Substance misuse in pregnancy

Most studies suggest that licit and illicit substance misuse has an adverse effect on pregnancy outcome. However, interpretation of many studies is complicated by the failure to control for important co-morbid reproductive risk factors and a publication bias towards positive findings. This article analyses research into the substances most commonly misused in pregnancy to determine the degree to which they directly affect obstetric outcome. Although substance misuse is a clear marker for high risk' pregnancy, it remains unclear whether many of these substances are directly responsible for the adverse consequences associated with them.     

Oxidative stress stimulates α-tocopherol transfer protein in human trophoblast tumor cells BeWo

α-Tocopherol transfer protein (α-TTP) has been identified as the major intracellular transport protein for the antioxidant vitamin E (α-tocopherol). Expression of α-TTP on the reproductive system has been described both in mouse uterus and lately in the human placenta. The aim of this study was to clarify if placental expression of α-TTP can be modified by substances causing oxidative reactions. The human choriocarcinoma cell line BeWo was, therefore, treated with two known pro-oxidants. α-TTP expression was determined with immunocytochemistry and evaluated by applying a semiquantitative score. The presence of pro-oxidants in BeWo cells induced α-TTP expression. We thus hypothesize that stimulation of α-TTP expression by oxidative stress, as this was induced by pro-oxidants, could be part of an antioxidant process occurring in the placenta in the aim of enhancing the supply of α-tocopherol. This process could occur both in normal pregnancies, as well as in pregnancy disorders presented with intensified oxidative stress. In that view, this model is proposed for further oxidative stress studies on trophoblast and placenta, on the grounds of clarifying the role of α-tocopherol in pregnancy physiology and pathophysiology.     

Immunosuppressant therapy in pregnant organ transplant recipients

Transplant recipients are becoming pregnant with increasing frequency, and successful pregnancy outcomes have now been reported for women with all types of solid organ transplants. To prevent rejection of the transplanted organ, these patients are maintained on a life-long immunosuppressive regimen that must also be continued through pregnancy. Controlled human studies of the safety of these drugs have not been conducted, and knowledge regarding the pharmacokinetics of these medications in pregnancy is limited. Significant experience and safety data regarding the use of some of the more common immunosuppressants in pregnancy have, however, been accumulated from large case series and national registries. These observational studies suggest that successful pregnancy outcomes are possible in female organ transplant recipients, although sporadic adverse outcomes have been reported after immunosuppressant use in pregnancy. In this chapter, we will outline the information available regarding the use of immunosuppressive medications in pregnant transplant recipients as well as general concepts regarding fetal exposure to immunosuppressants.     

Lutealphase

Cytokines, growth factors and their receptors, produced in the endometrium and the preimplantation embryo, play important roles in maternal-fetal interaction during the peri-implantation period. Although only LIF has been shown to be absolutely necessary for embryonic implantation in mice, other cytokines and growth factors have important functional roles in this process. Many of these cytokines and growth factors can be knocked out in transgenic mice without leading to complete reproductive failure, but some of these knockouts show reproductive inefficiency and pregnancy wastage. Further studies on cytokine and growth factor expression in the endometrium and in preimplantation embryos will provide a better understanding of their role in human infertility and pregnancy loss, and open the way to finding new treatment options.     

