Thrombophilia-associated pregnancy wastage

OBJECTIVE: To critically review the literature regarding inherited thrombophilia and recurrent fetal loss. DESIGN: English-language literature review. PATIENT(S): Women who experienced repeated pregnancy wastage. INTERVENTION(S): Aspirin, glucocorticoids, heparin, and IV immunoglobulin for the prevention of miscarriage. MAIN OUTCOME MEASURE(S): Live birth, miscarriage, preeclampsia, and pregnancy loss. RESULT(S): Recurrent fetal loss and other placental vascular pathologies of pregnancy have long been associated with antiphospholipid syndrome, an acquired autoimmune thrombophilic state. The number of known heritable thrombophilic disorders has grown rapidly in recent years with the identification of activated protein C resistance, factor V Leiden mutation, and hyperhomocysteinemia as major causes of thrombosis. Data accumulated over the past 2 years suggest that heritable thrombophilia is associated with an increased risk of fetal loss and preeclampsia. The present review discusses potential pathogenetic mechanisms for this association and evaluates reported therapeutic regimens for the prevention of fetal loss in women with thrombophilia. CONCLUSION(S): Placental thrombosis may be the final common pathophysiologic pathway in most women with habitual abortions and repeated pregnancy wastage. Prophylactic antithrombotic therapy is indicated in women with heritable thrombophilia and antiphospholipid syndrome and probably is more effective than the previously used modalities of prednisone, aspirin, and IV immunoglobulin.     

Reproductive outcomes in women with congenital uterine anomalies detected by three-dimensional ultrasound screening.

OBJECTIVE: To determine reproductive outcomes in women with congenital uterine anomalies detected incidentally by three-dimensional ultrasound. METHODS: We studied 1089 women with no history of infertility or recurrent miscarriage who were seen for a transvaginal ultrasound scan. They were screened for uterine abnormalities using three-dimensional ultrasound. We determined prevalence of miscarriage and preterm labor in women with normal and abnormal uterine morphology. RESULTS: We found that 983 women had a normally shaped uterine cavity, 72 an arcuate, 29 a subseptate, and five a bicornuate uterus. Women with a subseptate uterus had a significantly higher proportion of first-trimester loss (Zeta = 4.68, P <.01) compared with women with a normal uterus. Women with an arcuate uterus had a significantly greater proportion of second-trimester loss (Zeta = 5.76, P <.01) and preterm labor (Zeta = 4.1, P <.01). There were no other significant differences in pregnancy outcomes between women with normal and abnormal uterine morphology. CONCLUSION: This study shows the potential value of three-dimensional ultrasound and confirmed that women with congenital uterine anomalies were more likely to have adverse pregnancy outcomes than women with a normal uterus.     

Abnormal immunoglobulin subclass patterns in women with a history of recurrent miscarriage.

OBJECTIVE: To determine whether IgG subclass patterns differed between nonpregnant women, healthy pregnant women, and pregnant women with a history of recurrent miscarriage. DESIGN: Controlled clinical study. SETTING: An academic setting. PATIENT(S): Group 1 was comprised of 10 nonpregnant women, group 2 of 10 healthy pregnant women, group 3 of eight pregnant women with a history of recurrent miscarriage and whose pregnancies on this occasion went to term, and group 4 of 10 women with a history of recurrent miscarriage whose pregnancies again failed later in the first trimester. INTERVENTION(S): None of the patients received any medication. MAIN OUTCOME MEASURE(S): Serum levels of total IgG and IgG 1, 2, 3, and 4. RESULT(S): The results obtained showed that normal pregnancy was associated with a significant increase in total IgG production and an increase in IgG subclasses 1, 2, and 3. Women with a history of miscarriage, but who had a successful pregnancy on this occasion, showed a similar pattern of IgG subclasses. Women with a history of miscarriage and whose pregnancy again ended in miscarriage showed a different IgG subclass pattern. CONCLUSION(S): Pregnancies that ended in miscarriage showed a different pattern of IgG subclasses than those that continued to term. The changes seen in immunoglobulin patterns could be linked to changes in cytokine production.     

