User:Saquiroz/Recurrent miscarriage

Lead
Recurrent miscarriage or recurrent pregnancy loss (RPL) is the spontaneous loss of 2-3 pregnancies that is estimated to affect up to 5% of women. The exact number of pregnancy losses and gestational weeks used to define RPL differs among medical societies. In the majority of cases, the exact cause of pregnancy loss is unexplained despite genetic testing and a thorough evaluation. When a cause for RPL is identified, almost half are attributed to a chromosomal abnormality (ie. aneuploidy). RPL has been associated with several risk factors including parental and genetic factors (ie. advanced maternal age, chromosomal abnormalities, sperm DNA fragmentation), congenital and acquired anatomical conditions, lifestyle factors (ie. cigarette smoking, caffeine, alcohol, stress), endocrine disorders, thrombophila (clotting disorders), immunological factors, and infections. The American Society of Reproductive Medicine recommends a thorough evaluation after 2 consecutive pregnancy losses, however, this can differ from recommendations by other medical societies. RPL evaluation be evaluated by numerous tests and imaging studies depending on the risk factors. These range from cytogenetic studies, blood tests for clotting disorders, hormone levels, diabetes screening, thyroid function tests, sperm analysis, antibody testing, and imaging studies. Treatment is typically tailored to the relevant risk factors and test findings. RPL can have a significant impact on the psychological well-being of couples and has been associated with higher levels of depression, anxiety, and stress. Therefore, it is recommended that appropriate screening and management (ie. pharmacologic, counseling) be considered by medical providers.

In contrast, infertility is the inability to conceive. TH It has been estimated that anywhere between 1% and 5% of couples are affected by recurrent miscarriage (these links are broken). RPL has been associated with several risk factors including age, genetics, lifestyle, anatomical conditions, clotting disorders, and other immunological conditions. In the majority of cases, the exact cause is unknown.* The American Society of Reproductive Medicine recommends a thorough evaluation after 2 consecutive pregnancy losses. While accurate figures are not available,

Epidemiology
'''Pregnancy loss, also referred to as miscarriage or spontaneous abortion, occurs in up to 25% of pregnancies. Recurrent pregnancy loss occurs less frequently and it is estimated that 5% of women experience two consecutive pregnancy losses while only 1% experience three or more.'''

Etiology and Risk Factors
'''The cause of recurrent pregnancy is unknown in about 50% of cases. Risk factors that have been associated with RPL include parental and genetic factors (advanced maternal age, chromosomal abnormalities, sperm DNA fragmentation), anatomical conditions, lifestyle factors, endocrine disorders, thrombophila (clotting disorders), immunological factors, and infections''' Despite thorough evaluation for these risk factors, the exact cause for recurrent pregnancy loss is unknown in about 50% of cases. Some couples never have a cause identified, often after extensive investigations. About 50–75% of cases of recurrent miscarriage are unexplained (not a good source).

Parental and Genetic Factors
Advanced maternal age: Maternal age is associated with increased risk of miscarriage with a rate of 50% in women over 40 years of age. This higher likelihood of pregnancy loss can be attributed to the higher incidence of trisomies, a chromosomal abnormality, seen in women over the age of 35.

Chromosomal abnormalities: Recurrent pregnancy loss is most commonly found to be caused by chromosomal abnormalities in the fetus, accounting for approximately 50% of cases. These include structural aberrations (such as chromosomal inversions, insertions, deletions, and translocations) and numerical aberrations, also called aneuploidies (trisomies, monosomy X, and triploidy). These can be detected by cytogenetic testing such as karyotyping (test that analyzes the structure and quantity of chromosomes), FISH, MLPA, aCGH, and SNP array.

Some research suggests that chromosomal abnormalities occur more frequently in sporadic pregnancy loss than in recurrent pregnancy loss, and the incidence of RPL is lower in women with 3 or more pregnancy losses. Parental chromosomal abnormalities is a rare cause of RPL, found in approximately 2-4% cases. Studies comparing pregnancy outcomes in couples experiencing RPL with and without chromosomal abnormalities found that parental carriers of chromosomal abnormalities had a lower live birth rate, specifically carriers of a reciprocal/balanced Robertsonian translocation. This evidence suggests that although RPL can occur in both couples with and without chromosomal aberrations, those that do are at higher risk of pregnancy loss. It should be noted that previous studies produced conflicting results.

