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Human Reproduction Update Sep 2020Although spontaneous miscarriage is the most common complication of human pregnancy, potential contributing factors are not fully understood. Advanced maternal age has... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Although spontaneous miscarriage is the most common complication of human pregnancy, potential contributing factors are not fully understood. Advanced maternal age has long been recognised as a major risk factor for miscarriage, being strongly related with fetal chromosomal abnormalities. The relation between paternal age and the risk of miscarriage is less evident, yet it is biologically plausible that an increasing number of genetic and epigenetic sperm abnormalities in older males may contribute to miscarriage. Previous meta-analyses showed associations between advanced paternal age and a broad spectrum of perinatal and paediatric outcomes. This is the first systematic review and meta-analysis on paternal age and spontaneous miscarriage.
OBJECTIVE AND RATIONALE
The aim of this systematic review and meta-analysis is to evaluate the effect of paternal age on the risk of spontaneous miscarriage.
SEARCH METHODS
PubMed, Embase and Cochrane databases were searched to identify relevant studies up to August 2019. The following free text and MeSH terms were used: paternal age, father's age, male age, husband's age, spontaneous abortion, spontaneous miscarriage, abortion, miscarriage, pregnancy loss, fetal loss and fetal death. PRISMA guidelines for systematic reviews and meta-analysis were followed. Original research articles in English language addressing the relation between paternal age and spontaneous miscarriage were included. Exclusion criteria were studies that solely focused on pregnancy outcomes following artificial reproductive technology (ART) and studies that did not adjust their effect estimates for at least maternal age. Risk of bias was qualitatively described for three domains: bias due to confounding, information bias and selection bias.
OUTCOMES
The search resulted in 975 original articles. Ten studies met the inclusion criteria and were included in the qualitative synthesis. Nine of these studies were included in the quantitative synthesis (meta-analysis). Advanced paternal age was found to be associated with an increased risk of miscarriage. Pooled risk estimates for miscarriage for age categories 30-34, 35-39, 40-44 and ≥45 years of age were 1.04 (95% CI 0.90, 1.21), 1.15 (0.92, 1.43), 1.23 (1.06, 1.43) and 1.43 (1.13, 1.81) respectively (reference category 25-29 years). A second meta-analysis was performed for the subgroup of studies investigating first trimester miscarriage. This showed similar pooled risk estimates for the first three age categories and a slightly higher pooled risk estimate for age category ≥45 years (1.74; 95% CI 1.26, 2.41).
WIDER IMPLICATIONS
Over the last decades, childbearing at later ages has become more common. It is known that frequencies of adverse reproductive outcomes, including spontaneous miscarriage, are higher in women with advanced age. We show that advanced paternal age is also associated with an increased risk of spontaneous miscarriage. Although the paternal age effect is less pronounced than that observed with advanced maternal age and residual confounding by maternal age cannot be excluded, it may have implications for preconception counselling of couples comprising an older aged male.
Topics: Abortion, Spontaneous; Adult; Aged; Fathers; Female; Humans; Male; Maternal Age; Middle Aged; Paternal Age; Pregnancy; Pregnancy Outcome; Prenatal Care; Risk Factors; Young Adult
PubMed: 32358607
DOI: 10.1093/humupd/dmaa010 -
Ultrasound in Obstetrics & Gynecology :... Oct 2019To estimate the procedure-related risk of miscarriage after amniocentesis and chorionic villus sampling (CVS) based on a systematic review of the literature and an... (Comparative Study)
Comparative Study Meta-Analysis
OBJECTIVE
To estimate the procedure-related risk of miscarriage after amniocentesis and chorionic villus sampling (CVS) based on a systematic review of the literature and an updated meta-analysis.
METHODS
A search of MEDLINE, EMBASE and The Cochrane Library was carried out to identify studies reporting complications following CVS or amniocentesis. Eligible for inclusion were large controlled studies reporting data for pregnancy loss prior to 24 weeks' gestation. Study authors were contacted when required to identify additional necessary data. Data for cases that had an invasive procedure and controls were inputted into contingency tables and the risk of miscarriage was estimated for each study. Summary statistics based on a random-effects model were calculated after taking into account the weighting for each study included in the systematic review. Procedure-related risk of miscarriage was estimated as a weighted risk difference from the summary statistics for cases and controls. Subgroup analyses were performed according to the similarity in risk levels for chromosomal abnormality between the invasive-testing and control groups. Heterogeneity was assessed using the I statistic. Egger's bias was estimated to assess reporting bias in published studies.
