an empirical framework for the estimation of preimplantation loss. This framework is summarized in a user-friendly Excel file included in supplement.
Participants/materials, setting, methods:
We draw from multiple sources to generate plausible estimates of fecundability, sterility, transient anovulation, intercourse patterns and the proportion of ova fertilized in the presence of sperm. We combine these estimates to generate a summary estimate of preimplantation loss. This estimate can be considered an average for couples in their prime reproductive years.
Main results and the role of chance:
Under a plausible range of assumptions, we estimate that 40 to 50% of fertilized ova fail to implant.
Limitations, reasons for caution:
A crucial factor in estimating preimplantation loss is the probability that an ovum will be fertilized when exposed to sperm. Human data are available only from in vitro fertilization (IVF), which may not accurately represent events in vivo. We therefore assume a range of in vivo fertilization rates, from 64% (human IVF data) to 90% (mouse data).
Wider implications of the findings:
Our estimate of preimplantation loss takes into account the biological processes relevant to fertilization and loss. Using this empirical basis for estimation, we find support for the usual assumption that risk of loss is highest in the earliest days following fertilization. Furthermore, this framework can provide improved estimates as better reproductive data become available. To the extent that our estimates are accurate, more fertilized ova are apparently lost in vitro than in vivo, suggesting that further improvements in IVF success rates may be possible.
Study funding/competing interest(s):
This study was supported by the Intramural Program of the National Institute of Environmental Health Sciences, NIH. Professor Adashi serves as Co-Chair of the Safety Advisory Board of Ohana Biosciences, Inc. The other authors have no competing interests.
Trial registration number:
N/A.
... Successful implantation should mainly consist of the following three steps: apposition and implantation, which occur notably in the upper posterior wall of the uterus, and stable adhesion (Hertig et al., 1959). Several studies have suggested that BPA exposure impairs uterine receptivity (Bromer et al., 2010;Salleh and Giribabu, 2014;Xiao et al., 2011), which is important for successful embryo implantation. ...
Bisphenol A (BPA) is a substance ubiquitously present in the environment, and its toxicity on reproductive function has been well characterised in animal models. However, it is still controversy about the effects of BPA exposure on human female reproduction. Therefore, in the present study, the associations of urinary BPA concentration with the outcomes of in vitro fertilisation (IVF) and embryo transfer from fresh and frozen cycles were analysed in the same cohort. 351 women who underwent IVF treatment from September 2013 to October 2016, at the Centre of Reproductive Medicine in the Women's Hospital School of Medicine at Zhejiang University were recruited. Single-spot urine samples were collected on the day of oocyte retrieval to detect BPA using solid-phase extraction and liquid chromatography coupled with tandem mass spectrometry. A multivariable generalised linear mixed model was used to evaluate the association between the urinary BPA concentration and IVF outcomes. After adjustment for age, body mass index, baseline follicle-stimulating hormone level, baseline oestradiol level, and antral follicle count, a significant decrease in the number of retrieved oocytes and in the rates of clinical pregnancy and implantation was observed in the patients with a high urinary BPA concentration. We concluded that BPA exposure exert negative effects on oocyte retrieval and embryo implantation in women undergoing IVF.
... In addition, a considerably large proportion of human conceptions seem to end in subclinical abortions. It seems that defective development occurs frequently in early human pregnancy and more than 90% of malformed embryos die in utero [20,21].Spontaneous abortion was considered to be a natural scavenging process that reduces the birth of abnormal babies. This is also a reason why the extrapolation of reproductive toxicity data in laboratory animals to the human is one of the most difficult tasks in developmental toxicology. ...
Representatives of applied science (e.g. governmental organizations, academia, and industry) met to discuss the progress towards a harmonized human health risk assessment in developmental toxicology of plant protection products, biocidal products, and other environmental chemicals at the 9th Berlin Workshop on Developmental Toxicity held in September 2018. Within the focus of the scientific discussion were the future of in-vitro methods for developmental and reproductive toxicology, the potential relevance of alternative species in testing of developmental effects, and risk and hazard assessment of developmental and endocrine effects.