Prenatal marijuana use: epidemiology, methodologic issues, and infant outcome

What do we know about marijuana use among women of reproductive age and about the use of marijuana during pregnancy? Marijuana is the most commonly used illicit substance, and after alcohol and tobacco, the most commonly used drug during pregnancy. Women who use marijuana are more likely to be white, younger, and to use other substances. The characteristics of women who use marijuana during early pregnancy are similar, although women who continue to use marijuana throughout pregnancy are somewhat different. These women are less-well educated, of lower social class, much more likely to use other substances, and more likely to be black. We do not know why some women use marijuana while others do not, and why some women discontinue their use during pregnancy while others do not. What do we know about the effects of marijuana use during pregnancy? A number of studies have investigated the relationship between prenatal marijuana exposure and outcome at birth. The results, unfortunately, are equivocal. Prospective studies that have examined women at regular and frequent intervals during pregnancy, in general, have not found a relationship between marijuana use and birthweight (Day NL, Sambamoorthi U, Taylor P, et al: unpublished data, 1990) although some have reported a small effect of marijuana use on birth length (Day NL, Sambamoorthi U, Taylor P, et al: unpublished data, 1990). Other studies, some prospective and some retrospective, have reported correlations between marijuana use during pregnancy and smaller size at birth. Several of these studies, however, failed to control adequately for other illicit drug use while one used marijuana only as a dichotomous variable in the analysis. Therefore, we do not yet know whether there is or is not an effect of marijuana use during pregnancy on intrauterine growth retardation. Only a few studies have reported on growth outside the neonatal period, and these studies have not found a consistent effect of prenatal marijuana exposure. There are, however, too few reports to assume that this is definitive. Several studies reported a relationship between prenatal marijuana use and the gestational age of the infant. As with growth, however, other studies have not corroborated these findings. Similarly, two studies have noted an increase in morphologic abnormalities, although one of these did not have a control group for comparison. Most studies have reported finding no relationship with either minor or major morphologic abnormalities. At birth, investigators have assessed the relationship between prenatal marijuana exposure and neurobehavioral outcome. Again, the results are contradictory.(ABSTRACT TRUNCATED AT 400 WORDS)     

Products toxic to reproduction used in the occupational environment: Definition, risk assessment, classification

European regulations (transcribed into French law) aimed at protecting employees from chemicals toxic to reproduction enable classification and labelling of such substances, if they are liable to cause an alteration of male or female reproductive functions or capacity, or to induce non-hereditary harmful effects on their offspring. Three categories can be used to classify these substances in two areas, namely their impairment of fertility and their effects on development. This classification is rarely based on epidemiological study results, but most often on those of experimental toxicological studies conducted by substance manufacturers. These reproduction toxicological studies are only compulsory above a certain tonnage placed on the market. The high level of this tonnage means that these tests are effectively only conducted on rare occasions. It is reckoned that there is no reproduction experimental data for over 95% of substances newly placed on the market. These products therefore appear to be reproduction non-toxic only because they have not been tested. This is a major fault in the current labelling system, which does not allow non-toxic products to be differentiated from non-tested products. The future EU regulatory framework for Registration, Evaluation and Authorisation of CHemicals (REACH) will only slightly enhance information in this area. It can be estimated that over 80% of chemical products will not be exhaustively tested for reproduction and nearly 75% will not be tested to any degree.     

Antidepressants during pregnancy and lactation: defining exposure and treatment issues.

The majority of psychiatric illness onsets early in an individual's life, typically before or during the reproductive years. The increased incidence of major depression, dysthymia, and panic disorder in women compared with men underscores the likelihood that the clinician will encounter the clinical dilemma of medication use during pregnancy and lactation. The emergence of specialized clinics at several academic centers specifically to investigate and address issues in Perinatal psychiatry illustrates this conundrum best. The extant literature derived from human studies suggests that maternal mental illness and stress may have an adverse impact on obstetrical outcome. These clinical investigations are complemented by a burgeoning series of laboratory studies in rodents and nonhuman primates, showing the profound deleterious impact of maternal stress during the perinatal and neonatal periods on the development of the offspring. Data obtained from pharmaceutical registries, cohort studies, toxicology centers, and case series have consistently failed to show an adverse effect associated with in utero antidepressant exposure. Despite these advances and treatment guidelines proposed by the various academic leaders, investigations describing the extent of fetal/neonatal exposure, clinical methods for minimizing such exposure, and clinical treatment guidelines that include the physiological impact of pregnancy are sparse. The available literature shows distinct pharmacokinetic profiles of the selective serotonin reuptake inhibitors in placental passage and breast milk. Preliminary animal studies have shown higher than expected central nervous system concentrations associated with exposure during pregnancy and mathematical modelling for calculating infant exposure when nursing. The clinical import of these data will require further investigations of central nervous system bioavailability in the fetus and neonate.     

