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1.  The relationship between lead in plasma and whole blood in women. 
Environmental Health Perspectives  2002;110(3):263-268.
Studies have suggested that plasma lead levels may better reflect the toxicologically labile fraction of circulatory Pb that is more freely available for exchange with target tissues than do Pb levels in whole blood. Studies have also reported an apparent severalfold variation in the relative partitioning of Pb between whole blood and plasma (or serum) for a given whole-blood Pb level. This may reflect inherent differences in the plasma Pb/whole blood Pb partitioning among individuals and/or methodologic challenges associated with the collection and analyses of samples that generally contain < 1-2 ng total Pb. Here, we conducted a longitudinal assessment of the relationship between Pb in whole blood and plasma in environmentally exposed reproductive-age women (n = 63) living in Mexico City, Mexico. We collected whole blood and plasma samples using trace metal clean techniques and analyzed them for Pb using high-resolution inductively coupled plasma mass spectrometry. A subset of subjects provided repeated blood samples weekly for 4 consecutive weeks (n = 17 subjects) or every 1-2 months over a 9-month period (n = 14 subjects). Plasma Pb concentration was significantly positively associated with whole-blood Pb in a curvilinear fashion over the range of blood Pb values observed here (2.13-39.7 microg/dL). This relationship was best described by the function Plasma Pb = e (-2.392 + 0.0898 x blood Pb), where SE(coefficient) = 0.0054, SE(constant) = 0.063 (n = 63 subjects, n = 141 observations). Results from the short- and long-term repeated collection subjects indicated that the within- and between-subject variance components were not significantly different between the two subsets of subjects. The between-subjects component accounts for 78% of the variance in plasma Pb levels, while the residual variance (22%) may be attributed to other unmeasured factors. Collectively, this study demonstrates that plasma Pb measurements may be applied to general clinical settings, provided that established trace metal clean techniques are adopted. This study also shows that the relative (%) partitioning of whole-blood Pb in plasma naturally varies by a factor of about 2-4-fold among subjects at a given blood Pb level. Because Pb in the plasma is considered to more closely represent the fraction of Pb in the circulation that is readily exchanged with peripheral target tissues (e.g., brain, kidney, skeleton), the routine assessment of plasma Pb may provide a more meaningful measure of toxicologically available Pb.
PMCID: PMC1240766  PMID: 11882477
2.  Short and long term mortality rates associated with first pregnancy outcome: Population register based study for Denmark 1980–2004 
Summary
Background
There is a growing interest in examining death rates associated with different pregnancy outcomes for time periods beyond one year. Previous population studies, however, have failed to control for complete reproductive histories. In this study we seek to eliminate the potential confounding effect of unknown prior pregnancy history by examining mortality rates associated specifically with first pregnancy outcome alone. We also examine differences in mortality rates associated with early abortion and late abortions (after 12 weeks).
Material/Method
Medical records for the entire population of women born in Denmark between 1962 and 1991 and were alive in 1980, were linked to death certificates. Mortality rates associated with first pregnancy outcomes (delivery, miscarriage, abortion, and late abortion) were calculated. Odds ratios examining death rates based on reproductive outcomes, adjusted for age at first pregnancy and year of women’s births, were also calculated.
Results
A total of 463,473 women had their first pregnancy between 1980 and 2004, of whom 2,238 died. In nearly all time periods examined, mortality rates associated with miscarriage or abortion of a first pregnancy were higher than those associated with birth. Compared to women who delivered, the age and birth year adjusted cumulative risk of death for women who had a first trimester abortion was significantly higher in all periods examined, from 180 days (OR=1.84; 1.11 <95% CI <3.71) through 10 years (1.39; 1.22 <95% CI <1.61), as was the risk for women who had abortions after 12 weeks from one year (OR=4.31; 2.18 <95% CI <8.54) through 10 years (OR=2.41; 1.56 <95% CI <2.41). For women who miscarried, the risk was significantly higher for cumulative deaths through 4 years (OR=1.75; 1.34 <95% CI <2.27) and at 10 years (OR=1.48; 1.18 <95% CI <1.85).
Conclusions
Compared to women who delivered, women who had an early or late abortion had significantly higher mortality rates within 1 through 10 years. A lesser effect may also be present relative to miscarriage. Recommendations for additional research are offered.
doi:10.12659/MSM.883338
PMCID: PMC3560645  PMID: 22936199
abortion; maternal mortality; childbirth; late-term abortion; miscarriage; mortality rates
3.  Reproductive outcomes in adolescents who had a previous birth or an induced abortion compared to adolescents' first pregnancies 
Background
Recently, attention has been focused on subsequent pregnancies among teenage mothers. Previous studies that compared the reproductive outcomes of teenage nulliparae and multiparae often did not consider the adolescents' reproductive histories. Thus, the authors compared the risks for adverse reproductive outcomes of adolescent nulliparae to teenagers who either have had an induced abortion or a previous birth.
Methods
In this retrospective cohort study we used perinatal data prospectively collected by obstetricians and midwives from 1990–1999 (participation rate 87–98% of all hospitals) in Lower Saxony, Germany. From the 9742 eligible births among adolescents, women with multiple births, >1 previous pregnancies, or a previous spontaneous miscarriage were deleted and 8857 women <19 years remained. Of these 8857 women, 7845 were nulliparous, 801 had one previous birth, and 211 had one previous induced abortion. The outcomes were stillbirths, neonatal mortality, perinatal mortality, preterm births, and very low birthweight. Bivariate and multivariable logistic regression models were conducted.