Furthermore, the need for a harmonized terminology for classification of anomalies in laboratory animals in developmental toxicity studies aiming for human health risk assessment was determined. Here, the DevTox database was identified as an extremely valuable tool. Overall, the participants agreed that still one of the biggest challenges for testing developmental toxicity in the 21st century is the development of animal-free test strategies and alternatives to animal testing that could provide human-relevant information in a rapid, efficient, and mechanistically informative manner.
... Studies on mammalian fertility indicated very soon that fundamental problems must occur during preimplantation development. A study in the 1950s found that only approximately 58% of naturally conceived embryos were able to implant in the uterus at blastocyst stage [1]. Subsequently, many studies examining oocytes and early embryos from several mammalian species, including human oocytes and embryos from patients undergoing assisted reproductive treatment, have provided clear evidence that the division fidelity of female meiosis and embryonic mitoses is substantially lower than in cells of somatic tissues [2][3][4]. ...
Chromosome segregation errors occur frequently during female meiosis but also in the first mitoses of mammalian preimplantation development. Such errors can lead to aneuploidy, spontaneous abortions, and birth defects. Some of the mechanisms underlying these errors in meiosis have been deciphered but which mechanisms could cause chromosome missegregation in the first embryonic cleavage divisions is mostly a “mystery”. In this article, we describe the starting conditions and challenges of these preimplantation divisions, which might impair faithful chromosome segregation. We also highlight the pending research to provide detailed insight into the mechanisms and regulation of preimplantation mitoses.
... It is well established that errors in mitosis and meiosis are very common among all women. It has been estimated that 50% of oocytes are aneuploid [29] and 30% of conceptuses are lost already before missed menstruation [30]. However, in a subset of RPL cases, an extremely increased rate of impaired chromosome segregation may point to systematic errors in the meiotic process. ...
Recurrent pregnancy loss (RPL) affects 1-5% of couples aiming at childbirth. Up to 50% of products of conception (POC) of RPL cases have gross genomic rearrangements. As parental chromosomal abnormalities occur in 10% of RPL couples, the rest of the cases indicate genomic instability in gametogenesis or early embryo, leading to major disturbances in developmental processes. Thus, RPL can be largely considered as a disorder caused by ‘unfavorable genomes’ of partners or their POCs, unable to result in a viable newborn. This concept is supported by the emerging links between RPL, developmental disorders and infertility. In clinical management, microarray-based analysis of submicroscopic rearrangements would improve counselling about the risks for additional pregnancy losses and future reproductive choices. An ultimate aim to improve the quality of personalized counselling of RPL couples is to develop a diagnostic gene panel for cost-effective screening of mutations predisposing to pregnancy losses in these families.
... To obtain an unbiased estimate of the abortion rate, we need to add to curve 2 in Fig. 3 (probability of abortion given that a clinically detected pregnancy occurs) an unbiased estimate of total occult abortions. Boklage [7] estimated the survival function for a human conceptus throughout gestation by combining information from: studies estimating the probability of fertilization per menstrual cycle in women trying to have children (e.g., [24]), ii) the fate of a sample of 107 ovulated eggs in women who had hysterectomies soon after a potential conception, and hence the fate of the egg could be evaluated by direct inspection [25], iii) combining information from all previous studies of preclinical (occult) abortions detected by elevated levels of hCG (e.g., [15]), and iv) life tables constructed by following the survival of 3,083 clinically detected pregnancies (e.g., [26]). These data were collected predominantly from women in the USA (most of European descent) living under economically developed conditions. ...
Information from many large data bases and published studies was integrated to estimate the age-specific spontaneous abortion rate in an economically-developed human population. Accuracy was tested with published data from a diverse array of studies. Spontaneous abortion was found to be: i) the predominant outcome of fertilization and ii) a natural and inevitable part of human reproduction at all ages. The decision to reproduce is inextricably coupled with the production of spontaneous abortions with high probability, and the decision to have a large family leads to many spontaneous abortions with virtual certainty. The lifetime number of spontaneous abortions was estimated for a canonical woman (constrained to have average age at marriage, first birth, inter-birth intervals, and family size) in two populations: one with and the other without effective birth control (including free access to elective abortions). Birth control was found to reduce lifetime abortions more than 6-fold.
