Fetal Wastage Research Articles

Inherited thrombophilia and poor pregnancy outcome

Gestational vascular complications are a major cause of maternal and fetal morbidity. A growing body of evidence suggests a significant role for inherited thrombophilia in the development of gestational vascular complications. While the majority of women with thrombophilia will have an uneventful gestation, case–control studies demonstrated that thrombophilia is more prevalent in cohorts of women with pregnancy loss and early-onset pre-eclampsia. Placental abruption and severe intrauterine growth restriction (IUGR) may also be associated with thrombophilia. Placental pathological findings in women with thrombophilia are hallmarked by thrombosis and fibrin deposition potentially to a greater degree than in normal pregnancy. Preliminary non-randomized studies suggest a benefit for prophylaxis with unfractionated and low-molecular-weight heparin (LMWH), and prospective randomized trials are in progress to define whether LMWH is effective in preventing pregnancy loss and other gestational vascular complications in women with thrombophilia and previous fetal wastage.

The pathogenic role of anti-thyroglobulin antibody on pregnancy: evidence from an active immunization model in mice.

The presence of antibodies to thyroglobulin (Tg) is associated with fetal loss even in the absence of thyroid dysfunction. The aim of this study was to examine whether active immunization with Tg could elicit anti-Tg autoantibodies and reproductive failure without interfering with thyroid function. BALB/c mice that were immunized with human Tg in complete Freund's adjuvant (CFA) or injected with only CFA were studied for the development of antibodies to Tg, T4, dsDNA, ssDNA and cardiolipin. Total T4, free T4 and thyroid-stimulating hormone (TSH) levels were also assessed before and during pregnancy. Percentages of resorbed fetuses (the equivalent to human missed abortion) were compared and autoantibody presence on the placentae and fetuses was examined. Following immunization, high levels of anti-Tg were observed in mice immunized with Tg, compared with mice injected with CFA [0.83 +/- 0.23 versus 0.012 +/- 0.016 respectively; mean +/- SD optical density (OD) at 405 nm; P < 0.001]. The specificity of binding to Tg was confirmed by competition assay. Although total T4 levels were increased in comparison with control mice, this was associated with the presence of antibodies to T4. Indeed, free T4 levels and TSH were similar to control mice. Mice were killed after 14 days of pregnancy. The thyroid function and the histology of the thyroid glands were normal. Increased fetal wastage was found among the Tg-immunized mice compared with the CFA-injected mice (P = 0.04), with lower fetal and placental weights (fetal weights: 194 +/- 4 mg versus 240 +/- 6 mg; placental weights: 105 +/- 2 mg versus 130 +/- 3; P < 0.001 for both). Antibodies to Tg were demonstrated only on the placentae of Tg-immunized mice. Immunization with Tg results in the production of Tg antibodies and fetal resorption. These effects occur in the absence of thyroid dysfunction.

Laparoscopic surgery in pregnancy: long-term follow-up.

To describe the long-term consequences of laparoscopic surgery during pregnancy. Laparoscopic surgery is well established in the surgical community. Laparoscopic surgery in the pregnant patient is not yet broadly accepted; concern has been for fetal wastage, effects of carbon dioxide (CO(2)) on the developing fetus, and long-term sequelae during childhood development. This report documents 11 laparoscopic cases in pregnancy with follow-up of 1 to 8 years. The patients were in their 16th to 28th week of pregnancy. Two patients had chronic cholecystitis and biliary colic resulting in weight loss and multiple admissions. Three patients had acute cholecystitis, and three patients had acute appendicitis. Two patients underwent exploration for a diagnosis of acute abdomen, and both were found to have small bowel obstruction. All patients had general anesthesia and underwent an open Hasson trocar procedure with end-tidal CO(2) monitoring, sequential compression devices, and partial left decubitus positioning. Insufflation pressure was maintained at 10 mm Hg. The operative time ranged from 25 to 90 minutes. Successful laparoscopic surgery was performed in 10 cases, with one conversion to an open procedure. Intraoperative and postoperative fetal monitoring was performed for at least 24 hours. No fetal distress or demise occurred, nor were any tocolytics used. The resultant children were then monitored, and no evidence of developmental or physical abnormalities was detected during the study period. Laparoscopic surgery is now proving to be as safe as open surgery in pregnancy. This article reports long-term follow-up with no deleterious effects to either mothers or children.