Results
In bivariate logistic regression analyses, compared to nulliparous teenagers, adolescents with a previous birth had higher risks for perinatal [OR = 2.08, CI = 1.11,3.89] and neonatal [OR = 4.31, CI = 1.77,10.52] mortality and adolescents with a previous abortion had higher risks for stillbirths [OR = 3.31, CI = 1.01,10.88] and preterm births [OR = 2.21, CI = 1.07,4.58]. After adjusting for maternal nationality, partner status, smoking, prenatal care and pre-pregnancy BMI, adolescents with a previous birth were at higher risk for perinatal [OR = 2.35, CI = 1.14,4.86] and neonatal mortality [OR = 4.70, CI = 1.60,13.81] and adolescents with a previous abortion had a higher risk for very low birthweight infants [OR = 2.74, CI = 1.06,7.09] than nulliparous teenagers.
Conclusion
The results suggest that teenagers who give birth twice as adolescents have worse outcomes in their second pregnancy compared to those teenagers who are giving birth for the first time. The prevention of the second pregnancy during adolescence is an important public health objective and should be addressed by health care providers who attend the first birth or the abortion and the follow-up care. Also, health care workers should attempt to improve the pregnancy outcomes of subsequent teenage pregnancies by addressing modifiable risk factors, for example, supporting smoking cessation and utilization of prenatal care.
doi:10.1186/1471-2393-8-4
PMCID: PMC2266899  PMID: 18237387
4.  How long after a miscarriage should women wait before becoming pregnant again? Multivariate analysis of cohort data from Matlab, Bangladesh 
BMJ Open  2012;2(4):e001591.
Objective
To determine the optimum interpregnancy interval (IPI) following a miscarriage.
Design
Multivariate analysis of population-based, prospective data from a demographic surveillance system.
Setting
Pregnancies in Matlab, Bangladesh, between 1977 and 2008.
Participants
9214 women with 10 453 pregnancies that ended in a miscarriage and were followed by another pregnancy outcome.
Main outcome measures
Outcome of pregnancy following the miscarriage was singleton live birth, stillbirth, miscarriage or induced abortion. For pregnancies that ended in live birth: early neonatal, late neonatal and postneonatal mortality.
Results
Compared with IPIs of 6–12 months, pregnancies that were conceived ≤3 months after a miscarriage were more likely to result in a live birth and less likely to result in a miscarriage (adjusted relative risk ratio (RRR) 0.70, 95% CI 0.57 to 0.86) or induced abortion (0.50, 0.29 to 0.89). Induced abortions were significantly more likely following IPIs of 18–24 months (2.36, 1.48 to 3.76), 36–48 months (2.73, 1.50 to 4.94), and >48 months (3.32, 1.68 to 2.95), and miscarriages were more likely following IPIs of 12–17 months (1.25, 1.01 to 1.56) and >48 months (1.90, 1.40 to 2.58). No significant effects of IPI duration are seen on the risks of a stillbirth. However, IPIs≤3 months following a miscarriage are associated with significantly higher late neonatal mortality for the infant born at the end of the IPI (adjusted hazard ratio (HR) 1.74, 1.06 to 2.84), and IPIs of 12–18 months are associated with a significantly lower unadjusted risk of postneonatal mortality (0.54, 0.30 to 0.96).
Conclusions
The shorter the IPI following a miscarriage, the more likely the subsequent pregnancy is to result in a live birth. However, very short IPIs may not be advisable following miscarriages in poor countries like Bangladesh because they are associated with a higher risk of mortality for the infants born after them.
doi:10.1136/bmjopen-2012-001591
PMCID: PMC3425891  PMID: 22907047
Reproductive Medicine; pregnancy outcome; pregnancy spacing; miscarriage; abortion; infant mortality
5.  Environmental tobacco smoke and stress as risk factors for miscarriage and preterm births 
Archives of Gynecology and Obstetrics  2012;286(5):1187-1191.
Back ground
Exposure of pregnant women to environmental tobacco smoke has been shown to be associated with low birth weight. Many studies have suggested that stress have a role in the etiology of preterm birth.
Aims
This study carried out from June 2008 to March 2009 to find the relation between environmental tobacco smoke, stress and miscarriage and preterm births.
Methods
A total of 33 subjects consisted of multiparous pregnant women that were in their early third trimester were chosen for this investigation. Subjects were divided into test group women with adverse pregnancy outcome, control group women with successful pregnancy. Four ml of unstimulated whole saliva were collected. The concentrations of cotinine and cortisol were evaluated using commercially available ELISA kit.
Results
Pregnancies in which the average standardized cortisol during history of previous miscarriage(s) which occurred within 6th–27th week or/and history of preterm labor which occurred within 28th–36th weeks of gestation, demonstrated higher cortisol level (1.0201 ± 0.1855 ng/ml) compared to control group 0.9757 ± 0.2860 ng/ml (P = 0.323); statistical analysis showed no significant differences. Women of control group were more likely to be environmental tobacco smoke exposed (1.2714 ± 1.7639 ng/ml) than women with miscarriage and preterm births (0.9889 ± 0.5498 ng/ml).
Conclusion
The results from this primarily study demonstrated no association between cotinine, cortisol, miscarriage and preterm births.
doi:10.1007/s00404-012-2417-0
PMCID: PMC3472053  PMID: 22718098
Environmental tobacco smoke; Stress; Miscarriage; Preterm births
6.  Risk of breast cancer after miscarriage or induced abortion: a Scottish record linkage case-control study 
Study objective: To assess the risk of breast cancer in patients with a previous history of miscarriage or induced abortion.