... However, this high rate of peri-implantation loss is not solely a feature of assisted conception treatment. The first indications of the high peri-implantation attrition that characterizes human reproduction were revealed by Hertig and colleagues 1950s exploration of 210 postovulation hysterectomy specimens where only 34 yielded fertilized ova, good, bad, and indifferent [5]. The development of sensitive urinary human chorionic gonadotropin (hCG) assays led to the landmark study of Wilcox et al. [6] in which serial urinary samples collected over 6 mo or until a positive pregnancy test were collected from 221 women trying to conceive. ...
Human embryos frequently harbor large-scale complex chromosomal errors that impede normal development. Affected embryos may fail to implant although many first breach the endometrial epithelium and embed in the decidualizing stroma before being rejected via mechanisms that are poorly understood. Here we show that developmentally impaired human embryos elicit an endoplasmic stress response in human decidual cells. A stress response was also evident upon in vivo exposure of mouse uteri to culture medium conditioned by low-quality human embryos. By contrast, signals emanating from developmentally competent embryos activated a focused gene network enriched in metabolic enzymes and implantation factors. We further show that trypsin, a serine protease released by pre-implantation embryos, elicits Ca2+ signaling in endometrial epithelial cells. Competent human embryos triggered short-lived oscillatory Ca2+ fluxes whereas low-quality embryos caused a heightened and prolonged Ca2+ response. Thus, distinct positive and negative mechanisms contribute to active selection of human embryos at implantation.
While model organisms have had many historians, this article places studies of humans, and particularly our development, in the politics of species choice. Human embryos, investigated directly rather than via animal surrogates, have gone through cycles of attention and neglect. In the past 60 years they moved from the sidelines to center stage. Research was resuscitated in anatomy, launched in reproductive biomedicine, molecular genetics, and stem-cell science, and made attractive in developmental biology. I explain this surge of interest in terms of rivalry with models and reliance on them. The greater involvement of medicine in human reproduction, especially through in vitro fertilization, gave access to fresh sources of material that fed critiques of extrapolation from mice and met demands for clinical relevance or “translation.” Yet much of the revival depended on models. Supply infrastructures and digital standards, including biobanks and virtual atlases, emulated community resources for model organisms. Novel culture, imaging, molecular, and postgenomic methods were perfected on less precious samples. Toing and froing from the mouse affirmed the necessity of the exemplary mammal and its insufficiency justified inquiries into humans. Another kind of model—organoids and embryo-like structures derived from stem cells—enabled experiments that encouraged the organization of a new field, human developmental biology. Research on humans has competed with and counted on models.
Although much of the foundational basic scientific and clinical research was conducted in the United States (U.S.), the first IVF birth occurred in the United Kingdom. Why? For centuries, all research surrounding the field of 'reproduction' has elicited bipolar passionate responses by the American public, and the issue of 'test tube babies' has been no different. The history of conception in the US is defined by complex interrelationships among scientists, clinicians, and politically charged decisions by various branches of the US government. With a focus on research in the U.S., this review will summarize early scientific and clinical advances important to the development of in vitro fertilization and then address potential future developments in IVF. We will also consider what future advances are possible in the U.S. given current regulations, laws, and funding.
The word “abortion” is associated with spontaneous pregnancy loss as well as both legal and illegal termination of pregnancy. This has been unhelpful in the discussion of this topic and led to confusion from the use of different terms for the same process. The term “abortion” may be used for losses under 12 weeks and for previable fetuses (20 and even up to 28 weeks). Others refer to “late abortions” for fetuses delivered at a gestation after viability, and “induced abortion” is sometimes used to refer to the process to deliver a fetus after spontaneous fetal demise.
Developmental errors occur frequently early in gestation and at least 10% of human embryos are morphologically and/or cytogenetically abnormal around the fifth week of gestation. The causes of developmental anomalies are genetic, environmental, or a combination of multiple factors. It appears that developmental errors and reproductive losses occur exceptionally frequently in the human species, but most abnormal embryos/fetuses die in utero and end in spontaneous abortion. High mutation rates in humans can be deleterious for human health and survival, but mechanisms may exist that favor normal over faulty conceptions and bring about natural elimination of abnormal human conceptuses.KeywordsReproductionPrenatal developmentDevelopmental errorReproductive loss
Background
Various malformations are frequently encountered in spontaneously aborted embryos and fetuses. Thus, spontaneous abortion appears to be a screening device for abnormal conceptuses (“teratothanasia”). However, the prevalence rate of abnormal conceptuses at each gestational stage is unknown and the true picture of prenatal natural selection remains to be elucidated.