Anesthetic Management of a Patient with Antiphospholipid Antibody Syndrome: A case report

The antiphospholipid antibody syndrome (APS) is characterized by the presence of auto antibodies to phospholipids in association with in vitro prolongation of phospholipid-dependent coagulation tests, recurrent pregnancy loss, multiple thrombotic events, etc. Due to strong predilection for thrombosis in both the arterial and venous system, perioperative thromboprophylaxis for APS patients is very important to avoid catastrophic major cardiovascular complications. We experienced general anesthesia for a total abdominal hysterectomy in a 47-year-old patient diagnosed as having APS by a past medical history of deep vein thrombosis, fetal wastages, and laboratory confirmation. Pre and postoperative management for hypercoagulability was done with oral warfarin and low dose heparin. To prevent intraoperative thrombosis, we maintained an activated clotting time (ACT) over 200 seconds by heparin 3000 U injection, applied antithrombotic stockings, and tried to avoid dehydration, hypothermia and infections.

Changing trends in the obstetric indications for cervical cerclage

Cervical incompetence causes repeated mid-trimester miscarriage and preterm delivery with high fetal wastage. Since the introduction of cervical cerclage in 1951, it has undergone many changes with regard to the techniques, indications and postoperative care. The objective of this study is to review the changing trends in the current indications of cervical cerclage and subsequent perinatal outcome at the maternity hospital from January 1992 to December 1999. All the files of women who had had cervical cerclage were evaluated in terms of characteristics of the women, indications and obstetric outcome after cervical cerclage. Of 65 539 who delivered in the hospital, 1021 women had had cervical cerclage, giving an incidence of 1.21%. There was a significant increase in the incidence of cervical cerclage, from 1.13% in 1992 to 1.40% in 1999 (P < 0.01). More women with multiple pregnancy in 1996 - 99 had cerclage than in 1992 - 94 period [22.7 vs. 8.5% (P < 0.01)]. It is clear that more cervical sutures are being performed in multiple pregnancies arising from assisted reproductive technology as well as after ultrasonographic evidence of cervical dilatation. A multicentre randomised clinical trial is therefore advocated to evaluate its effectiveness in these cases.

Thrombophilia and fetal loss.

A large body of evidence obtained during the last 6 years suggests a significant role for inherited thrombophilia in the development of gestational vascular complications. Case-control studies demonstrated that thrombophilia is more prevalent in cohorts of women with pregnancy loss. Other complications such as preeclampsia, placental abruption, and intrauterine growth retardation may also be associated with thrombophilia. Placental pathologic findings in women with thrombophilia are hallmarked by thrombosis and fibrin deposition. Preliminary case-control studies suggest that low-molecular-weight heparins are effective in preventing pregnancy loss in women with thrombophilia and previous fetal wastage.

Arteriovenous aberration as a cause of idiopathic repeated fetal wastage and its treatment by laparoscopic intrauterine injection of interferon 2α

Objective: Arteriovenous aberration of the uterus is a new etiological factor of repeated early pregnancy wastage. Historically, hysterectomy has been the only treatment option of these patients. Advances in interventional radiology have allowed for conservative management. We introduce for the first time in the literature laparoscopic intrauterine injection of interferon alfa 2α. So our aim was to evaluate the effectiveness of this modality in the treatment of this problem.

Therapy with Dendritic Cells (DCs) control fetal abortion rate in the CBA/J × DBA/2J mouse model

DBA/2J mated‐CBA/J female mice are prone to a high incidence of fetal abortions. This fetal wastage can be dramatically reduced by immunizing the female mice with BALB/c, but not DBA/2J spleen cells during early gestation, whereas underlying mechanisms remain to be elucidated. Recently, DCs have been described at the feto‐maternal interface in human uterus. The aim of this study was to analyse the role of DCs in the maintenance of pregnancy in the CBA/J × DBA/2J model. Bone marrow derived DCs were generated from virgin female CBA/J mice (6–8 weeks old) by using a modified version of Inaba's et al. technique, some of the DCs were pulsed with paternal DBA/2 J antigens lisate ex vivo. Immunization with DCs of the CBA/J females took place twice before matings. Four different experimental groups were included: (1) no treatment control, (2) mice injected with conditionated medium (GM‐CSF), (3) immunized with DCs and (4) immunized with Ag‐pulsed DCs, n = 5, respectively. Therapy with paternal antigen lisate pulsed DCs as well as the therapy with DCs alone significantly reduced the abortion rate from 23.8% in the controls (1 + 2) to 2.2% in Group 3 and 5% in Group 4. Our results indicate a protective role of DCs at the feto‐maternal interface during pregnancy. Putative pathways are the induction of an immunological response necessary in the prevention of abortion, i.e. a Th2 milieu or the production of asymmetric antibodies. These preliminary results may foster additional experiments on DCs in reproductive biology, which may soon be translated into clinically relevant health applications in a novel area of DCs research.