Design: Case-control study relating "exposure" to outcome by linkage of national hospital discharge and maternity records, the national cancer registry, and death records.
Setting: Scotland.
Participants: Miscarriage analysis—2828 women with breast cancer and 9781 matched controls; induced abortion analysis—2833 women with breast cancer and 9888 matched controls.
Main results: After stratification for age at diagnosis, parity, and age at first birth, the odds ratio (95% confidence intervals) of breast cancer was 1.02 (0.88 to 1.18) in women with a previous miscarriage, and 0.80 (0.72 to 0.89) in women with a previous induced abortion. Further adjustments for age at bilateral oophorectomy, socioeconomic status (based on small area of residence), and health board area of residence had only minor effects on these odds ratios.
Conclusion: These data do not support the hypothesis that miscarriage or induced abortion represent substantive risk factors for the future development of breast cancer.
doi:10.1136/jech.2004.026393
PMCID: PMC1733063  PMID: 15767381
7.  Inflammatory Cytokines in Maternal Circulation and Placenta of Chromosomally Abnormal First Trimester Miscarriages 
The impact of abnormal placental karyotype on the inflammatory response within the villous tissue and peripheral circulation of women with miscarriage was evaluated. Villous (n = 38) and venous blood samples (n = 26) were obtained from women with missed miscarriage. Tissue chromosome analysis indicated 23 abnormal and 15 normal karyotypes. Concentration of tumour necrosis factor alpha (TNFα), TNF-R1 and TNF-R2, and interleukin (IL)-10 were measured using flowcytometric bead array in fresh villous homogenate, cultured villous extracts, culture medium, maternal whole blood, and plasma. Plasma TNFα/IL-10 ratios were significantly (P < 0.05) lower in miscarriages with abnormal karyotype. In the abnormal karyotype group, there were significantly higher levels of TNFα (P < 0.01), IL-10 (P < 0.01), TNF-R1 (P < 0.001), and TNF-R2 (P < 0.001) in the villous extracts and culture-conditioned medium compared to normal karyotype group. In miscarriage with abnormal karyotype, there is an exacerbated placental inflammatory response, in contrast to miscarriage of normal karyotype where maternal systemic response is increased.
doi:10.1155/2012/175041
PMCID: PMC3184430  PMID: 21977049
8.  Multiple Miscarriages Are Associated with the Risk of Ovarian Cancer: Results from the European Prospective Investigation into Cancer and Nutrition 
PLoS ONE  2012;7(5):e37141.
While the risk of ovarian cancer clearly reduces with each full-term pregnancy, the effect of incomplete pregnancies is unclear. We investigated whether incomplete pregnancies (miscarriages and induced abortions) are associated with risk of epithelial ovarian cancer. This observational study was carried out in female participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 274,442 women were followed from 1992 until 2010. The baseline questionnaire elicited information on miscarriages and induced abortions, reproductive history, and lifestyle-related factors. During a median follow-up of 11.5 years, 1,035 women were diagnosed with incident epithelial ovarian cancer. Despite the lack of an overall association (ever vs. never), risk of ovarian cancer was higher among women with multiple incomplete pregnancies (HR≥4vs.0: 1.74, 95% CI: 1.20–2.70; number of cases in this category: n = 23). This association was particularly evident for multiple miscarriages (HR≥4vs.0: 1.99, 95% CI: 1.06–3.73; number of cases in this category: n = 10), with no significant association for multiple induced abortions (HR≥4vs.0: 1.46, 95% CI: 0.68–3.14; number of cases in this category: n = 7). Our findings suggest that multiple miscarriages are associated with an increased risk of epithelial ovarian cancer, possibly through a shared cluster of etiological factors or a common underlying pathology. These findings should be interpreted with caution as this is the first study to show this association and given the small number of cases in the highest exposure categories.
doi:10.1371/journal.pone.0037141
PMCID: PMC3356371  PMID: 22623987
9.  Blood glutathione peroxidase and selenium in abortion 
This study was carried out to estimate the levels of glutathione peroxidase and selenium in blood of abortion cases. Glutathione peroxidase and selenium were determined in 52 abortion cases (22 in 1st trimester, 30 in second trimester), 45 normal pregnant cases and 25 nonpregnant control cases. The selenium concentration in whole blood and plasma in abortion cases was almost the same as in normal pregnant women but significantly low when compared with the control non-pregnant group. The glutathione levels was higher in abortion cases when compared with normal pregnant and non-pregnant control groups. Red cell and plasma glutathione peroxidase activities of women who had abortion were significantly lower compared with both non-pregnant control group and normal pregnancies.
doi:10.1007/BF02867673
PMCID: PMC3453745  PMID: 23105379
10.  The Liver X Receptor in Correlation with Other Nuclear Receptors in Spontaneous and Recurrent Abortions 
PPAR Research  2013;2013:575604.