双胎妊娠介入性产前诊断不同取样方法术后流产风险评估及相关因素分析

目的:探讨介入性产前诊断不同取样方法应用于双胎妊娠的术后流产风险,并分析影响术后流产风险的相关因素.方法:回顾性分析2015年1月至2019年3月广东省妇幼保健院产前诊断中心行介入性产前诊断的452例双胎妊娠的临床资料.按照介入性产前诊断不同取样方法分为3组:绒毛取材组(33例)、羊膜腔穿刺组(376例)、脐血取样组(...     

A case-control study of membrane cofactor protein mutations in two populations of patients with early pregnancy loss

Mouse models have demonstrated a strong link between complement activation and pregnancy loss. The purpose of this study was to assess if mutations or polymorphisms in the complement regulatory gene membrane cofactor protein (MCP) are associated with recurrent miscarriage (RM) or sporadic fetal loss (FL). This was a case-control study comprising two different populations of cases and controls: subjects with recurrent miscarriage (RM) and controls and maternal-fetal pairs with early fetal loss (at 10-20 weeks' gestation) and controls. In the RM cases and controls, we studied maternal DNA extracted from either whole blood or saliva samples. In the FL cases and controls, fetal DNA was obtained from evacuated products of conception (cases) or cord blood (controls). Exons from the MCP gene, previously identified as having functional mutations, were amplified with flanking primers, purified, and sequenced. Sequences were analyzed against the published reference sequence, the presence of known mutations and polymorphisms and novel polymorphisms. We enrolled and obtained maternal DNA from 75 women with RM and 115 controls. In the FL group, we identified 33 cases and 37 controls. We detected the previously described A304V variant, but neither genotype nor allele frequencies differed significantly between cases and controls in any of the populations (RM, FL (maternal) or FL (fetal)). Although other variants and mutations in MCP were identified, no significant differences were found between the groups. Thus, we conclude that the A304V mutation in the MCP gene is not strongly associated with RM or FL.     

Is miscarriage a coagulopathy?

PURPOSE OF REVIEW: Pregnancy is a hypercoaguable state. The hypothesis has been developed that many cases of recurrent miscarriage and of later pregnancy complications are caused by a defective maternal haemostatic response leading to thrombosis of the uteroplacental vasculature and subsequent fetal loss. The evidence upon which this hypothesis is based is reviewed. RECENT FINDINGS: The majority of studies report an increased prevalence of genetic thrombophilic mutations in the female partner of couples with recurrent miscarriage. It is important to note, however, that this is not a uniform finding. A sub-group of women with recurrent miscarriage has been demonstrated to be in a prothrombotic state before pregnancy, and that women in such a state are at an increased risk of miscarriage in future untreated pregnancies. Furthermore, the long-term health implications of this hypercoaguability have been highlighted in a large retrospective study reporting an increased risk of ischaemic heart disease among women with a history of pregnancy loss. SUMMARY: Although recurrent miscarriage is a heterogeneous condition and no single abnormality will account for all cases of pregnancy loss, the relationship between abnormalities in the haemostatic pathways and pregnancy outcome is increasingly recognized. The challenges we face are how to discriminate between women with a thrombophilic defect who are destined to miscarry from those whose pregnancy will be successful, the pathology of pregnancy loss associated with thrombophilic defects, the role of the fetal genotype in determining pregnancy outcome, and the management of women with thrombophilic defects both during and beyond their reproductive years.     

Early pregnancy loss in in vitro fertilization (IVF) is a positive predictor of subsequent IVF success

OBJECTIVE: To determine the significance of biochemical pregnancy losses and clinical spontaneous abortion (SAB) on outcomes of future IVF cycles. DESIGN: Retrospective cohort study. SETTING: Academic IVF program. PATIENT(S): Women with a history of unsuccessful IVF attempts undergoing IVF. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate. RESULT(S): Patients with an early pregnancy loss had a greater ongoing clinical pregnancy rate in the immediate next cycle when compared with those women who had a negative pregnancy test (37.3% vs. 27.3%). Patients with a history of a biochemical pregnancy or a clinical spontaneous abortion had an ongoing clinical pregnancy rate in the next cycle of 38.4% and 42.3%, respectively, compared with 27.3% in women who had a history of a negative pregnancy test. The cumulative pregnancy rate after the first IVF attempt was 54.1% in patients with a previous biochemical pregnancy loss, 61.4% in those with a previous clinical SAB, and 46.5% in women with a previous negative pregnancy test. CONCLUSION(S): Women who experience an early pregnancy loss after IVF have a greater likelihood of success in subsequent IVF cycles when compared with patients who fail to conceive.     