Autoimmunity and pregnancy loss

Certain autoimmune conditions, such as systemic lupus erythematosus (SLE), are associated with pregnancy loss. Almost 30 years ago, investigators published data that focused on fetal wastage in women with antiphospholipid antibodies (aPLs) and that included fetal loss as one clinical criterion for the diagnosis of antiphospholipid syndrome (APS) [1,2]. After these initial publications, interest in other autoimmune disorders as possible causes of pregnancy loss has increased. This interest prompted an ongoing effort to link the presence of a specific autoantibody or patterns of autoantibodies to recurrent pregnancy loss. A multitude of candidate autoantibodies have been evaluated, and some clinicians routinely perform assays for multiple autoantibodies in the evaluation of women with recurrent pregnancy loss; however, there is only modest evidence to support the concept that most autoantibodies cause pregnancy loss. This article discusses the potential association between several specific autoimmune conditions and recurrent pregnancy loss. Recurrent pregnancy loss may be caused by a myriad of factors, including anatomic, hormonal, thrombotic, autoimmune, genetic, infectious, or unknown causes. Most women with two or three unexplained, consecutive embryonic losses are otherwise healthy and have no other signs or symptoms that might be considered part of an autoimmune condition.

Interleukin-10 Administration and Bacterial Endotoxin-Induced Preterm Birth in a Rat Model

In Brief OBJECTIVE To determine whether intrauterine infusion of interleukin-10 prevents preterm delivery in rats treated with endotoxin. METHODS Pregnant rats underwent implantation of uterine catheters and were randomly assigned to receive intrauterine infusion of either normal saline, 50 μg lipopolysaccharide endotoxin, or 50 μg lipopolysaccharide with 500 ng interleukin-10 administered either concurrently or 24 hours later. The interval from infusion to delivery for each group was recorded, along with the number of live born pups and their birth weight. We calculated that to obtain a power of 80%, assuming a 24-hour difference in the treatment to delivery times between the test and control subjects, at least six animals would be needed in each group. RESULTS In females receiving lipopolysaccharide (50 μg) alone, the interval to delivery (P < .05), live birth rate (P < .05), and pup weight (P < .001) were reduced compared with the saline-infused controls. In contrast, females receiving interleukin-10 at the time of the endotoxin challenge or 24 hours after delivered at term with no difference in litter size or live birth weight compared with the controls. CONCLUSION Animals treated with both lipopolysaccharide and interleukin-10, administered concurrently or 24 hours after the endotoxin challenge, delivered normal weight pups at term with a similar litter size as the saline-infused controls. Interleukin-10 appears to be effective in preventing endotoxin-induced preterm birth and fetal wastage in pregnant rats. Interleukin-10 prevents endotoxin-induced preterm birth in a rat model.

Interleukin-10 administration and bacterial endotoxin-induced preterm birth in a rat model

Objective: To determine whether intra-uterine infusion of interleukin-10 prevents preterm delivery in rats treated with endotoxin. Methods: Pregnant rats underwent implantation of uterine catheters and were randomly assigned to receive intrauterine infusion of either normal saline, 50 μg lipopolysaccharide endotoxin, or 50 μg lipopolysaccharide with 500 ng interleukin-10 administered either concurrently or 24 hours later. The interval from infusion to delivery for each group was recorded, along with the number of live born pups and their birth weight. We calculated that to obtain a power of 80%, assuming a 24-hour difference in the treatment to delivery times between the test and control subjects, at least six animals would be needed in each group. Results: In females receiving lipopolysaccharide (50 μg) alone, the interval to delivery ( P < .05), live birth rate ( P < .05), and pup weight ( P < .001) were reduced compared with the saline-infused controls. In contrast, females receiving interleukin-10 at the time of the endotoxin challenge or 24 hours after delivered at term with no difference in litter size or live birth weight compared with the controls. Conclusion: Animals treated with both lipopolysaccharide and interleukin-10, administered concurrently or 24 hours after the endotoxin challenge, delivered normal weight pups at term with a similar litter size as the saline-infused controls. Interleukin-10 appears to be effective in preventing endotoxin-induced preterm birth and fetal wastage in pregnant rats.

Micronutrients in pregnancy.