The liver X receptors (LXRs) have been shown to be crucially involved in maternal-fetal cholesterol transport and placentation. The aim of this study was to investigate the expression pattern and frequency of LXR under normal physiological circumstances and in spontaneous abortion and/or recurrent miscarriage. A total of 29 (12 physiologic pregnancies/10 spontaneous abortions/7 recurrent miscarriages) human pregnancies in first trimester were analysed for LXR expression. Expression changes were evaluated by immunohistochemistry for receptor and quantitative RT-PCR (TaqMan) was performed to determine the level of LXR mRNA expression. We also stained for RXRα and PPARγ as possible heterodimers of LXR. LXR expression was downregulated in the syncytiotrophoblast of spontaneous abortion placentas compared to normal pregnancy. In recurrent miscarriage there was a trend for a downregulation. Decidua showed an even stronger downregulation in both groups. In the syncytiotrophoblast we found a positive correlation for the combination of LXR/PPARγ in abortions and a negative correlation for LXR/RXRα. In addition, double-immunofluorescence staining showed that LXR as well as RXRα and PPARγ are expressed by the extravillous trophoblast. Finally, RXRα and LXR showed coexpression in the same extravillous trophoblast cells. To conclude, our data show that LXR expression is decreased in miscarriage.
doi:10.1155/2013/575604
PMCID: PMC3649716  PMID: 23690759
11.  The Impact of Miscarriage and Parity on Patterns of Maternal Distress in Pregnancy 
Research in nursing & health  2010;33(4):316-328.
The purpose of the current study was to examine patterns of state anxiety and pregnancy-specific distress across pregnancy in a diverse sample of women with (n = 113) and without (n = 250) prior miscarriage. For both groups, state anxiety and pregnancy-specific distress were highest in the first trimester and decreased significantly over the course of pregnancy. Compared to women without prior miscarriage, women with prior miscarriage experienced greater state anxiety in the second and third trimesters. Having a living child did not buffer state anxiety in women with a prior miscarriage. Attention to patterns of distress can contribute to delivery of appropriate support resources to women experiencing pregnancy after miscarriage and may help reduce risk for stress-related outcomes.
doi:10.1002/nur.20389
PMCID: PMC3070408  PMID: 20544819
miscarriage; pregnancy; anxiety; prenatal stress; perinatal loss
12.  Fetal Lead Exposure at Each Stage of Pregnancy as a Predictor of Infant Mental Development 
Environmental Health Perspectives  2006;114(11):1730-1735.
Background
The impact of prenatal lead exposure on neurodevelopment remains unclear in terms of consistency, the trimester of greatest vulnerability, and the best method for estimating fetal lead exposure.
Objective
We studied prenatal lead exposure’s impact on neurodevelopment using repeated measures of fetal dose as reflected by maternal whole blood and plasma lead levels.
Methods
We measured lead in maternal plasma and whole blood during each trimester in 146 pregnant women in Mexico City. We then measured umbilical cord blood lead at delivery and, when offspring were 12 and 24 months of age, measured blood lead and administered the Bayley Scales of Infant Development. We used multivariate regression, adjusting for covariates and 24-month blood lead, to compare the impacts of our pregnancy measures of fetal lead dose.
Results
Maternal lead levels were moderately high with a first-trimester blood lead mean (± SD) value of 7.1 ± 5.1 μg/dL and 14% of values ≥10 μg/dL. Both maternal plasma and whole blood lead during the first trimester (but not in the second or third trimester) were significant predictors (p < 0.05) of poorer Mental Development Index (MDI) scores. In models combining all three trimester measures and using standardized coefficients, the effect of first-trimester maternal plasma lead was somewhat greater than the effect of first-trimester maternal whole blood lead and substantially greater than the effects of second- or third-trimester plasma lead, and values averaged over all three trimesters. A 1-SD change in first-trimester plasma lead was associated with a reduction in MDI score of 3.5 points. Postnatal blood lead levels in the offspring were less strongly correlated with MDI scores.
Conclusions
Fetal lead exposure has an adverse effect on neurodevelopment, with an effect that may be most pronounced during the first trimester and best captured by measuring lead in either maternal plasma or whole blood.
doi:10.1289/ehp.9067
PMCID: PMC1665421  PMID: 17107860
bone; IQ; lead; plasma; pregnancy; neurodevelopment
13.  Array comparative genomic hybridization and flow cytometry analysis of spontaneous abortions and mors in utero samples 
BMC Medical Genetics  2009;10:89.
Background
It is estimated that 10-15% of all clinically recognised pregnancies result in a spontaneous abortion or miscarriage. Previous studies have indicated that in up to 50% of first trimester miscarriages, chromosomal abnormalities can be identified. For several decades chromosome analysis has been the golden standard to detect these genomic imbalances. A major drawback of this method is the requirement of short term cultures of fetal cells. In this study we evaluated the combined use of array CGH and flow cytometry (FCM), for detection of chromosomal abnormalities, as an alternative for karyotyping.
Methods
In total 100 spontaneous abortions and mors in utero samples were investigated by karyotyping and array CGH in combination with FCM in order to compare the results for both methods.
Results
Chromosome analysis revealed 17 abnormal karyotypes whereas array CGH in combination with FCM identified 26 aberrations due to the increased test success rate. Karyotyping was unsuccessful in 28% of cases as compared to only two out of hundred samples with inconclusive results for combined array CGH and FCM analysis.
Conclusion
This study convincingly shows that array CGH analysis for detection of numerical and segmental imbalances in combination with flow cytometry for detection of ploidy status has a significant higher detection rate for chromosomal abnormalities as compared to karyotyping of miscarriages samples.
doi:10.1186/1471-2350-10-89
PMCID: PMC2753309  PMID: 19751515
14.  Recurrent miscarriage 
Clinical Evidence  2008;2008:1409.