Methods
An in utero life‐table of normal and malformed human conceptuses was constructed utilizing the data for human embryos and fetuses procured after therapeutic abortion and kept in the Kyoto Collection of Human Embryos (N = 21,798).
Results
The prevalence of external major malformations was estimated to be 9.6% at the start of the fifth week after fertilization and drop to 9.2, 8.5, and 7.5% during the following weeks. The malformation rate decreased to 5.3% by the end of the embryonic period (the eighth week), 2.8% by the 13th week and 1% at term. The prenatal mortality rate of externally malformed conceptuses between the fifth week of gestation and term was 92.8%, whereas the corresponding rate for externally normal embryos was 24.9%. The prenatal mortality rates of embryos with neural tube defects and holoprosencephaly were 96.0 and 99.7%, respectively.
Conclusions
Abnormal development occurs frequently early in development and many of the malformed embryos/fetuses die in utero to end in spontaneous abortion. Natural prenatal screening of abnormal conceptuses most likely contributes to reducing the birth of malformed infants.
Preimplantation genetic diagnosis (PGD) involves the genetic screening of cleavage-stage embryos generated by in vitro fertilisation (IVF), and has been introduced for couples at high risk of transmitting a genetic defect many of whom have experienced recurrent spontaneous or induced abortion. Prompted by growing patient demand, this study has centred on developing new approaches for PGD of chromosomal abnormalities using fluorescent in situ hybridisation (FISH). Dual and triple combinations of locus-specific FISH probes for chromosomes 13, 14, 15, 18 and 21 were developed, and evaluated in seventy-one surplus IVF embryos. In the normally developing group (43 embryos), 67% were uniformly normal, 19% were diploid mosaic, 9% were aneuploid mosaic and 5% were chaotic. In the abnormally developing group (28 embryos), 21% were normal and 79% were chromosomally abnormal. PGD strategies were designed for fifty referrals involving chromosomal indications, 12% of which reached the embryo biopsy stage of PGD whilst 18% are awaiting treatment. Over two thirds withdrew from further treatment, reasons included: 26% losing contact with the Centre, 16% naturally conceived normal pregnancy, 10% electing for alternative treatment, 10% personal circumstances and 8% IVF-related problems. Six couples underwent PGD, one gonadal mosaic for trisomy 21, two balanced reciprocal translocation carriers and three Robertsonian translocation carriers. Over ten IVF cycles, a total of 160 oocytes were retrieved and 72% (53/74) of resulting embryos were biopsied. FISH analysis showed 15% of embryos were normal for the chromosomes tested, whilst 85% were chromosomally unbalanced, categorised as 50% aneuploid/mosaic and 35% chaotic. No clinical pregnancies resulted from three single and three double embryo transfers. From these data three distinct mechanisms were identified which appear to be implicated in the reproductive problems experienced by these patients: gonadal mosaicism with precocious chromatid segregation; increased abnormal meiotic segregation associated with terminal translocation breakpoints; and a high incidence of chaotic chromosome distribution and division in early cleavage-stages.
With the advent of efficient, easy-to-use genome editing by CRISPR–Cas9, editing human embryos is now possible, providing tremendous opportunities to study gene function and cell fate in early human development. The technique can also be used to modify the human germline. Unresolved questions about pre-implantation human development could be addressed by basic research using CRISPR–Cas9. In this Perspective, we discuss advances in human genome editing and consider ethical questions and potential clinical implications of this technology.
In a review written in 1987 entitled “Pioneering mammalian embryo culture,” John Biggers (The mammalian preimplantation embryo: regulation of growth and differentiation in vitro, Plenum Press, New York, 1987) summarized the history of early preimplantation embryo culture as follows “The culture of early mammalian embryos has been studied predominantly in two species: the rabbit and the mouse. Up to 1949, the rabbit was used almost exclusively, with media composed of ill-defined biological fluids. After this time, techniques for the culture of preimplantation mouse embryos rapidly developed using simple, defined media with relatively few components… In the 1960s, there was renewed interest in the culture of early rabbit embryos and a marked difference in the nutritional requirements of the two species was found.” This chapter describes the history of the development of the semi-defined medium that stimulated this “renewed interest” referred to above and includes some of the initial difficulties in getting the work published. The phrase “semi-defined medium” is understood here to mean a defined medium (all of whose components are chemically known) supplemented with an undefined component such as albumin.