RESULTS
The electronic search yielded 2943 potential citations, from which 12 controlled studies for amniocentesis and seven for CVS were selected for inclusion in the systematic review. A total of 580 miscarriages occurred following 63 723 amniocentesis procedures, resulting in a weighted risk of pregnancy loss of 0.91% (95% CI, 0.73-1.09%). In the control group, there were 1726 miscarriages in 330 469 pregnancies with a loss rate of 0.58% (95% CI, 0.47-0.70%). The weighted procedure-related risk of miscarriage following amniocentesis was 0.30% (95% CI, 0.11-0.49%; I = 70.1%). A total of 163 miscarriages occurred following 13 011 CVS procedures, resulting in a risk of pregnancy loss of 1.39% (95% CI, 0.76-2.02%). In the control group, there were 1946 miscarriages in 232 680 pregnancies with a loss rate of 1.23% (95% CI, 0.86-1.59%). The weighted procedure-related risk of miscarriage following CVS was 0.20% (95% CI, -0.13 to 0.52%; I = 52.7%). However, when studies including only women with similar risk profiles for chromosomal abnormality in the intervention and control groups were considered, the procedure-related risk for amniocentesis was 0.12% (95% CI, -0.05 to 0.30%; I = 44.1%) and for CVS it was -0.11% (95% CI, -0.29 to 0.08%; I = 0%).
CONCLUSIONS
The procedure-related risks of miscarriage following amniocentesis and CVS are lower than currently quoted to women. The risk appears to be negligible when these interventions were compared to control groups of the same risk profile. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
Topics: Abortion, Spontaneous; Adult; Amniocentesis; Chorionic Villi Sampling; Chromosome Aberrations; Embryo Loss; Female; Gestational Age; Humans; Pregnancy; Pregnancy Trimester, Second; Prenatal Diagnosis; Randomized Controlled Trials as Topic; Risk Assessment
PubMed: 31124209
DOI: 10.1002/uog.20353 -
Human Reproduction (Oxford, England) Apr 2023In women with threatened miscarriage, does progesterone supplementation until the completion of the first trimester of pregnancy increase the probability of live birth? (Randomized Controlled Trial)
Randomized Controlled Trial
STUDY QUESTION
In women with threatened miscarriage, does progesterone supplementation until the completion of the first trimester of pregnancy increase the probability of live birth?
SUMMARY ANSWER
In women with threatened miscarriage, 400 mg vaginal progesterone nightly, from onset of bleeding until 12 weeks, did not increase live birth rates.
WHAT IS KNOWN ALREADY
Limited evidence has indicated that vaginal micronized progesterone may make little or no difference to the live birth rate when compared with placebo in women with threatened miscarriage. Subgroup analysis of one recent randomized trial reported that in women with bleeding and at least one previous miscarriage, progesterone might be of benefit.
STUDY DESIGN, SIZE, DURATION
We performed a randomized, double-blinded, placebo-controlled trial between February 2012 and April 2019. Eligible pregnant women under 10 weeks gestation, experiencing a threatened miscarriage as apparent from vaginal bleeding were randomized into two groups in a 1:1 ratio: the intervention group received 400 mg progesterone as vaginal pessaries, the control group received placebo vaginal pessaries, both until 12 weeks gestation. The primary endpoint was live birth. We planned to randomize 386 women (193 per group). The study was stopped at a planned interim analysis for futility after randomization of 278 women.
PARTICIPANTS/MATERIALS, SETTING, METHODS
This trial was conducted at the Mater Mothers' Hospital, a tertiary centre for maternity care in South Brisbane, Queensland, Australia. We randomized 139 women to the intervention group and 139 women to the placebo group. Primary outcome data were available for 136 women in the intervention group and 133 women in the placebo group.
MAIN RESULTS AND THE ROLE OF CHANCE
The live birth rates were 82.4% (112/136) and 84.2% (112/133) in the intervention group and placebo group, respectively (risk ratio (RR) 0.98, 95% CI 0.88 to 1.09; risk difference -0.02, 95% CI -0.11 to 0.07; P = 0.683). Among women with at least one previous miscarriage, live birth rates were 80.6% (54/67) and 84.4% (65/77) (RR 0.95, 95% CI 0.82-1.11; P = 0.550). No significant effect was seen from progesterone in women with two (RR 1.28, 95% CI 0.96-1.72; P = 0.096) or more (RR 0.79, 95% CI 0.53-1.19; P = 0.267) previous miscarriages. Preterm birth rates were 12.9% and 9.3%, respectively (RR 1.38; 95% CI 0.69 to 2.78; P = 0.361). Median birth weight was 3310 vs 3300 g (P = 0.992). There were also no other significant differences in obstetric and perinatal outcomes.