Introduction
Recurrent miscarriage is the spontaneous loss of three or more consecutive pregnancies with the same biological father in the first trimester, and affects 1-2% of women, half of whom have no identifiable cause. Overall, 75% of affected women will have a successful subsequent pregnancy, but this rate falls for older mothers and with increasing number of miscarriages. Antiphospholipid syndrome, with anticardiolipin or lupus anticoagulant antibodies, is present in 15% of women with recurrent first and second trimester miscarriage.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for unexplained recurrent miscarriage? What are the effects of treatments for recurrent miscarriage caused by antiphospholipid syndrome? We searched: Medline, Embase, The Cochrane Library and other important databases up to April 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: aspirin (low dose), bed rest, corticosteroids, early scanning in subsequent pregnancies, heparin plus low-dose aspirin, human chorionic gonadotrophin, intravenous immunoglobulin treatment, lifestyle adaptation, oestrogen, paternal white cell immunisation, progesterone, trophoblastic membrane infusion, and vitamin supplementation.
Key Points
Recurrent miscarriage is the spontaneous loss of three or more consecutive pregnancies with the same biological father in the first trimester; it affects 1-2% of women, in half of whom there is no identifiable cause. Overall, 75% of affected women will have a successful subsequent pregnancy, but this rate falls for older mothers and with increasing number of miscarriages.Antiphospholipid syndrome, with anticardiolipin or lupus anticoagulant antibodies, is present in 15% of women with recurrent first- and second-trimester miscarriage.
We don't know whether bed rest, early scanning, lifestyle adaptation to stop smoking, reduce alcohol consumption and lose weight, low-dose aspirin, human chorionic gonadotrophin, trophoblastic membrane infusion, or vitamin supplementation increase the likelihood of a successful pregnancy in women with unexplained recurrent miscarriage.
We also don't know whether oestrogen supplementation increases the live birth rate in women with unexplained recurrent miscarriage, but it may increase the miscarriage rate and cause abnormalities in the fetus. We don't know whether progesterone supplementation or corticosteroids reduce miscarriage rates compared with placebo in women with unexplained recurrent miscarriage.
Paternal white cell immunisation and intravenous immunoglobulin treatment do not seem likely to improve live birth rates compared with placebo in women with unexplained recurrent miscarriage.
We don't know whether low-dose aspirin, alone or combined with heparin, can increase the live birth rate compared with placebo in women with antiphospholipid syndrome. Prednisolone plus aspirin may not increase live birth rates in women with antiphospholipid syndrome, and increases the risk of adverse effects compared with placebo.
PMCID: PMC2907979  PMID: 19450314
15.  Recurrent miscarriage 
Clinical Evidence  2011;2011:1409.
Introduction
Recurrent miscarriage is the spontaneous loss of three or more consecutive pregnancies with the same biological father in the first trimester, and affects 1% to 2% of women, half of whom have no identifiable cause. Overall, 75% of affected women will have a successful subsequent pregnancy, but this rate falls for older mothers and with increasing number of miscarriages. Antiphospholipid syndrome, with anticardiolipin or lupus anticoagulant antibodies, is present in 15% of women with recurrent first and second trimester miscarriage.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for unexplained recurrent miscarriage? What are the effects of treatments for recurrent miscarriage caused by antiphospholipid syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: aspirin (low dose), bed rest, corticosteroids, early scanning in subsequent pregnancies, heparin plus low-dose aspirin, human chorionic gonadotrophin, intravenous immunoglobulin treatment, lifestyle adaptation, oestrogen, paternal white cell immunisation, progesterone, trophoblastic membrane infusion, and vitamin supplementation.
Key Points
Recurrent miscarriage is the spontaneous loss of three or more consecutive pregnancies with the same biological father in the first trimester; it affects 1% to 2% of women, in half of whom there is no identifiable cause. Overall, 75% of affected women will have a successful subsequent pregnancy, but this rate falls for older mothers and with increasing number of miscarriages.Antiphospholipid syndrome, with anticardiolipin or lupus anticoagulant antibodies, is present in 15% of women with recurrent first- and second-trimester miscarriage.
We don't know whether bed rest, early scanning, lifestyle adaptation (to stop smoking, reduce alcohol consumption, and lose weight), low-dose aspirin, human chorionic gonadotrophin, trophoblastic membrane infusion, or vitamin supplementation increase the likelihood of a successful pregnancy in women with unexplained recurrent miscarriage.
We also don't know whether oestrogen supplementation increases the live birth rate in women with unexplained recurrent miscarriage, but it may increase the miscarriage rate and cause abnormalities in the fetus. We don't know whether progesterone supplementation or corticosteroids reduce miscarriage rates compared with placebo in women with unexplained recurrent miscarriage.
Paternal white cell immunisation and intravenous immunoglobulin treatment do not seem likely to improve live birth rates compared with placebo in women with unexplained recurrent miscarriage.
We don't know whether low-dose aspirin, alone or combined with heparin, can increase the live birth rate compared with placebo in women with antiphospholipid syndrome. Prednisolone plus aspirin does not seem to increase live birth rates, compared with placebo or aspirin alone, in women with antiphospholipid syndrome, and it increases the risk of adverse effects including hypertension, preterm birth, low birth weight, and admission to neonatal intensive care.
PMCID: PMC3275302  PMID: 21718553
16.  Maternal age and fetal loss: population based register linkage study 
BMJ : British Medical Journal  2000;320(7251):1708-1712.
Objective
To estimate the association between maternal age and fetal death (spontaneous abortion, ectopic pregnancy, stillbirth), taking into account a woman's reproductive history.
Design
Prospective register linkage study.