Genetic evaluation of RPL is generally recommended in order to determine the need for genetic counseling and appropriate treatment. This, however, can differ among medical societies where others recommend against routine cytogenetic testing for couples experiencing RPL as it is of little clinical benefit. It is instead considered after individual risk assessment (ie. family history) and recommended to test parental chromosomes rather than the products of conception.

Anatomical Conditions
*** Fifteen percent of women who have experienced three or more recurring miscarriages have some anatomical reason for the inability to complete the pregnancy. The structure of the uterus has an effect on the ability to carry a child to term. Anatomical differences are common and can be congenital or acquired.

Congenital: Congenital uterine malformations include unicornuate, septate, bicornate, didelphic, and arcuate uteri. The relationship between uterine abnormalities that are present from birth and RPL is unclear, however, there is an association with pregnancy loss. These structural anomalies are a result of distruption of the Mullerian tract during development. These can be found in approximately 12.6% of RPL cases with the highest incidences occurring in patients with septate (44.3%), bicornuate (36%), and arcuate (25.7%) uteri. These Structural uterine abnormalities can be visualized by several imaging studies including, hysterosalpingography, ultrasound, and MRI.

Acquired: Other structural uterine anomalies such as uterine fibroids, polyps, and adhesions have a less clear association with recurrent pregnancy loss. Cervical weakness has been shown to lead to premature pregnancy loss resulting in miscarriages or preterm deliveries. It has been estimated that cervical insufficiency is a cause in about 8% of women with second trimester recurrent miscarriages.

Lifestyle Factors
While lifestyle factors have been associated with increased risk for miscarriage in general, and are usually not listed as specific causes for RPL, every effort should be made to address these issues in patients with RPL. Of specific concern are chronic exposures to toxins including smoking, alcohol, and drugs. (acog practice bulletin)


 * Smoking: There is limited research that directly looks at the association of cigarette smoking and RPL. Recently, a systematic review that looked at studies evaluating the link between RPL and smoking was unable to find a significant difference in risk of recurrent pregnancy loss between people that smoke and non-smokers. This review did not address e-cigarettes and vaping given that the authors did not find any studies that looked into the relationship between these forms of smoking and RPL. It should be noted that the relationship between smoking and the risk of miscarriage has been extensively researched. According to a systematic review and meta-analysis, there is some evidence that active cigarette smoking increases the risk of miscarriage and this risk is further increased the more cigarettes that a person smokes a day. This same review highlights that according to the Surgeon General's report in 2010, research supports that smoking during pregnancy can also lead to pregnancy complications such as placental abruption, preterm delivery, and low birthweight among other maternal health risks.


 * Caffeine: research regarding the association of caffeine intake and spontaneous pregnancy loss has produced inconsistent results in previous years due to the influence of multiple factors and limitations in data collection among the studies. The same systematic review that looked at the relationship between cigarette smoking and RPL in 2021 found that there was no increased risk of RPL with the consumption of caffeine. There have been more recent studies that have assessed the relationship between caffeine and miscarriage. A systematic review found that coffee consumption before and during pregnancy was associated with a higher risk of pregnancy loss. The risk of pregnancy loss increased by 3% with each additional cup of coffee consumed during pregnancy. There was also an increased risk of pregnancy loss of 14-26% with the consumption of an additional 100mg of caffeine (coffee, tea, soda, cacao) per day during pregnancy. This increased risk was not seen if the caffeine products were consumed prior to pregnancy. The harmful effects of caffeine during pregnancy can be attributed to its ability to absorb rapidly into the bloodstream and cross into the placenta, along with the slowed breakdown of caffeine that occurs during pregnancy which can expose the fetus to caffeine and its metabolites for a prolonged period of time. Caffeine consumption can also lead to maternal cardiovascular effects that reduce placental blood flow, putting the development of the fetus at risk.