LIMITATIONS, REASONS FOR CAUTION
Our study was single centre and did not reach the planned sample size because it was stopped prematurely at an interim analysis.
WIDER IMPLICATIONS OF THE FINDINGS
We did not find evidence supporting the treatment effect of vaginal progesterone in women with threatened miscarriage. Progesterone in this setting should not be routinely used for threatened miscarriage. The treatment effect in women with threatened miscarriage after previous miscarriages warrants further research.
STUDY FUNDING/COMPETING INTEREST(S)
Mothers' and babies Golden Casket Clinical Fellowship (L.A.M.). Progesterone and placebo pessaries were provided by Perrigo Australia.B.W.J.M. reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck KGaA, personal fees from Guerbet, personal fees from iGenomix, outside the submitted work.
TRIAL REGISTRATION NUMBER
ACTRN12611000405910.
TRIAL REGISTRATION DATE
19 April 2011.
DATE OF FIRST PATIENT’S ENROLMENT
06 February 2012.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Progesterone; Abortion, Spontaneous; Abortion, Threatened; Premature Birth; Maternal Health Services; Pregnancy Rate
PubMed: 36806843
DOI: 10.1093/humrep/dead029 -
Fertility and Sterility Nov 2023Infections with certain pathogens can lead to perinatal complications. Several infections have been also associated with an increased likelihood of miscarriage. This... (Review)
Review
Infections with certain pathogens can lead to perinatal complications. Several infections have been also associated with an increased likelihood of miscarriage. This manuscript discusses these infections, their modes of transmission, the evidence linking them to an increased risk of miscarriage, and whether prevention or treatment strategies are available.
Topics: Pregnancy; Female; Humans; Abortion, Spontaneous; Pregnancy Outcome
PubMed: 37625478
DOI: 10.1016/j.fertnstert.2023.08.719 -
Fertility and Sterility Aug 2023The evidence on the association between diet and miscarriage risk is scant and conflicting. (Meta-Analysis)
Meta-Analysis Review
IMPORTANCE
The evidence on the association between diet and miscarriage risk is scant and conflicting.
OBJECTIVE
To summarize the evidence on the association between periconceptual diet and miscarriage risk in healthy women of reproductive age.
DATA SOURCES
Electronic databases were searched from inception to August 2022 without restriction of regions, publication types, or languages.
STUDY SELECTION AND SYNTHESIS
Experimental or observational studies were considered for inclusion. The population was healthy women of reproductive age. Exposure was periconception diet. Study quality was assessed using the modified Newcastle-Ottawa Scale. Summary effect sizes (odds ratio [OR] with 95% confidence interval [CI]) were calculated for each food category.
MAIN OUTCOMES
Miscarriage rate (as defined by primary studies).
RESULTS
We included 20 studies (11 cohort and 9 case-control), of which 6 presented data suitable for meta-analysis (2 cohort and 4 case-control, n = 13,183 women). Our primary analyses suggest a reduction in miscarriage odds with high intake of the following food groups: fruit (OR, 0.39; 95% CI, 0.33-0.46), vegetables (OR, 0.59; 95% CI, 0.46-0.76), fruit and vegetables (OR, 0.63; 95% CI, 0.50-0.81), seafood (OR, 0.81; 95% CI, 0.71-0.92), dairy products (OR, 0.63; 95% CI, 0.54-0.73), eggs (OR, 0.81; 95% CI, 0.72-0.90), and cereal (grains) (OR, 0.67; 95% CI, 0.52-0.87). The evidence was uncertain for meat, red meat, white meat, fat and oil, and sugar substitutes. We did not find evidence of an association between adherence to predefined dietary patterns and miscarriage risk. However, a whole diet containing healthy foods as perceived by the trialists, or with a high Dietary Antioxidant Index score (OR, 0.43; 95% CI, 0.20-0.91) may be associated with a reduction in miscarriage risk. In contrast, a diet rich in processed food was demonstrated to be associated with increased miscarriage risk (OR, 1.97; 95% CI, 1.36-3.34).
CONCLUSION AND RELEVANCE
A diet abundant in fruit, vegetables, seafood, dairy, eggs, and grain may be associated with lower miscarriage odds. Further interventional studies are required to accurately assess the effectiveness of periconception dietary modifications on miscarriage risk.
PROSPERO REGISTRATION
CRD42020218133.