Subjects
All women with a reproductive outcome (live birth, stillbirth, spontaneous abortion leading to admission to hospital, induced abortion, ectopic pregnancy, or hydatidiform mole) in Denmark from 1978 to 1992; a total of 634 272 women and 1 221 546 pregnancy outcomes.
Main outcome measures
Age related risk of fetal loss, ectopic pregnancy, and stillbirth, and age related risk of spontaneous abortion stratified according to parity and previous spontaneous abortions.
Results
Overall, 13.5% of the pregnancies intended to be carried to term ended with fetal loss. At age 42 years, more than half of such pregnancies resulted in fetal loss. The risk of a spontaneous abortion was 8.9% in women aged 20-24 years and 74.7% in those aged 45 years or more. High maternal age was a significant risk factor for spontaneous abortion irrespective of the number of previous miscarriages, parity, or calendar period. The risk of an ectopic pregnancy and stillbirth also increased with increasing maternal age.
Conclusions
Fetal loss is high in women in their late 30s or older, irrespective of reproductive history. This should be taken into consideration in pregnancy planning and counselling.
PMCID: PMC27416  PMID: 10864550
17.  A Bioplex Analysis of Cytokines and Chemokines in First Trimester Maternal Plasma to Screen for Predictors of Miscarriage 
PLoS ONE  2014;9(4):e93320.
Background
We have previously shown in two independent cohorts that circulating first trimester Macrophage Inhibitory Cytokine-1 (MIC-1) levels are lower in women in early pregnancy who are destined to miscarriage. While promising, the diagnostic performance of measuring MIC-1 alone was not sufficient for it to be a useful predictive test for miscarriage. Besides MIC-1, there are other cytokines, as well as chemokines, involved in facilitating early pregnancy. We reasoned that screening these factors in maternal plasma could uncover other predictive markers of miscarriage.
Methods
This was a nested case control study, of 78 women from a prospective study of 462 attending the Early Pregnancy Assessment Unit in the first trimester (EPAU) with a threatened miscarriage; 34 of these subsequently miscarried (cases) and 44 went on to have a normal delivery (controls) Cytokines IL-1β, IL-6 and IL-10, and the chemokines, CXCL8, CCL2, CCL5, CCL7 and CX3CL1 were measured in plasma from our cohort.
Results
The cytokines IL-1β, IL-6, IL-10 and the chemokine CXCL8 were not detectable in first trimester plasma. The chemokines CCL2, CCL5, CCL7 and CX3CL1 were detectable in all samples but levels did not vary across 5–12 weeks of gestation among controls. Plasma levels of these chemokines were no different in the miscarriage cohort compared to controls.
Conclusion
The chemokines CCL2, CCL5, CCL7 and CX3CL1 were detectable in plasma during the first trimester while IL-1β, IL-6, IL-10 and CXCL8 were not. However, none of the cytokines and chemokines screened were different in maternal plasma in cases or controls. These therefore do not appear to have potential for application as predictive biomarkers of miscarriage.
doi:10.1371/journal.pone.0093320
PMCID: PMC3974717  PMID: 24699265
18.  Relation between single serum progesterone assay and viability of the first trimester pregnancy 
Objective:
This study was designed to detect the relation between serum progesterone and viability of pregnancy during the first trimester.
Material and Methods:
Two hundred and sixty women during the first trimester of their pregnancies were hospitalised due to vaginal bleeding and/or abdominal pain and were included in this study. Criteria for inclusion in this study were: certain dates, foetus conceived spontaneously with no history of infertility and a positive serum pregnancy test. Blood samples were taken from women included in this study for serum progesterone assay; the patients were followed by ultrasound until the end of the first trimester for the viability of the pregnancy and the outcome of their pregnancy was recorded.
Results:
By the end of the first trimester, women included in this study were classified into: viable pregnancy group (n=178; 68.5%) and non-viable pregnancy group (ended by miscarriage) (n=82; 31.5%). The mean serum progesterone of the studied population was significantly higher in the viable pregnancy group (46.5±7.4 ng/mL) compared to non-viable pregnancy group (9.9±4.8 ng/mL; p<0.05). The serum progesterone cut-off level of 10 ng/mL was 79.3% sensitive for diagnosing non-viable pregnancy and 93.3% specific for the diagnosis of viable pregnancy, while a cut-off level of 20 ng/mL was 95.1% sensitive for the diagnosis of non-viable pregnancy and 98.9% specific for diagnosing viable pregnancy.
Conclusion:
Serum progesterone is a reliable marker for early pregnancy failure and a single assay of its serum level can differentiate between viable and non-viable pregnancies.
doi:10.5152/jtgga.2013.09471
PMCID: PMC3881742  PMID: 24592077
First trimester; pregnancy; serum progesterone; single; viability
19.  The comparison of insulin resistance frequency in patients with recurrent early pregnancy loss to normal individuals 
BMC Research Notes  2012;5:133.
Background
Patients with ≥ 3 recurrent spontaneous miscarriages are classified as having RSM. Polycystic ovary syndrome (PCOS) is associated with insulin resistance (IR). The purpose of this study is to evaluate the association of IR and RMS.
Methods
Present case- control prospective study was performed on 100 women in control group (with a history of at a live birth and no history of one more abortion) and study group (with a history of ≥ 3 RMS) who were not diabetes and PCOS. Two groups matched in base of age and body mass index. Blood was withdrawn from the case and control patients for the determination of the fasting blood glucose (FG), fasting insulin (FI) levels and ultrasonography was performed on all the patients.