Purpose of Review
Human reproduction is a common process and one that unfolds over a relatively short time, but pregnancy and birth processes are challenging to study. Selection occurs at every step of this process (e.g., infertility, early pregnancy loss, and stillbirth), adding substantial bias to estimated exposure-outcome associations. Here, we focus on selection in perinatal epidemiology, specifically, how it affects research question formulation, feasible study designs, and interpretation of results.
Recent Findings
Approaches have recently been proposed to address selection issues in perinatal epidemiology. One such approach is the ongoing pregnancies denominator for gestation-stratified analyses of infant outcomes. Similarly, bias resulting from left truncation has recently been termed “live birth bias,” and a proposed solution is to control for common causes of selection variables (e.g., fecundity, fetal loss) and birth outcomes. However, these approaches have theoretical shortcomings, conflicting with the foundational epidemiologic concept of populations at risk for a given outcome.
Summary
We engage with epidemiologic theory and employ thought experiments to demonstrate the problems of using denominators that include units not “at risk” of the outcome. Fundamental (and commonsense) concerns of outcome definition and analysis (e.g., ensuring that all study participants are at risk for the outcome) should take precedence in formulating questions and analysis approaches, as should choosing questions that stakeholders care about. Selection and resulting biases in human reproductive processes complicate estimation of unbiased causal exposure-outcome associations, but we should not focus solely (or even mostly) on minimizing such biases.
Four topics on normal and abnormal human prenatal development are briefly reviewed. These studies were made possible by using the Kyoto Collection of Human Embryos, the largest collection of human embryo specimens procured after therapeutic abortion. The topics discussed include: (1) variability of human embryo development and implications for clinical teratology, (2) abnormal development in human embryos and intrauterine fate of human conceptuses, (3) holoprosencephaly, and (4) maternal hyperthermia in early pregnancy and birth defects. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc.
A mail questionnaire was sent to Finnish anaesthetists and paediatricians to evaluate the risks of reproductive, teratogenic and health complications related to the professions. The incidence of diagnosed spontaneous miscarriages in anaesthetists' families was 10.2% of all pregnancies and it was 13.2% in paedia-tricians' families. Smoking seemed to increase markedly the incidence of spontaneous miscarriages, which was 22.9% in smoking female anaesthetists and 17.2% in smoking female paediatricians. The gestation times in cases of both full-term pregnancies and miscarriages were shorter in the anaesthetist group than those in the paediatrician group. Congenital abnormalities appeared at an equal rate in both anaesthetist and paediatrician groups, but strikingly, there were nine musculoskeletal abnormalities in the anaesthetists' children compared to no such defects in paediatricians' children. Serious diseases occurred at low frequencies, but three cases of hepatic jaundice and three cases of viral myocarditis in anaesthetists indicate possible infectious hazards to health in anaesthetic work. Different infectious diseases to the respiratory and urinary tracts were commonest among paediatricians. Cancer was not reported in the anaesthetist group. The study does not indicate that gas pollution in operating rooms is harmful to the personnel.
Surveillance of pregnancy loss as a way to detect hazardous exposures is attractive in principle. However, there are no established methods for monitoring pregnancy loss in humans. Surveillance is difficult because most loss occurs within the first 12 weeks of gestation, when pregnancy may not he documented or even recognized. Three possible approaches to surveillance of pregnancy loss are discussed here: direct surveillance of recognized loss, direct surveillance of unrecognized loss, and indirect surveillance of all loss. These approaches vary in cost, technique, power, and interpretability. While these surveillance methods appear potentially useful, their effectiveness in practice has not yet been determined.