Topics: Pregnancy; Female; Humans; Abortion, Spontaneous; Diet; Fruit; Vegetables; Meat
PubMed: 37061157
DOI: 10.1016/j.fertnstert.2023.04.011 -
Women's Health (London, England) Jul 2015The relationship between miscarriage and fertility is complex. While most healthcare settings treat miscarriage as a problem of subfertility in assisted reproduction... (Review)
Review
The relationship between miscarriage and fertility is complex. While most healthcare settings treat miscarriage as a problem of subfertility in assisted reproduction units, others believe that miscarriage occurs in super-fertile women. Infertile women undergoing assisted reproduction are at a greater risk of having a miscarriage especially at an advanced age compared with women conceiving naturally. Aberrant expression of immunological factors and chromosomal abnormalities underlie both infertility and miscarriage. Common risk factors include increased maternal age, obesity, smoking, alcohol, pre-existing medical conditions and anatomical abnormalities of the reproductive system. Management pathways of both conditions may be similar with pre-implantation genetic testing and assisted reproductive technology used in both conditions. This paper discusses the synergies and differences between the two conditions in terms of their epidemiology, etiopathogenesis, risk factors and management strategies. The two conditions are related as degrees of severity of reproductive failure with common pathways in manifestation and management.
Topics: Abortion, Spontaneous; Adult; Age Factors; Alcohol Drinking; Antibodies, Antiphospholipid; Chromosome Aberrations; Comorbidity; Cytokines; Female; HLA Antigens; Humans; Infertility, Female; Integrins; Killer Cells, Natural; Leukemia Inhibitory Factor; Mucin-1; Obesity; Pregnancy; Prevalence; Reproductive Techniques, Assisted; Risk Factors; Smoking
PubMed: 26238301
DOI: 10.2217/whe.15.19 -
Hormones (Athens, Greece) 2008The relation of thyroid autoimmunity to miscarriage is an important issue that has attracted the interest of many investigators. A number of papers have been published... (Review)
Review
The relation of thyroid autoimmunity to miscarriage is an important issue that has attracted the interest of many investigators. A number of papers have been published so far, which include healthy women, women with recurrent miscarriage and those undergoing assisted reproductive techniques. Most studies have shown a significant positive association between the presence of thyroid autoantibodies and miscarriage rate. It is of interest that women with high titers do not show a higher miscarriage rate when compared with women having low titers, although, there is no general agreement on this issue. There are three possible explanations for the assumed association of thyroid autoimmunity with miscarriage: 1) pregnancy loss is an epiphenomenon and not a direct effect of the thyroid autoantibodies, the presence of thyroid autoantibodies reflecting a generalized activation of the immune system; 2) delayed conception from the presence of thyroid autoantibodies; hence, when women with thyroid autoimmunity become pregnant, face a higher risk of miscarriage because of older age; and 3) the pregnancy loss is secondary to a subtle deficiency in thyroid hormone concentrations or a lower capacity of the thyroid to adequately adapt to the demands of pregnancy.
Topics: Abortion, Spontaneous; Autoantibodies; Autoimmune Diseases; Autoimmunity; Female; Humans; Pregnancy; Thyroid Diseases; Thyroxine
PubMed: 19121990
DOI: 10.14310/horm.2002.1210 -
Heart (British Cardiac Society) Nov 2013The 2011 American Heart Association guidelines identified pregnancy complications as a risk factor for cardiovascular disease in women. However, miscarriage was not... (Meta-Analysis)
Meta-Analysis Review
CONTEXT
The 2011 American Heart Association guidelines identified pregnancy complications as a risk factor for cardiovascular disease in women. However, miscarriage was not mentioned within the guidelines, and there is no consensus on the association between miscarriage and future risk of cardiovascular disease.
OBJECTIVE
To confirm or refute the association, a meta-analysis of published papers was conducted.
DATA SOURCES
PubMed, Web of Knowledge and Scopus were systematically searched to identify appropriate articles. Reference lists were then hand searched for additional relevant titles.
STUDY SELECTION
To be included, articles had to assess the association between miscarriage and subsequent cardiovascular disease in otherwise healthy women. Only women who had miscarriages were considered exposed. Pooled association measures, using random effects meta-analysis, were calculated for coronary heart disease and cerebrovascular disease. Publication bias and between-study heterogeneity were evaluated.
DATA EXTRACTION
Two authors individually reviewed all studies and extracted data on patient and study characteristics along with cardiovascular outcomes.
RESULTS
10 studies were identified, with 517 504 individuals included in the coronary heart disease meta-analysis and 134 461 individuals in the cerebrovascular disease analysis. A history of miscarriage was associated with a greater odds of developing coronary heart disease, OR (95% CI) =1.45 (1.18 to 1.78), but not with cerebrovascular disease, OR=1.11 (0.72 to 1.69). There was a strong association between recurrent miscarriage and coronary heart disease OR=1.99 (1.13 to 3.50). Evidence was found for moderate between-study heterogeneity and publication bias in the coronary heart disease analysis.