Human Tumour Necrosis Factor: Physiological and Pathological Roles in Placenta and Endometrium

The cytokine tumour necrosis factor α (TNF) is a well known member of the TNF superfamily consisting of at least 18 ligands and 29 different receptors involved in numerous cellular processes. TNF signals through two distinct receptors TNFR1 and TNFR2 thereby controlling expression of cytokines, immune receptors, proteases, growth factors and cell cycle genes which in turn regulate inflammation, survival, apoptosis, cell migration, proliferation and differentiation. Since expression of TNF was discovered in amnion and placenta many studies demonstrated the presence of the cytokine and its receptors in the diverse human reproductive tissues. Whereas TNF has been implicated in ovulation, corpus luteum formation and luteolysis, this review focuses on the functions of TNF in human placental, endometrial and decidual cell types of normal tissues and also discusses its role in endometrial and gestational diseases. Physiological levels of the cytokine could be important for balancing cell fusion and apoptotic shedding of villous trophoblasts and to limit trophoblast invasion into maternal decidua. Regulation of the TNF/TNFR system by steroid hormones also suggests a role in uterine function including menstrual cycle-dependent destruction and regeneration of endometrial tissue. Aberrant levels of TNF, however, are associated with diverse reproductive diseases such as amniotic infections, recurrent spontaneous abortions, preeclampsia, preterm labour or endometriosis. Hence, concentrations, receptor distribution and length of stimulation determine whether TNF has beneficial or adverse effects on female reproduction and pregnancy.     

AIDS in women: epidemiology

Several facts concerning the distribution of AIDS in U.S. female populations are clear. This disease has made significant inroads, in a quantitative sense, into the female segment of our society as documented by AIDS surveillance data, information on pregnant women and parturients, and by screening data from the military. The impact on women in the reproductive years, on the reproductive health of these women, and on the reproductive outcome of their pregnancies is of substantial concern. Monitoring epidemiologic trends in certain groups will require clever and creative strategies like those of Hoff and colleagues. Additional data may be derived from the CDC's Family of Surveys that will examine HIV prevalence in five groups (in addition to the newborn infant survey described above): intravenous drug users, patients admitted to hospitals, sexually transmitted disease clinic patients, women's health and reproductive health clinics, and tuberculosis clinics. It is hoped that the data obtained from these studies, as well as data gathered on college students and Job Corps applicants, will contribute additional information on HIV infection in women. Monitoring the progress of the AIDS epidemic in women will be difficult. Even more difficult will be the effort to respond to the epidemic in the women it most frequently affects: the poor, minority, disenfranchised women who may be involved in illegal activities (drug use, prostitution, illegal immigration) who are not well networked into the medical and social services of our society.     

Epidemiological studies on primipaternity and immunology in preeclampsia--a statement after twelve years of workshops

Hypertensive disorders of pregnancy (HDP) represent 10% of human births globally and the major complication preeclampsia has a 3-5% prevalence. The etiology of HDP remains uncertain; however, major advances have been made over the last 25 years. The Seventh International Workshop on Reproductive Immunology, Immunological Tolerance and Immunology of Preeclampsia 2010 celebrated its 12th Anniversary in Tioman Island in 2010. Over this period, these seven workshops have contributed extensively to immunological, epidemiological, anthropological, and even vascular debates. The defect of trophoblastic invasion encountered in preeclampsia, intra-uterine growth restriction, and to some extent preterm labor, was understood only at the end of the 1970s. On the other hand, clinical and epidemiological findings at the end of the 20th century permitted us to apprehend that "preeclampsia, the disease of primiparae" may well be a disease of first pregnancy for a couple. Among the important advances, reproductive immunology is certainly the topic where knowledge has exploded in the last decade. This paper relates some major steps in the comprehension of this disease and provides a review of epidemiological studies on the "primipaternity paradigm". It focuses on the relevance of new developments and new concepts in immunology. At the beginning of the 21st century we are possibly closer than ever to understanding the etiology of this obstetrical enigma and also the pathophysiology of global endothelial inflammation in preeclamptic women. In this quest, reproductive immunology will certainly emerge as one of the main players.     