A study of pregnancy loss in 352 women with recurrent miscarriages

Aim The aim of the study was to investigate the type of pregnancy loss (PL) in women with recurrent miscarriages.Materials and methods The study population included 411 women with a history of recurrent pregnancy loss (RPL) attending the Recurrent Miscarriage Clinic of the 2nd Department of Obstetrics and Gynecology, University of Athens (tertiary referral center). Subjects were divided in groups according to their underlying pathology and in some of them appropriate treatment was applied.Results The study of the 323 pregnancies achieved after referral, revealed that the PL after ultrasonographic detection of fetal heart (FH) is overall increased, is more common in women with anatomical uterine anomalies and unexplained RPL, and treatment reduces its rate in women with anatomical uterine anomalies and an inadequate luteal phase. The PL before the detection of FH is reduced after treatment in women with thrombotic tendency and an inadequate luteal phase.     

Recurrent early pregnancy loss and consanguinity

The present authors have studied the possible relationship between recurrent miscarriage and consanguinity in the Qatari population, where the prevalence of first cousin marriage is 47%. The maternal of three or more early pregnancy losses were compared with those of 92 non-consanguineous women from the same population and with the same obstetrical history, matched for maternal age. The retrospective investigation showed no difference in the rate of previous pregnancy loss and maternal disorders, including diabetes, thyroid dysfunction and immunity, abnormal uterine and ovarian anatomy or thrombophilia. There was also no evidence of familial clustering of recurrent miscarriage in both groups. The prospective study showed no difference in the rate of subsequent pregnancy loss and the median gestational age and fetal weight at delivery in ongoing pregnancies. The absence of a relationship between recurrent miscarriage and consanguinity in Qatar could be due to the particular characteristics of the native Qatari population, in which rare recessive genes are uncommon, or overall to the absence of an association between recurrent miscarriage and consanguinity.     

High frequency of thrombophilic disorders in women with recurrent fetal miscarriage

OBJECTIVES: Our purpose was to examine whether genetic thrombophilias are etiological factors for recurrent fetal miscarriage or not. STUDY DESIGN: We compared the rate of thrombophilic anomalies in women with unexplained recurrent fetal miscarriages to the rate of age-matched women with successful pregnancies as a case-control study. RESULTS: A total of 101 consecutive patients with 102 age-matched controls were included in the study. The rate of Factor V (FV) Leiden mutation, Factor (F) II mutation, protein S, protein C, antithrombin III deficiencies and overall thrombophilia in patients with recurrent fetal loss was significantly higher than the frequencies in control patients. CONCLUSION: Women with recurrent fetal miscarriages have an increased incidence of thrombophilia. Genetic thrombophilias may be one of the major etiological factors for recurrent abortion and fetal demise.     

Probability of early pregnancy loss in women with vaginal bleeding and a singleton live fetus at ultrasound scan.

Bleeding is a common feature of early pregnancy affecting about one-fifth of pregnant women in the first trimester. The chance of miscarriage after bleeding and a live fetus at scan has not previously been defined precisely. The purpose of this study was to evaluate the outcome of early pregnancies with a viable singleton fetus that had been complicated by bleeding. A prospective study was performed on 370 women with a singleton live fetus who had presented to the early pregnancy assessment clinic (EPAC) with vaginal bleeding. Women were grouped into light, moderate and heavy loss according to the self-assessed degree of vaginal bleeding. The women were also categorised according to the presence or absence of an intrauterine haematoma. The overall spontaneous miscarriage rate in the study was 11.1%; almost 90% of pregnancies continued to viability. Women with moderate or heavy bleeding had more than twice the rate of miscarriage compared with those with light bleeding. A total of 14% of the women had an intrauterine haematoma and those women were 2.6 times more likely to miscarry than those without (23% vs 9%). This relationship appeared to hold true even after controlling for blood loss. The data presented can be used to guide women with a live fetus about the chance of miscarriage after an episode of vaginal bleeding. We propose that a large multi-centre study should be undertaken to define precisely the risk miscarriage for each gestational week according to a range of clinical and ultrasound characteristics.     