Vitamins and minerals, referred to collectively as micronutrients, have important influences on the health of pregnant women and the growing fetus. Iron deficiency results in anemia which may increase the risk of death from hemorrhage during delivery, but its effects on fetal development and birth outcomes is still unclear. Folic acid deficiency can lead to hematological consequences, pregnancy complications and congenital malformations, but again the association with other birth outcomes is equivocal. Zinc deficiency has been associated in some, but not all studies with complications of pregnancy and delivery, as well as with growth retardation, congenital abnormalities and retarded neurobehavioral and immunological development in the fetus. Iodine deficiency during pregnancy results in cretinism and possible fetal wastage and preterm delivery. Deficiency of other minerals such as magnesium, selenium, copper, and calcium have also been associated with complications of pregnancy, childbirth or fetal development. Deficiencies of vitamins other than folate may likewise be related to such complications; and vitamin A or beta-carotene supplements in pregnancy reduced maternal mortality by 50 % in a controlled trial in Nepal. Additional research is need on the prevalence of such deficiencies and their consequences and on cost-effective public health interventions for their control.

Self-assessment questions*1

The management of gestational ovarian cancer can be challenging because of the risk of fetal wastage, and the possibility of treatment-related complications to the fetus; it is based on insufficient data from retrospective studies and case series. Here, a literature review of the diagnostic and surgical approaches to the gestational ovarian cancer has been performed; moreover, data on safety of chemotherapeutic treatments in pregnancy, including both oncologic and fetal outcomes, have also been reviewed. Up to now, 193 cases of ovarian cancers during pregnancy have been reported in the English literature. Treatment of ovarian malignancies during pregnancy depends on histology, stage, and gestational weeks. When possible, surgical excision is indicated, and fertility-sparing surgery can be offered to stage I epithelial ovarian tumours (EOC), germ cell ovarian, or sex-cord stromal ovarian tumours. Neoadjuvant and/or adjuvant chemotherapy for advanced ovarian tumours is indicated as in non-pregnant women. Administration of chemotherapy after the first trimester, can cause fetal growth restriction, while being seemingly safe. The therapeutic approach of ovarian cancer in pregnancy should be individualized and intended in specialized centers.

Satellite III sequences on 14p and their relevance to Robertsonian translocation formation.

Robertsonian translocations (ROBs) are the most common rearrangements in humans, contributing significantly to genetic imbalance, fetal wastage, mental retardation and birth defects. Rob(14q21q) and rob(13q14q), which are formed predominantly during female meiosis, comprise the majority (approximately 85%) of all ROBs. Previous studies have shown that the breakpoints are consistently located within specific regions of the proximal short arms of chromosomes 13, 14, and 21. The high prevalence of these translocations, the consistent breakpoints found, and the fact that roughly 50% of cases occur sporadically suggest that the sequences at or near the breakpoints confer susceptibility to chromosome rearrangement and that the rearrangements occur through a specific mechanism. To investigate this hypothesis, we developed hamster-human somatic cell hybrids derived from de novo rob(14q21q) patients that contained the translocated chromosome segregated from the other acrocentric chromosomes. We determined the physical order of five satellite III subfamilies on 14p, and investigated their involvement in formation of these de novo translocations.

Neonatal mortality and stillbirths in early twentieth century Derbyshire, England

Neonatal mortality and stillbirths are recognised to be subject to similar influences, but survival after a successful live birth is usually considered in isolation of foetal wastage. Moreover, individual-level data on age-specific influences and causes of death in a historical context are rare. This paper uses an unusual data set to compare the influences on neonatal mortality and stillbirths in early twentieth century Derbyshire, England. Multivariate hazard and logistic analyses are performed to examine the relative roles of various social, environmental, and demographic factors. The influences on and causal structures of neonatal mortality and stillbirths emerge as broadly similar, with previous reproductive history linked to a considerable amount of variation. The clustering of endogenous deaths was much greater than the clustering of exogenous and post-neonatal deaths, probably reflecting the cause-of-death structure and the relatively healthy social and environmental position of early twentieth century Derbyshire.

Foetal Wastage and Infant Mortality in Four Endogamous Population of Purnia District (Bihar)

A survey of 826 families of the Kisan, Kulhaiya, Brahmin and Oraon of Pumia district in Bihar was carried out to assess the effects of different factors on foetal and infant deaths. Highest percent...

Physiology of a microgravity environment selected contribution: effects of spaceflight during pregnancy on labor and birth at 1 G.