In-vitro model systems for the study of human embryo–endometrium interactions

Implantation requires highly orchestrated interactions between the developing embryo and maternal endometrium. The association between abnormal implantation and reproductive failure is evident, both in normal pregnancy and in assisted reproduction patients. Failure of implantation is the pregnancy rate-limiting step in assisted reproduction, but, as yet, empirical interventions have largely failed to address this problem. Better understanding of the mechanisms underlying human embryo–endometrium signalling is a prerequisite for the further improvement of assisted reproduction outcomes and the development of effective interventions to prevent early pregnancy loss. Studying human embryo implantation is challenging since in-vivo experiments are impractical and unethical, and studies in animal models do not always translate well to humans. However, in recent years in-vitro models have been shown to provide a promising way forward. This review discusses the principal models used to study early human embryo development and initial stages of implantation in vitro. While each model has limitations, exploiting these models will improve understanding of the molecular mechanisms and embryo–endometrium cross-talk at the early implantation site. They provide valuable tools to study early embryo development and pathophysiology of reproductive disorders and have revealed novel disease mechanisms such as the role of epigenetic modifications in recurrent miscarriage.Embryo implantation is dependent on a complex interaction between the developing embryo and maternal uterine cells. An association between abnormal implantation and reproductive failure is evident, both in normal pregnancy and in assisted reproduction patients. Failure of implantation is the pregnancy rate-limiting step in assisted reproduction. A better understanding of the mechanisms underlying the responsible signals in the interaction between human embryo and maternal uterine cells in embryo implantation is a prerequisite for further improvement of assisted reproduction outcomes and the development of effective interventions to prevent reproductive problems. Due to practical and ethical considerations, embryo implantation cannot be studied in humans, and no representative animal model has been identified. However, in recent years, substitute in-vitro (laboratory) models have been shown to provide a promising way forward in our understanding of the implantation processes. In this review, the principal models which have been used to study human embryo–maternal uterine cell interactions are discussed. While each model has its limitations, exploiting these in-vitro models will improve our understanding of the molecular mechanisms and embryo–uterus cross-talk at the early implantation site. In addition, they provide tools to study early embryo development and processes underlying developing reproductive disorders such as implantation failure and recurrent miscarriage.     

Female genital anomalies affecting reproduction

OBJECTIVE: A multitude of female congenital anomalies are uncommon. However, their impact on reproduction can be profound. The aim of this review is to remind the practicing physician of the clinically relevant embryology and summarize the studies that look at the impact of such various anomalies on a woman's fecundity. We review particular surgical therapies that possibly may improve fertility in such women. DESIGN: Review and critique of available studies in which particular surgical therapies were done and whether they truly improved fertility in these women with congenital reproductive anomalies. RESULTS: Clear evidence demonstrates that uterine septum resection is effective in women with demonstrated recurrent pregnancy losses. Arcuate uterus has little impact on reproduction. Other studies fail to definitively show that surgical correction will improve pregnancy retention or fertility except for specifically indicated clinical scenarios. CONCLUSIONS: The practicing reproductive specialist should have working knowledge of evidence-based therapeutic options for women with reproductive congenital anomalies. A summary chart has been devised to clearly associate embryologic structures with normal adult derivative as well as anomalous structures.     