How many human embryos die between fertilisation and birth under natural conditions? It is widely accepted that natural human embryo mortality is high, particularly during the first weeks after fertilisation, with total prenatal losses of 70% and higher frequently claimed. However, the first external sign of pregnancy occurs two weeks after fertilisation with a missed menstrual period, and establishing the fate of embryos before this is challenging. Calculations are additionally hampered by a lack of data on the efficiency of fertilisation under natural conditions. Four distinct sources are used to justify quantitative claims regarding embryo loss: (i) a hypothesis published by Roberts & Lowe in The Lancet is widely cited but has no practical quantitative value; (ii) life table analyses give consistent assessments of clinical pregnancy loss, but cannot illuminate losses at earlier stages of development; (iii) studies that measure human chorionic gonadotrophin (hCG) reveal losses in the second week of development and beyond, but not before; and (iv) the classic studies of Hertig and Rock offer the only direct insight into the fate of human embryos from fertilisation under natural conditions. Re-examination of Hertig’s data demonstrates that his estimates for fertilisation rate and early embryo loss are highly imprecise and casts doubt on the validity of his numerical analysis. A recent re-analysis of hCG study data concluded that approximately 40-60% of embryos may be lost between fertilisation and birth, although this will vary substantially between individual women. In conclusion, natural human embryo mortality is lower than often claimed and widely accepted. Estimates for total prenatal mortality of 70% or higher are exaggerated and not supported by the available data.
Along with errors in meiosis, mitotic errors during post-zygotic cell division contribute to pervasive aneuploidy in human embryos. Relatively little is known, however, about the genesis of these errors or their fitness consequences. Rapid technological advances are helping to close this gap, revealing diverse molecular mechanisms contributing to mitotic error. These include altered cell cycle checkpoints, aberrations of the centrosome, and failed chromatid cohesion, mirroring findings from cancer biology. Recent studies are challenging the idea that mitotic error is abnormal, emphasizing that the fitness impacts of mosaicism depend on its scope and severity. In light of these findings, technical and philosophical limitations of various screening approaches are discussed, along with avenues for future research.
Aus einer allgemein biologischen Betrachtungsweise ist jede nachweisbare Abweichung vom normalen Entwicklungsgang im submikroskopischen, mikroskopischen oder makroskopischen Bereich eine Mißbildung. Dieser biologische Mißbildungsbegriff, der sich theoretisch auch auf die postnatale Entwicklung bezieht, besitzt keine scharfen Konturen und ist nur für die Erfassung der Streubreite spezieller Entwicklungsstörungen brauchbar (Goerttler). In bezug auf die intrauterine Entwicklungsentgleisung ist der Begriff angeborene Mißbildung klar definiert: Es handelt sich um eine strukturelle anatomische Abweichung von der Form, Größe und Differenzierung eines oder mehrerer Organe oder des gesamten Organismus außerhalb der physiologischen Variabilität.
Leben und Gesundheit des Kindes sind schon lange vor der Geburt gefährdet. Die pränatalen Schäden und ihre Folgen sind aber im Dunkel des Mutterleibes der direkten Beobachtung nicht zugänglich. Grundsätzliche Erkenntnisse über Häufigkeit, Intensität und Termingebundenheit der einzelnen Schäden sind in den letzten Jahren und Jahrzehnten erarbeitet worden (Abb. 286).
Specific learning difficulties and behavioral and emotional problems occur for many different reasons. In 1976, series of screening questionnaires in an attempt to identify children and adults for whom neurological and developmental factors were a primary source of secondary educational, emotional, or behavioral symptoms. Over the many years that the INPP questionnaire has been in use, it has been found that if a child scores more than seven “yes” answers on each numbered question, it is highly probable that further investigations would reveal immaturity in the functioning of the central nervous system (CNS). This questionnaire is adapted from the original Blythe-McGlown Child Questionnaire. It includes questions on family history, child conception, medical problems during pregnancy, term of pregnancy, and the birth process. Labor is usually considered prolonged if it exceeds 24 h in a mother delivering her first baby and 12 h for a woman who has had a prior delivery.
This report presents the results of a computer analysis of 1672 specimens of embryonic material which were obtained by induced abortion in normal pregnancies. The study was undertaken to evaluate the effect of maternal age, parity, fetal sex and seasonal variations on the growth rate of embryos and fetuses which were between six and 20 weeks' gestation. Two parameters of intrauterine growth were analyzed: (a) the relation between menstrual age and crown‐to‐rump length and (b) the crown‐to‐rump length versus the body weight ratio. None of the quoted factors seemed to affect the linear growth of the embryo or fetus. The correlations between fetal crown‐to‐rump length and body weight were not influenced by maternal age, parity or fetal sex. Significant (p < 0.001) differences in early intrauterine growth rates were detected in relation to the season of conception. The rate of increase of body weight was far above average in those embryos and fetuses conceived during the summer months, while the opposite was the case when the conception occurred in the fall. An increase in the rate of the weight gain was demonstrated among the products of conceptions which occurred in the winter. There were insufficient data about those fetuses that resulted from conceptions which occurred in the spring.