Some research on the maternal use of caffeine before conception found appreciable evidence that caffeine usage in excess of 300 mg/d increases the risk of miscarriage. The same study found that use of caffeine smaller usage than this amount is correlated with an increase in the risk of miscarriage, though with odds ratios that included 1 at the 95% CI. (got rid bc this is a primary source, there is no secondary source to support this evidence)*


 * Alcohol Use: Prenatal exposure to alcohol has been shown to have damaging effects on the cognitive development of the fetus and has been associated with low birthweight among other features of Fetal alcohol spectrum disorders due to its teratogenic effects. Similar to smoking and caffeine consumption, research studies assessing the relationship between alcohol use and pregnancy loss have produced inconsistent results. A systematic review that looked at several maternal lifestyle factors and the risk of recurrent pregnancy loss found no statistically significant increased risk in women that consumed any form of alcohol during pregnancy compared to those that did not. These findings are similar to a recent review that looked at alcohol intake in the first and second trimester and found no increased risk of miscarriage. The authors report that this may have been due to a limited number of studies included in the review, considering the exclusion of studies that did not differentiate trimesters or account for other external factors (such as smoking, maternal age, maternal BMI) that have been linked to pregnancy loss. It should be noted that there is evidence that in women that drink 5 or less alcoholic drinks per week, there is a 6% increased risk of miscarriage with each additional alcoholic drink consumed when the specific trimester is not specified. Due to the inability to determine a safe range of alcohol consumption during pregnancy, multiple medical societies recommend avoiding alcohol to prevent the potential harm to the fetus.


 * BMI: Maternal obesity and an elevated Body mass index (BMI) has been associated with an increased risk of miscarriage, although no clear cause has been established. Studies suggest that pregnancy loss could be influenced by the downstream effects of the hormonal disruption of the HPA axis and insulin resistance that can be associated with obesity, on the reproductive system disrupting the development of oocytes, embryos, or the integrity of the endometrium (uterine lining). Despite this evidence, research studies aimed to establish a relationship between RPL and BMI, which incorporates height and weight, have produced inconsistent results. A systematic review found that women with a history of RPL had higher BMI's by an average difference of 0.9kg/m² than women without. These findings, however, were not statistically significant and not exclusive to BMI's within the overweight and obese range. Another review and meta-analysis found that women with a BMI above 25 were more likely to have RPL and more likely to have a subsequent miscarriage, although the quality of evidence was low given that most of the studies were observational. It is important to consider that BMI can be influenced by numerous other conditions and modifiable risk factors (ie. poor nutrition, activity level, diabetes), therefore should not be regarded as a direct cause of RPL.


 * Stress: Research found that there is "increased relative risk of spontaneous abortion (odds ratio 1.28, 95% confidence interval 1.05-1.57)...for women experiencing high job stress." Another research review found that the risk of miscarriage is higher for women with a "history of exposure to psychological stress (OR 1.42, 95% CI 1.19–1.70)" However, the authors of these studies also point out that measuring stress is difficult, and that the results must therefore be interpreted with some caution. In addition, one of the studies notes that, while there are no randomized trials to study stress as it relates to pregnancy loss, one study found that a program of structured psychological support increased live birth rate among women with recurrent miscarriage.

Endocrine Disorders
- PCOS

- Diabetes Mellitus

- Luteal Phase Defects

- Thyroid

Thrombophilia
- FVL, prothrombin, Protein C deficiency, APL

Infection
There are numerous bacterial, fungal, protozoal, and viral infections that have been associated with risk of pregnancy loss, however, no direct link to recurrent pregnancy loss has been established. Infections known to increase the risk of miscarriage include bacterial vaginosis (M. hominis and U. urealyticum), syphilis, CMV, dengue fever, malaria, brucellosis, and HIV. There is mixed evidence regarding the risk of miscarriage with Chlamydia trachomatis, HPV, Hepatitis B, Toxoplasma gondii, HSV1/HSV2, and parvovirus B19. Chronic endometritis (CE) due to common bacteria has been found to be prevalent in some women with a history of recurrent miscarriage.

Infections are estimated to be responsible for between 0.5 and 5% of cases with recurrent miscarriage. The main suspected pathogens are mycoplasma, ureaplasma, Chlamydia trachomatis, Listeria monocytogenes, and herpes simplex virus. An infectious evaluation may be warranted in people with immunodeficiency, or with signs of chronic endometritis/cervicitis on examination. Otherwise, there is no evidence that routine infectious evaluation is appropriate or productive. --> not secondary source, will remove and paraphrase.

One study found that 71 percent of women who tested positive for this condition were successfully treated by an antibiogram-based antibiotic treatment. 78.4 percent of these women subsequently became pregnant in the year following treatment. The study concludes that "CE is frequent in women with recurrent miscarriages," and that "antibiotic treatment seems to be associated with an improved reproductive outcome." The authors also conclude, "that hysteroscopy should be a part of the diagnostic workup of infertile women complaining of unexplained recurrent miscarriage." Despite challenges in diagnosing chronic endometritis, often done by identifying plasma cells within the lining of the womb, a recent study identified women with chronic endometritis were more likely to have a miscarriage than women without. --> not secondary sources and using direct quotes.