Occupational, environmental and lifestyle factors associated with spontaneous abortion

Scientific evidence indicates extreme exposure sensitivity of embryos, fetuses, and infants to the persistent environmental/occupational chemicals directly and or indirectly as compared to the same magnitude of exposure in adults. Paternal/maternal exposure to some of these chemicals might have a effect on the gamete structure and function, which might have significant implication for the adverse effect on pregnancy and their outcome. The available data point that some of the organochlorine chemicals such as dichlorodiphenyl trichloroethane (DDT); metals such as lead, mercury; industrial pollutants such as dioxin, organic solvents, radiations; and some of the lifestyle-associated factors such as tobacco smoking (active and passive) and excessive maternal intake of alcohol had adverse effect on pregnancy outcome. The existing data support the hypothesis that, in general, working women have a higher risk of undesirable reproductive outcomes, even though the data are scanty. Studies are needed to find out the effects of those reproductive toxicants on priority basis which have been proved to be toxic in animal studies as well as data on human related to these chemicals are scanty. There is a need to educate the childbearing women to avoid exposure to the known or suspected risk factors and their employers to take measures to reduce the toxicant levels in workplace.     

Regulation of prostaglandin synthesis in the human uterus

Prostaglandins are important regulators of many aspects of reproductive processes from ovulation, fertilization and pregnancy recognition to labor and parturition. These biologically potent compounds are members of the large family of eicosanoids, derived from polyunsaturated fatty acids, principally arachidonic acid, found in the membrane phospholipids of virtually every cell of the human body, accounting for the ubiquity of prostaglandins, which act in a paracrine or autocrine fashion via discrete receptors. The availability of specific prostaglandins in various cells and tissues depends on the presence and activity of specific enzymes that convert a common precursor to the end product, as well as on the rate of enzymatic or spontaneous inactivation of the bioactive compounds. Here we offer a brief review of the regulation of prostaglandin generation in human uterine tissues, focusing on their role in labor and parturition at term and preterm.     

Reprint of: In-vitro model systems for the study of human embryo–endometrium interactions

Implantation requires highly orchestrated interactions between the developing embryo and maternal endometrium. The association between abnormal implantation and reproductive failure is evident, both in normal pregnancy and in assisted reproduction patients. Failure of implantation is the pregnancy rate-limiting step in assisted reproduction, but, as yet, empirical interventions have largely failed to address this problem. Better understanding of the mechanisms underlying human embryo–endometrium signalling is a prerequisite for the further improvement of assisted reproduction outcomes and the development of effective interventions to prevent early pregnancy loss. Studying human embryo implantation is challenging since in-vivo experiments are impractical and unethical, and studies in animal models do not always translate well to humans. However, in recent years in-vitro models have been shown to provide a promising way forward. This review discusses the principal models used to study early human embryo development and initial stages of implantation in vitro. While each model has limitations, exploiting these models will improve understanding of the molecular mechanisms and embryo–endometrium cross-talk at the early implantation site. They provide valuable tools to study early embryo development and pathophysiology of reproductive disorders and have revealed novel disease mechanisms such as the role of epigenetic modifications in recurrent miscarriage.Embryo implantation is dependent on a complex interaction between the developing embryo and maternal uterine cells. An association between abnormal implantation and reproductive failure is evident, both in normal pregnancy and in assisted reproduction patients. Failure of implantation is the pregnancy rate-limiting step in assisted reproduction. A better understanding of the mechanisms underlying the responsible signals in the interaction between human embryo and maternal uterine cells in embryo implantation is a prerequisite for further improvement of assisted reproduction outcomes and the development of effective interventions to prevent reproductive problems. Due to practical and ethical considerations, embryo implantation cannot be studied in humans, and no representative animal model has been identified. However, in recent years, substitute in-vitro (laboratory) models have been shown to provide a promising way forward in our understanding of the implantation processes. In this review, the principal models which have been used to study human embryo–maternal uterine cell interactions are discussed. While each model has its limitations, exploiting these in-vitro models will improve our understanding of the molecular mechanisms and embryo–uterus cross-talk at the early implantation site. In addition, they provide tools to study early embryo development and processes underlying developing reproductive disorders such as implantation failure and recurrent miscarriage.VIDEO LINK: http://sms.cam.ac.uk/media/1400935     

Comprehending the role of LPS in Gram-negative bacterial vaginosis: ogling into the causes of unfulfilled child-wish