The events of parturition (labor, delivery, maternal care, placentophagia, and onset of nursing) were analyzed in female Norway rats (Rattus norvegicus) flown on either 11- or 9-day-long spaceflights beginning at the approximate midpoint of their pregnancies. Each space shuttle flight landed on the 20th day of the rats' pregnancies, just 48-72 h before parturition. After spaceflight, dams were continuously monitored and recorded by time-lapse videography throughout the completion of parturition and onset of nursing (days 22 and 23). Analyses of parturition revealed that, compared with ground controls, flight dams displayed twice the number of lordosis contractions, the predominant labor contraction type in rats. The number of vertical contractions (those that immediately precede expulsion of a pup from the womb), the duration of labor, fetal wastage, number of neonates born, neonatal birth weights, placentophagia, and maternal care during parturition, including the onset of nursing, were comparable in flight and ground control dams. Our findings indicate that, with the exception of labor contractions, mammalian pregnancy and parturition remain qualitatively and quantitatively intact after spaceflight during pregnancy.

Essay: Rediscovering The Social Determinants Of Health

Essay: Rediscovering The Social Determinants Of Health

The hypothalamic-pituitary-thyroid axis and the female reproductive system.

Increasing evidence derived from experimental and clinical studies suggests that the hypothalamic-pituitary-thyroid axis (HPT) and the hypothalamic-pituitary-ovarian axis (HPO) are physiologically related and act together as a unified system in a number of pathological conditions. The suggestion that specific thyroid hormone receptors at the ovarian level might regulate reproductive function, as well as the suggested influence of estrogens at the higher levels of the HPT axis, seems to integrate the reciprocal relationship of these two major endocrine axes. Both hyper- and hypothyroidism may result in menstrual disturbances. In hyperthyroidism the most common manifestation is simple oligomenorrhea. Anovulatory cycles are very common. Increased bleeding may also occur, but it is rare. Hypothyroidism in girls can cause alterations in the pubertal process; this is usually a delay, but occasionally it can result in pseudo-precocious puberty. In mature women hypothyroidism usually is associated with abnormal menstrual cycles characterized mainly by polymenorrhea, especially anovulatory cycles, and an increase in fetal wastage.

Anticoagulation of Pregnant Women With Mechanical Heart Valves

The management of women with prosthetic heart valves during pregnancy poses a particular challenge as there are no available controlled clinical trials to provide guidelines for effective antithrombotic therapy. Oral anticoagulants such as warfarin sodium cause fetal embryopathy; subcutaneous administration of heparin sodium has been reported to be ineffective in preventing thromboembolic complications. To identify the risks of maternal and fetal complications in women with mechanical heart valves treated with different anticoagulation regimens during pregnancy. We performed a systematic review of the literature to determine pooled estimates of maternal and fetal risks associated with the 3 commonly used approaches: (1) oral anticoagulants (OA) throughout pregnancy, (2) replacing OA with heparin in the first trimester (from 6-12 weeks' gestation), and (3) heparin use throughout pregnancy. Fetal outcomes included spontaneous abortions and fetopathic effects, and maternal outcomes were major bleeding, thromboembolic complications, and death. The use of OA throughout pregnancy is associated with warfarin embryopathy in 6.4% (95% confidence interval [CI], 4.6%-8.9%) of livebirths. The substitution of heparin at or prior to 6 weeks, and continued until 12 weeks, eliminated this risk. Overall risks for fetal wastage (spontaneous abortion, stillbirths, and neonatal deaths) were similar in women treated with OA throughout, compared with women treated with heparin in the first trimester. Maternal mortality was 2.9% (95% CI, 1.9%-4.2%). Maj or bleeding events occurred in 2.5% (95% CI, 1.7%-3.5%) of all pregnancies, most at the time of delivery. The regimen associated with the lowest risk of valve thrombosis (3.9%; 95% CI, 2.9-5.9%) was the use of OA throughout; using heparin only between 6 and 12 weeks' gestation was associated with an increased risk of valve thrombosis (9.2%; 95% CI, 5.9%-13.9%). Thromboembolic prophylaxis of women with mechanical heart valves during pregnancy is best achieved with OA; however, this increases the risk of fetal embryopathy. Substituting OA with heparin between 6 and 12 weeks reduces the risk of fetopathic effects, but with an increased risk of thromboembolic complications. The use of low-dose heparin is definitely inadequate; the use of adjusted-dose heparin warrants aggressive monitoring and appropriate dose adjustment. Large prospective trials to determine the best regimen for these women are needed.