Results
The observed differences between age, FG and FG to FI ratio levels in case and control groups were not significant (p > 0.05) but it was significant about fasting insulin (p = 0.0119). FI of < 20 μu/ml or ≥ 20 μu/ml in case and control group was significant (Chi-square: 4.083, p: 0.0433, odds ratio: 4.4386, CI95% = 1.1541 to 17.0701), whereas the difference between absolute and proportional frequency of patients with FG to FI ratio of < 4.5 and ≥ 4.5 in case and control groups was not significant (Chi-square: 2.374, p = 0.123).
Conclusion
Current study showed that in women with RPL, in Iranian race like Americans, frequency of insulin resistance in high, therefore there is a probability of the degree of insulin resistance in women with RPL.
doi:10.1186/1756-0500-5-133
PMCID: PMC3329408  PMID: 22405326
20.  Nitric oxide levels and endothelial nitric oxide synthase gene polymorphisms in Turkish women with idiopathic recurrent miscarriage 
Objective
To determine whether endothelial nitric oxide synthase (eNOS) gene polymorphisms are associated with an increased risk for Idiopathic Recurrent Miscarriage (IRM) in the Turkish population and to evaluate the association between Nitric Oxide (NO) levels and eNOS gene polymorphisms in women with IRM.
Material and Methods
A total of 120 Turkish women were enrolled in this study in four groups. Of these, 30 women were first trimester pregnant who had IRM (Group I). Thirty healthy multipara women were in the first trimester of pregnancy with no history of abortion (Group II). Thirty women were non pregnant with a history of IRM (Group III). The remaining 30 subjects were healthy multipara non-pregnant women with no history of abortion (Group IV). DNA analysis of four groups were performed for the two polymorphisms using the PCR and/or PCR-RFLPs method and NO levels were measured spectrophotometrically.
Results
We observed statistically significant decreased NO levels in the pregnant patient group (p=0.001) while elevated NO levels were measured in the non pregnant patient group (p=0.004). We demonstrated that, while there was no significant difference in terms of VNTR 4/eNOS genotype, there was a marginally significant difference in terms of Glu298Asp/eNOS genotype frequency (p=0.055) in patients with IRM in the Turkish population. We observed no association between NO levels and Glu298Asp/eNOS or VNTR 4/eNOS genotypes in any of the groups.
Conclusion
The Glu298Asp polymorphism of eNOS could be an intriguing susceptibility factor that modulates an individual’s risk of IRM in Turkish population. Further studies to explain the role of the NO pathway in the pathophysiology of IRM are needed.
doi:10.5152/jtgga.2011.48
PMCID: PMC3939256  PMID: 24592001
Idiopathic recurrent miscarriage; nitric oxide; gene polymorphisms
21.  Methylenetetrahydrofolate Reductase C677T and A1298C Mutations in Women with Recurrent Spontaneous Abortions in the Northwest of Iran 
ISRN Obstetrics and Gynecology  2012;2012:945486.
Introduction. Recurrent spontaneous abortion (RSA) is a significant obstetrical complication that may occur during pregnancy. Various studies in recent years have indicated that two common mutations (C677T and A1298C) of the methylenetetrahydrofolate reductase (MTHFR) gene are risk factor for RSA. This study was carried out to determine the influence of (C677T and A1298C) of the methylenetetrahydrofolate reductase (MTHFR) gene mutations with RSA. Materials and Methods. A total of 139 women were included in this study: 89 women with two or more consecutive miscarriages and 50 healthy controls. Total genomic DNA was isolated from blood leukocytes. To determine the frequency of the two common C677T and A1298C MTHFR gene mutations in the patients and controls, we used two methods, amplification refractory mutation system-PCR and PCR-restriction fragment length polymorphism. Results. There is no significant difference in the prevalence of 677T/T genotype among women with RSA and healthy controls (P = 0.285). Also no statistically significant difference in the frequency of A1298C MTHFR gene mutation was detected between the two groups (P = 0.175 ). Conclusion. In conclusion, the results indicate that the Amplification Refractory Mutation System-PCR method was in complete concordance with the results obtained by standard PCR-restriction fragment length polymorphism method. The results also show no significant difference in MTHFR C677T/A1298C genotype distribution among the two groups; therefore, further studies on larger population and other genetic variants to better understand the pathobiology of RSA are needed.
doi:10.5402/2012/945486
PMCID: PMC3504415  PMID: 23209927
22.  Acupuncture as a therapeutic treatment option for threatened miscarriage 
Background
Threatened miscarriage involves vaginal bleeding in a pregnancy that remains viable. This is a common early pregnancy complication with increased risk factors for early pregnancy loss, preterm premature rupture of membranes (PPROM), preterm delivery, low birth weight babies and maternal antepartum haemorrhage. Currently there are no recommended medical treatment options, rather women receive advice that centres on a 'wait and see' approach. For women with a history of unexplained recurrent miscarriage providing supportive care in a subsequent pregnancy improves live birthing outcomes, but the provision of supportive care to women experiencing threatened miscarriage has to date not been examined.
Discussion
While it is known that 50-70% of miscarriages occur due to chromosomal abnormalities, the potential for therapeutic intervention amongst the remaining percentage of women remains unknown. Complementary and alternative medicine (CAM) therapies have the potential to provide supportive care for women presenting with threatened miscarriage. Within fertility research, acupuncture demonstrates beneficial hormonal responses with decreased miscarriage rates, raising the possibility acupuncture may promote specific beneficial effects in early pregnancy. With the lack of current medical options for women presenting with threatened miscarriage it is timely to examine the possible treatment benefits of providing CAM therapies such as acupuncture.