CONCLUSIONS
The meta-analysis indicates that a history of miscarriage or recurrent miscarriage is associated with a greater risk of subsequent coronary heart disease.
Topics: Abortion, Spontaneous; Coronary Disease; Female; Humans; Risk
PubMed: 23539554
DOI: 10.1136/heartjnl-2012-303237 -
BMJ (Clinical Research Ed.) May 2011To evaluate the association between thyroid autoantibodies and miscarriage and preterm birth in women with normal thyroid function. To assess the effect of treatment... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To evaluate the association between thyroid autoantibodies and miscarriage and preterm birth in women with normal thyroid function. To assess the effect of treatment with levothyroxine on pregnancy outcomes in this group of women.
DESIGN
Systematic review and meta-analysis.
DATA SOURCES
Medline, Embase, Cochrane Library, and SCISEARCH (inception-2011) without any language restrictions. We used a combination of key words to generate two subsets of citations, one indexing thyroid autoantibodies and the other indexing the outcomes of miscarriage and preterm birth.
STUDY SELECTION
Studies that evaluated the association between thyroid autoantibodies and pregnancy outcomes were selected in a two stage process. Two reviewers selected studies that met the predefined and explicit criteria regarding population, tests, and outcomes.
DATA SYNTHESIS
Odds ratios from individual studies were pooled separately for cohort and case-control studies with the random effects model.
RESULTS
30 articles with 31 studies (19 cohort and 12 case-control) involving 12,126 women assessed the association between thyroid autoantibodies and miscarriage. Five studies with 12,566 women evaluated the association with preterm birth. Of the 31 studies evaluating miscarriage, 28 showed a positive association between thyroid autoantibodies and miscarriage. Meta-analysis of the cohort studies showed more than tripling in the odds of miscarriage with the presence of thyroid autoantibodies (odds ratio 3.90, 95% confidence interval 2.48 to 6.12; P < 0.001). For case-control studies the odds ratio for miscarriage was 1.80, 1.25 to 2.60; P = 0.002). There was a significant doubling in the odds of preterm birth with the presence of thyroid autoantibodies (2.07, 1.17 to 3.68; P = 0.01). Two randomised studies evaluated the effect of treatment with levothyroxine on miscarriage. Both showed a fall in miscarriage rates, and meta-analysis showed a significant 52% relative risk reduction in miscarriages with levothyroxine (relative risk 0.48, 0.25 to 0.92; P=0.03). One study reported on the effect of levothyroxine on the rate of preterm birth, and noted a 69% relative risk reduction (0.31, 0.11 to 0.90).
CONCLUSION
The presence of maternal thyroid autoantibodies is strongly associated with miscarriage and preterm delivery. There is evidence that treatment with levothyroxine can attenuate the risks.
Topics: Abortion, Spontaneous; Autoantibodies; Female; Humans; Maternal Age; Pregnancy; Pregnancy Outcome; Premature Birth; Risk Factors; Thyroid Gland; Thyroxine
PubMed: 21558126
DOI: 10.1136/bmj.d2616 -
Taiwanese Journal of Obstetrics &... Sep 2020Human papilloma virus (HPV) infection is the most common viral infection of the reproductive tract. HPV infection is more prevalent in pregnant than in age-matched... (Review)
Review
Human papilloma virus (HPV) infection is the most common viral infection of the reproductive tract. HPV infection is more prevalent in pregnant than in age-matched non-pregnant women and its prevalence increases as pregnancy progresses. A number of reports evaluated the role of HPV infection in miscarriages. In the present review, we summarize the existing evidence regarding the association between HPV infection and miscarriage. It is still unclear whether HPV infection is associated with increased risk for miscarriage. Studies in the field yielded conflicting findings and their conclusions are limited by a small sample size and/or methodological limitations. On the other hand, preclinical data support a role of HPV infection in placental dysfunction. Given the high prevalence of HPV infection and the possibility that vaccination against HPV might protect against miscarriage, more studies are needed to elucidate whether this common infection is associated with increased risk for miscarriage.
Topics: Abortion, Spontaneous; Case-Control Studies; Causality; Female; Humans; Incidence; Papillomaviridae; Papillomavirus Infections; Pregnancy; Pregnancy Complications, Infectious
PubMed: 32917313
DOI: 10.1016/j.tjog.2020.07.005