Natural human embryonic mortality is generally considered to be high. Values of 70% and higher are widely cited. However, it is difficult to determine accurately owing to an absence of direct data quantifying embryo loss between fertilisation and implantation. The best available data for quantifying pregnancy loss come from three published prospective studies (Wilcox, Zinaman and Wang) with daily cycle by cycle monitoring of human chorionic gonadotrophin (hCG) in women attempting to conceive. Declining conception rates cycle by cycle in these studies indicate that a proportion of the study participants were sub-fertile. Hence, estimates of fecundability and pre-implantation embryo mortality obtained from the whole study cohort will inevitably be biased. This new re-analysis of aggregate data from these studies confirms the impression that discrete fertile and sub-fertile sub-cohorts were present. The proportion of sub-fertile women in the three studies was estimated as 28.1% (Wilcox), 22.8% (Zinaman) and 6.0% (Wang). The probability of conceiving an hCG pregnancy (indicating embryo implantation) was, respectively, 43.2%, 38.1% and 46.2% among normally fertile women, and 7.6%, 2.5% and 4.7% among sub-fertile women. Pre-implantation loss is impossible to calculate directly from available data although plausible limits can be estimated. Based on this new analysis and a model for evaluating reproductive success and failure it is proposed that a plausible range for normal human embryo and fetal mortality from fertilisation to birth is 40-60%.
It is generally accepted that natural human embryo mortality during pregnancy is high – losses of 70% and higher from fertilisation to birth are frequently claimed. The first external sign of pregnancy occurs two weeks after fertilisation with a missed menstrual period. Establishing the fate of embryos before this is challenging, and hampered by a lack of data on the efficiency of fertilisation under natural conditions. Four distinct sources are cited to justify quantitative claims regarding embryo loss: (i) a hypothesis published by Roberts & Lowe in TheLancet is widely cited but has no quantitative value; (ii) life table analyses give consistent assessments of clinical pregnancy loss, but cannot illuminate losses at earlier stages of development; (iii) studies that measure human chorionic gonadotrophin (hCG) reveal losses in the second week of development and beyond, but not before; and (iv) the classic studies of Hertig and Rock offer the only direct insight into the fate of human embryos from fertilisation under natural conditions. Re-examination of Hertig’s data demonstrates that his estimates for fertilisation rate and early embryo loss are highly imprecise and casts doubt on the validity of his numerical analysis. A recent re-analysis of hCG study data suggests that approximately 40-60% of embryos may be lost between fertilisation and birth, although this will vary substantially between individual women. In conclusion, it is clear that some published estimates of natural embryo mortality are exaggerated. Although available data do not provide a precise estimate, natural human embryo mortality is lower than is often claimed.
Human reproductive failure is a significant health problem. Each year there are approximately four million births in the USA; these are accompanied by at least 600,000 spontaneous abortions and 240,000 fetal deaths. Of those babies born alive, 10% are premature, 13% have a low birthweight, and 3–7% possess a malformation. In addition, 30,000 liveborn babies die as neonates and 26,000 do not survive to begin their second year.
The normal site of fertilisation and early embryonic development in women is the ampullary — isthmic junction of the fallopian tube, just medial to its midpoint.1 The fertilised ovum remains there for about 80 hours,1 while it undergoes cleavage to reach the 16-cell stage, before compacting to a morula. After a relatively quick transit of the isthmus, the ovum lies free in the endometrial cavity as it forms a blastocele. As a blastocyst, it then hatches through the zona pellucida to implant itself in the endometrium.3 In conventional IVF the embryo reaches the endometrial cavity after about 50 to 70 hours’ culture, before compaction, when it has two to eight cells. There may be disadvantages in such early transfer to the uterus, but experience has not demonstrated any clinical benefit from longer culture in vitro. Experiments in mice and sheep have shown that tubal epithelial factors are important both in producing the best early embryonic growth rates in culture and, later, in enabling transferred embryos to survive beyond the stage of implantation.4,5
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