Causes:


 * Will check that sources are secondary and adjust based on most current available evidence for the subsections listed below. Will also add article links.
 * Consider renaming section to Etiology and risk factors
 * Will include section for advanced reproductive age

Chromosomal disorders→ re-write and try to simplify and more coherent

Lifestyle Factors → Check for most current available data. Remove statistical vocab ie. odds ratio. Check that sources are secondary. There are two subsections that mention caffeine, will get rid of one.

Anatomical Conditions→ Will add subsections for “congenital” and “acquired” conditions. Check that rates are up to date. Include uterine fibroids and polyps.

Cervical conditions → will consider removing and including under “acquired” subsection.

Endocrine Disorders → Will add sources, prevalence of each condition, include luteal phase defects under this section. Will consider separating conditions (PCOS, Thyroid, luteal phase defects, DM) depending on available evidence.

https://pubmed-ncbi-nlm-nih-gov.proxy.cc.uic.edu/36482358/

Thrombophilia → Review sources. Only mentions FVL and a prothrombin mutation. Will briefly mention others ie. Protein C deficiency and mention acquired→ APL here

Immune Factors→ review sources

Ovarian Factors→ remove this section. Include information on luteal phase defect in “Endocrine Disorders” section

Infection


 * Review sources and add article links

Assessment
Update diagnostic approach, imaging, and relevant tests

Treatment
- Check sources

Psychological Impact
Experiencing pregnancy loss can have a significant and at times prolonged psychological impact, including higher levels of stress and mood disorders such as anxiety and depression. There is evidence that women struggling with recurrent pregnancy loss in particular may be affected to a greater degree. Grief is a normal and expected response to the loss of a pregnancy. However, prolonged and intense grief can be significantly distressing and detrimental to the mental health of the individual. This can particularly be seen in women that developed maladaptive coping mechanisms following a miscarriage, isolated themselves as a result of the cultural and societal stigma, or received inadequate social support from medical providers, partners, families, and other personal relationships. In heterosexual couples, men also experience grief as a result of pregnancy loss and have reported feeling obligated to disregard their feelings in order to support their partner. The psychological effects of RPL on paternal emotional and mental wellbeing has not been studied extensively, however, there are emerging studies that further look into this. According to a recent meta-analysis that compared the psychological impact among men and women with a history of RPL, women were found to have higher levels of moderate to severe depression, stress, and anxiety than women without RPL and than men who experienced RPL.

Given the impact that RPL can have on the mental health and psychologic well-being of couples, mental health evaluation, anxiety/depression screening, and treatment can be considered. There is also emerging research that suggests that untreated depression and depressive symptoms can lead to adverse outcomes in future pregnancies such as preterm birth and low Apgar scores. Consequently, there has been a rise in antidepressant (ie. SSRI) use during pregnancy over the last few years with a prevalence of 1-8%. This decision should be made with the guidance of a medical provider given the teratogenicity and potential adverse effects of antidepressants on the fetus.

In addition to psychotherapy, psychological care for people experiencing recurrent pregnancy loss can include counseling and other supportive services. There is some evidence to support that women that received bereavement counseling (based on the Guidelines for Medical Professionals Providing Care to the Family Experiencing Perinatal Loss, Neonatal Death, SIDS, or other Infant Death) after pregnancy loss were able to cope better, with women reporting 50% less despair than those that did not receive this intervention.

_____

There is significant, and often unrecognized, psychological and psychiatric trauma for the mother – for many, miscarriage represents the loss of a future child, of motherhood, and engenders doubts regarding her ability to procreate. will get rid of this bc it is a narrative review!

"There is tremendous psychological impact of recurrent miscarriage. Psychological support in the form of frequent discussions and sympathetic counseling are crucial to the successful evaluation and treatment of the anxious couple. When no etiologic factor is identified, no treatment started at 60% to 80% fetal salvage rate still may be expected. Therefore, couples with unexplained recurrent miscarriage should be offered appropriate emotional support and reassurance." --> Direct quote from the citation, also not sure if this can be considered a systematic review/guidelines. Will remove for now.

Prognosis
Association with later disease


 * Cut this section or rename to Prognosis

Additional Sections:


 * Add prognosis section