The cellular immunity and oxidative stress markers in early pregnancy loss

Objective: We investigated whether changes in cellular immunity and oxidative stress in pregnancy have any association with spontaneous miscarriage.

Material and methods: Circulating adenosine deaminase (ADA) activity as a marker of cellular immunity and malondialdehyde (MDA) and catalase (CAT), glutathione peroxidase (GPx) as markers of T lymphocyte activation and parameters of oxidative stress and antioxidant defense were compared between 40 women with early pregnancy loss and another 40 women with ungoing healthy pregnancy.

Results: Women with miscarriage had higher serum ADA and GPx levels when compared with women with normal pregnancy (p?=?0.034 and p?<?0.001, respectively). Although serum MDA level was slightly higher in women with miscarriage, the difference was not significant (p?=?0.083). CAT levels were alike in both groups.

Conclusion: We have demonstrated an increased cellular immunity and perhaps a compensated oxidative stress related to increased antioxidant activation in women with early spontaneous pregnancy loss.     

Early pregnancy loss in Belagavi,Karnataka, India 2014–2017: a prospective population-based observational study in a low-resource setting

Background

The prevalence of early pregnancy loss through miscarriage and medically terminated pregnancy (MTP) is largely unknown due to lack of early registration of pregnancies in most regions, and especially in low- and middle-income countries. Understanding the rates of early pregnancy loss as well as the characteristics of pregnant women who experience miscarriage or MTP can assist in better planning of reproductive health needs of women.

Methods

A prospective, population-based study was conducted in Belagavi District, south India. Using an active surveillance system of women of childbearing age, all women were enrolled as soon as possible during pregnancy. We evaluated rates and risk factors of miscarriage and MTP between 6 and 20 weeks gestation as well as rates of stillbirth and neonatal death. A hypothetical cohort of 1000 women pregnant at 6 weeks was created to demonstrate the impact of miscarriage and MTP on pregnancy outcome.

Results

A total of 30,166 women enrolled from 2014 to 2017 were included in this analysis. The rate of miscarriage per 1000 ongoing pregnancies between 6 and 8 weeks was 115.3, between 8 and 12 weeks the miscarriage rate was 101.9 per 1000 ongoing pregnancies and between 12 and 20 weeks the miscarriage rate was 60.3 per 1000 ongoing pregnancies. For those periods, the MTP rate was 40.2, 45.4, and 48.3 per 1000 ongoing pregnancies respectively. The stillbirth rate was 26/1000 and the neonatal mortality rate was 24/1000. The majority of miscarriages (96.6%) were unattended and occurred at home. The majority of MTPs occurred in a hospital and with a physician in attendance (69.6%), while 20.7% of MTPs occurred outside a health facility. Women who experienced a miscarriage were older and had a higher level of education but were less likely to be anemic than those with an ongoing pregnancy at 20 weeks. Women with MTP were older, had a higher level of education, higher parity, and higher BMI, compared to those with an ongoing pregnancy, but these results were not consistent across gestational age periods.

Conclusions

Of women with an ongoing pregnancy at 6 weeks, about 60% will have a living infant at 28 days of age. Two thirds of the losses will be spontaneous miscarriages and one third will be secondary to a MTP. High maternal age and education were the risk factors associated with miscarriage and MTP.

Trial registration

The trial is registered at clinicaltrials.gov. ClinicalTrial.gov Trial Registration: NCT01073475.

     

Unfavorable outcome in penultimate pregnancy and premature rupture of membranes in successive pregnancy.