Introduction Intrauterine infection is frequently associated with pregnancy loss in pregnant women.Discussion This article reviews the role of Gram-negative bacterial infection in various complications related to early pregnancy and subsequent pregnancy loss. Here we discus the pathways of ascending intrauterine infection, microbiology and the pathophysiology of such infections. The clinical impact, therapy, consequences, prevention and implications of Gram-negative bacterial infections in women during their reproductive life span is also discussed. This article also makes an attempt to discuss our studies and findings, related to the effect of the LPS component of the Gram-negative bacterial endotoxin on preimplantation stage embryonic development and implantation. This early phase of pregnancy remains mostly unnoticed by the mother as well as the health care provider, and therefore holds more threat to the life of the fetus and the mother. The molecular mechanisms of LPS-induced pregnancy losses through abnormal embryonic development, implantation failure, and preterm labor and birth with specific references to the role of proinflammatory cytokines like IL-1 and TNF are discussed.Conclusion Once these inflammatory mediators have increased in the feto-maternal tissues, it may be too late or harmful to try and prevent the adverse outcomes of pregnancy.     

From Fallopius to fantasy.

Knowledge of the female reproductive system in classical times is reviewed briefly. Current knowledge of tubal physiology is explained in greater detail. This knowledge, which is relevant to the study of fertility and sterility, includes sections dealing with: 1) sperm transport; 2) sperm capacitation; 3) fertilization; and 4) ovum and embryo transport. Since human data for some of these areas is lacking, data obtained in the study of other species is used as a supplement. Although it is now believed that microsurgical plastic repair of the fallopian tubes is preferable to macrosurgery, the author maintains that this has not been proven. Proof would involve studies in which the skill of the surgeon, the degree of damage requiring repair, and the method of assessing results were all held constant. The pregnancy rates following microsurgery as compared to those obtained with macrosurgery do not seem to justify the cost, prolonged operating time, and increased risk of ectopic pregnancy associated with microsurgical procedures.     

Does hyaluronan improve embryo implantation?

PURPOSE OF REVIEW: Taking into consideration the increasing interest on hyaluronan and its biological as well as physiological properties, this review will focus on the role of this molecule in human embryo implantation. RECENT FINDINGS: Several studies have been performed up to date in order to assess whether the addition of hyaluronan in the human embryo culture system can improve pregnancy and implantation rates, including one retrospective and six randomized controlled trials. On the one hand, four of those studies showed significant increase in clinical pregnancy and/or implantation rates after using embryo transfer medium containing high concentration of hyaluronan. On the other hand, three studies did not demonstrate any significant improvement in clinical pregnancy and implantation rates. However, regardless of statistical significance, almost all studies demonstrate higher pregnancy and implantation rates after using embryo transfer medium containing high concentration of hyaluronan. SUMMARY: Up to date, the results regarding the role of hyaluronan in human embryo implantation are still conflicting and, thus, further prospective randomized clinical trials are necessary to draw solid conclusions.     

Feto-placental communication system with the myometrium inpregnancy and parturition: The role of hormones,neurohormones, inflammatory mediators,and locally active factors

Pregnancy is a unique condition in which the conceptus is allowed to implant, survive, develop, and reach a considerable organ growth and maturation within the maternal body despite the fact that it is half genetically different from the mother. Moreover, it deeply influences the overall endocrine, metabolic, and immunological functions of the recipient mother. These objectives are accomplished through the establishment of several communication systems in which a large array of substances produced by the feto-placental unit reach specific maternal target organs and/or systems and modulate their function. The myometrium is a fundamental reproductive tissue involved in pregnancy maintenance as well as in labor onset and progression and is a potential target organ for such a communication system. An appropriate regulation of myometrial function is a key condition required for pregnancy to develop physiologically until full term is reached and for labor to start. Emerging experimental and clinical evidence suggests that a very complex feto-placental biomolecular communication system exists with the myometrium and is actively operative in the control of myometrial contractility in pregnancy and parturition through the production of a continuously increasing number of substances with endocrine, paracrine, and immunoregulatory actions.