Summary
Despite vaginal bleeding being a common complication of early pregnancy there is often reluctance from practitioners to discuss with women and medical personal how and why CAM may be beneficial. In this debate article, the physiological processes of early pregnancy together with the concept of providing supportive care and acupuncture are examined. The aim is to raise awareness and promote discussion as to the beneficial role CAM may have for women presenting with threatened miscarriage.
doi:10.1186/1472-6882-12-20
PMCID: PMC3342918  PMID: 22439880
23.  Interpreting Tacrolimus Concentrations During Pregnancy and Postpartum 
Transplantation  2013;95(7):908-915.
Summary
Pregnancy following solid organ transplantation, although considered high risk for maternal, fetal and neonatal complications, has been quite successful. Tacrolimus pharmacokinetic changes during pregnancy make interpretation of whole blood trough concentrations particularly challenging. There are multiple factors that can increase the fraction of unbound tacrolimus, including but not limited to low albumin concentration and low RBC count. The clinical titration of dosage to maintain whole blood tacrolimus trough concentrations in the usual therapeutic range can lead to elevated unbound concentrations and possibly toxicity in pregnant women with anemia and hypoalbuminemia. Measurement of plasma or unbound tacrolimus concentrations for pregnant women might better reflect the active form of the drug, though these are technically-challenging and often unavailable in usual clinical practice. Tacrolimus crosses the placenta with in utero exposure being approximately 71% of maternal blood concentrations. The lower fetal blood concentrations are likely due to active efflux transport of tacrolimus from the fetus toward the mother by placental P-glycoprotein. To date, tacrolimus has not been linked to congenital malformations, but can cause reversible nephrotoxicity and hyperkalemia in the newborn. In contrast, very small amounts of tacrolimus are excreted in the breast milk and are unlikely to elicit adverse effects in the nursing infant.
doi:10.1097/TP.0b013e318278d367
PMCID: PMC3637974  PMID: 23274970
tacrolimus; pregnancy; nephrotoxicity; pharmacokinetics; protein binding
24.  Does suppressing luteinising hormone secretion reduce the miscarriage rate? Results of a randomised controlled trial. 
BMJ : British Medical Journal  1996;312(7045):1508-1511.
OBJECTIVE--To determine whether prepregnancy pituitary suppression of luteinising hormone secretion with a luteinising hormone releasing hormone analogue improves the outcome of pregnancy in ovulatory women with a history of recurrent miscarriage, polycystic ovaries, and hypersecretion of luteinising hormone. DESIGN--Randomised controlled trial. SETTING--Specialist recurrent miscarriage clinic. SUBJECTS--106 women with a history of three or more consecutive first trimester miscarriages, polycystic ovaries, and hypersecretion of luteinising hormone. INTERVENTIONS--Women were randomised before conception to receive pituitary suppression with a luteinising hormone releasing hormone analogue followed by low dose ovulation induction and luteal phase progesterone (group 1) or were allowed to ovulate spontaneously and then given luteal phase progesterone alone or luteal phase placebo alone (group 2). No drugs were prescribed in pregnancy. MAIN OUTCOME MEASURES--Conception and live birth rates over six cycles. RESULTS--Conception rates in the pituitary suppression and luteal phase support groups were 80% (40/50 women) and 82% (46/56) respectively (NS). Live birth rates were 65% (26/40) and 76% (35/46) respectively (NS). In the luteal phase support group there was no difference in the outcome of pregnancy between women given progesterone and those given placebo pessaries. Live birth rates from an intention to treat analysis were 52% (26/50 pregnancies) in the group given pituitary suppression and 63% (35/56) in the controls (NS). CONCLUSIONS--Prepregnancy suppression of high luteinising hormone concentrations in ovulatory women with recurrent miscarriage and hypersecretion of luteinising hormone does not improve the outcome of pregnancy. The outcome of pregnancy without pituitary suppression is excellent.
PMCID: PMC2351255  PMID: 8646142
25.  Incidence and outcome of bleeding before the 20th week of pregnancy: prospective study from general practice. 
BMJ : British Medical Journal  1997;315(7099):32-34.
OBJECTIVE: To estimate the miscarriage rate in a cohort of pregnant women and the final outcome of pregnancy. DESIGN: Two year prospective community study. SETTING: Women registered with four semirural practices at one health centre. SUBJECTS: 626 pregnant women from a population 21448, 5140 of whom were women aged 15-44 years. MAIN OUTCOME MEASURES: Vaginal bleeding and outcome of pregnancy. Results: 76 of the 89 women with an unwanted pregnancy requested a termination. In the 550 ongoing pregnancies bleeding occurred before the 20th week in 117 (21%), and 67 (12%) ended in miscarriage. The risk of miscarriage was not significantly increased after a miscarriage in the previous pregnancy (11 (15%) women had miscarriage v 55 (12%) women who had not had miscarriage) who had previously had a live birth). Of the 117 women with bleeding, 64 were not admitted to hospital by the general practitioner; 42 of these women had an ultrasound examination at the health centre and 19 subsequently miscarried at home. In hospital 41 of 46 women who miscarried had evacuation of the uterus. CONCLUSIONS: Bleeding occurred in one fifth of recognised pregnancies before the 20th week and over half of these miscarried. Treatment of women with miscarriage at home means current statistics on miscarriage in Britain are missing many cases.
PMCID: PMC2127042  PMID: 9233324

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