OBJECTIVES: Previous adverse obstetric events are known to influence the outcome of the succeeding pregnancy. We tested the hypothesis that preterm premature rupture of membranes (PROM), full-term PROM, and preterm delivery without PROM relate independently to the outcome of the immediately preceding pregnancy. METHODS: In a case-control study, 345 women 15-45 years old with preterm PROM, full-term PROM, or preterm delivery without PROM were singly matched by age, race, and parity to women having full-term delivery. Information about the penultimate pregnancy, household smoking, and sociodemographic variables were obtained during face-to-face interviews. Obstetric history, infections during pregnancy, and pregnancy complications abstracted from medical records were cross-checked with patient interview data. Penultimate pregnancy outcomes included full-term delivery, premature delivery, fetal loss or miscarriage, and planned abortion. RESULTS: Women having preterm PROM or preterm delivery without PROM in the index pregnancy were, respectively, 6.34 and 21.28 times more likely than controls to have had preterm delivery in the preceding pregnancy. A preceding fetal loss or miscarriage also increased 4.39-fold the risk for preterm PROM. Exposure to cigarette smoke, urinary tract infections, and vaginal bleeding during the index pregnancy independently increased the risk for preterm PROM. Women with full-term PROM did not differ significantly from controls in the outcomes of the penultimate pregnancy. CONCLUSION: Preterm delivery in the preceding pregnancy is associated with an increased risk for preterm delivery with or without PROM.     

The identification of risk of spontaneous fetal loss through second-trimester maternal serum screening

OBJECTIVE: The purpose of this study was to investigate associations between risk of spontaneous fetal loss and risk estimates for Down syndrome, trisomy 18, and neural tube defects assigned by second-trimester maternal serum screening. STUDY DESIGN: The study involved 264,653 women with available pregnancy outcomes who were screened between 15 and 20 weeks of gestation in the Ontario Maternal Serum Screening Program between October 1995 and September 2000. Pregnancies complicated by fetal chromosomal or structural abnormalities, insulin-dependent diabetes mellitus, and multiple pregnancies were excluded. Spontaneous fetal loss was defined as spontaneous miscarriage and intrauterine fetal demise as classified by the ICD-9 system, but including only those > or = 15 weeks of gestation. Women were grouped according to risk estimates for Down syndrome, trisomy 18, and neural tube defects, respectively. Spontaneous fetal loss rates by each risk group were evaluated after adjusting for losses associated with maternal age and amniocentesis. RESULTS: Fetal loss rates increased in women with risk estimates of > or = 1 in 1110 for trisomy 18 or neural tube defects, and > or = 1 in 130 for Down syndrome. The excessive fetal loss rates for these 3 groups of women were 14.4%, 3.2%, and 1.5% respectively. CONCLUSION: Fetal loss rate markedly increased in women with high-risk estimates for trisomy 18, neural tube defects, and Down syndrome. Risk estimates assigned by triple marker screening may provide an early means of stratifying pregnancies into risk for fetal loss.     

Alterations in humoral immune responses associated with recurrent pregnancy loss

OBJECTIVE: To investigate the reactivity of maternal antibodies with endometrium-derived antigens and to correlate their association with recurrent pregnancy loss (RPL). DESIGN: Prevalence study. SETTING: Academic research center. PATIENT(S): Nulliparous women (n = 10), women with RPL (n = 15), pregnant women (n = 8), and multiparous women with a normal obstetric history (n = 20). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Reactive antibodies were analyzed by Western immunoblot techniques and quantitated by densitometry. RESULT(S): Antibodies from women with RPL and multiparous women recognized antigens ranging from 10-120 kd on normal endometrium and endometrial tumors. Antibodies from most women with RPL (10/15) and from multiparous women (15/20) recognized 65-kd and 80-kd proteins in normal endometrium. Antibodies from women with RPL recognized 21-kd and 28-kd antigens (12/15 and 13/15, respectively) in endometrial tumors at a significantly greater rate (than did antibodies from multiparous women (5/20 and 8/20, respectively). Women with RPL had significantly lower levels of asymmetric IgG compared with controls. CONCLUSION(S): Recurrent pregnancy loss may be linked with the failure to elicit asymmetric IgG and a unique immunologic recognition of endometrial antigens.     

Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomized controlled trial

OBJECTIVE: This pilot investigation was undertaken to assess the efficacy of low-dose aspirin therapy for the treatment of women with antiphospholipid antibodies when recurrent miscarriage is the only sequela. STUDY DESIGN: A double-blind, randomized, placebo-controlled trial was conducted in the setting of the recurrent miscarriage clinic of a tertiary referral obstetric hospital. The participants were 50 women with a history of recurrent miscarriages (>/=3) and antiphospholipid antibodies. Women with systemic lupus erythematosus or a history of thrombosis were excluded. Women were recruited after full investigative screening at the recurrent miscarriage clinic. Women with >/=3 fetal losses and persistently positive results for antiphospholipid antibodies were randomly allocated to receive either aspirin (75 mg daily) or placebo. Investigators, clinicians, and patients were blinded to the treatment. Rates of live births, antenatal complications, and delivery and neonatal outcomes were recorded prospectively. Data were compared by chi(2) analysis with Yates' correction, the Fisher exact test, or the Student t test as appropriate. RESULTS: There were 10 exclusions after random assignment because of inappropriate inclusion. Eighty-five percent of the placebo (17/20) group and 80% of the aspirin-treated group (16/20) were delivered of live infants. This difference was not significant. There were no significant differences in antenatal complications or neonatal morbidity between the groups. CONCLUSIONS: This preliminary study suggests that low-dose aspirin has no additional benefit when added to supportive care for women for whom recurrent early fetal loss is the only sequela of the antiphospholipid syndrome. This live birth rate with supportive care alone exceeds the published live birth rates for women with antiphospholipid antibody-mediated recurrent fetal loss who were treated with heparin or corticosteroids. This trial, like all other trials in this field, is small, but its results bring into question the need for pharmacologic intervention for women with antiphospholipid syndrome for whom recurrent fetal loss is the only sequela. Our results highlight the need for a large randomized controlled trial to identify the optimal treatment for this group of women and justify the inclusion of a placebo arm in any such trial.     

Women and health care professionals' preferences for Down's Syndrome screening tests: a conjoint analysis study

OBJECTIVE: To describe and compare women and health care professionals' preferences for Down's Syndrome screening tests with different test characteristics. DESIGN: Cross sectional questionnaire based conjoint analysis study. SETTING: London teaching hospital. SAMPLE: 291/383 women in their first or second trimester of pregnancy and 98/122 health care professionals (41 obstetricians, senior house officers and above and 57 qualified midwives) providing care at the same hospital. METHODS: Women completed a questionnaire while attending a clinic visit for a dating scan or a routine 20-week anomaly scan. Health care professionals completed a postal questionnaire. MAIN OUTCOME MEASURES: The relative values participants attach to Down's Syndrome screening test attributes: time of test, detection rate and risk of miscarriage of a baby unaffected by Down's Syndrome as a result of subsequent diagnostic tests. RESULTS: Pregnant women and health care professionals shared broadly similar relative values regarding the importance of safe tests, conducted early and with high detection rates. When asked to choose between different Down's Syndrome screening tests, health care professionals valued earlier tests more highly than did women. CONCLUSIONS: While pregnant women and health care professionals share similar relative values regarding optimal prenatal tests, health care professionals place a higher value on earlier tests. This may result in screening policies that overweight timing in the selection of a test to the relative neglect of tests associated with lower miscarriage rates and higher detection rates but conducted later in pregnancy.     

Can preimplantation genetic diagnosis overcome recurrent pregnancy failure?

PURPOSE OF REVIEW: Preimplantation genetic diagnosis is widely used for the detection of embryo aneuploidy before implantation, with the aim of avoiding miscarriage or pregnancy termination of an aneuploid fetus. The majority of first trimester miscarriages occur due to chromosomal imbalances. The aim of this review is to assess whether preimplantation genetic diagnosis can help women who suffer from recurrent pregnancy loss. RECENT FINDINGS: Several in-vitro fertilization clinics have employed preimplantation genetic diagnosis in women with recurrent pregnancy loss. Patients were classified into groups according to their age. Preimplantation genetic diagnosis was very successful in treating couples where one of the parents was a carrier of a balanced chromosomal abnormality such as a translocation. Similarly, recurrent pregnancy loss rate was reduced in women more than 35 years in age with a normal karyotype. On the other hand, in younger patients the beneficial effect of this procedure is debatable. In general, women with recurrent pregnancy loss produced more abnormal embryos than control groups. SUMMARY: Preimplantation genetic diagnosis can be beneficial for three major subgroups of patients with recurrent pregnancy loss: couples carrying chromosomal translocations; women more than 35 years of age; women of any age whose previous miscarriages were due to fetal aneuploidy. It is likely that the rate of miscarriage will be further reduced with the new advances in methods of performing preimplantation genetic diagnosis for more chromosomes.