MISCARRIAGE: SYMPTOMS, CAUSES, AND RISK FACTORS

Updated 6th March 2024

Sadly, miscarriage is more common than it ought to be. On average, 10-25% of reported pregnancies are known to end in miscarriage. While it may be the case, most miscarriages are not a sign of underlying health problems and can sometimes be prevented.

For those looking to conceive without difficulties, the article below describes common and uncommon causes of miscarriage, and covers symptoms, complications, risk factors, prevention methods, and treatment.

Signs and Symptoms of Miscarriage

A usual pregnancy commonly covers a 40-week period from the point of conception, which is a little over 9 months. Miscarriage can occur between the 6^th - 20^th week of pregnancy. Before week 6, it is defined as a biochemical loss (little to no embryo development), and after week 20 it is referred to as a stillbirth.

Not all miscarriages exhibit symptoms, and not all symptoms confirm a miscarriage. Roughly 20% of pregnant women experience symptoms of miscarriage in the first 20 weeks, yet only 30-50% go on to have a true miscarriage.[1] Miscarriage symptoms are easy to miss and may be confused with unusual menstruation or ordinary symptoms of pregnancy (when pregnancy is confirmed).

Confirming a miscarriage requires a diagnostic validation involving an ultrasound and a medical examination. Further blood and genetic testing may be required to rule out underlying causes.

3 common symptoms of miscarriage include[2]:

• Vaginal bleeding or spotting
• Cramping or abdominal pain
• Uterine fluid or tissue loss

If experiencing any of these symptoms, it is vital to consult a qualified doctor or obstetrician to discuss them. If you are losing uterine tissue or fluid, it is advisable to take a sample along for analysis.

Miscarriage Types, Stages, and Complications

There are several types of miscarriage based on the stage and severity. Healthcare practitioners assess the type of miscarriage for optimal treatment[3]. The various types of miscarriage are briefly described below:

• Missed. This refers to asymptomatic miscarriage, where the fetus or embryo dies without the usual symptoms of miscarriage. The cervical os is closed in this type without the presence of bleeding. There is no viable fetus when tested for. It occurs in approximately 15% of pregnancies.
• Threatened. This is a miscarriage that has not occurred, yet threatens to. It is clinically defined as vaginal bleeding during early pregnancy with a closed cervical os and viable fetus.
• Inevitable. If bleeding is present with an open cervical os, then a miscarriage is inevitable. Ultrasound exams may show a viable fetus or not.
• Complete. Miscarriage has occurred with all the classic symptoms, with ultrasound revealing no remaining fetal contents in the uterus. A complete miscarriage is naturally over within 8 weeks for 80% of all women undergoing a miscarriage. With the help of Misoprostol, a prostaglandin analog, it can be sped up to be complete within 3 days.
• Recurrent. A recurrent miscarriage is defined as having 2 or more miscarriages[4]. Sometimes referred to as miscarriage syndrome, it is known to affect 1-5% of couples.

Complications. The following miscarriage complications should not be ignored and warrants immediate medical attention:

• Septic Miscarriage. This type of miscarriage occurs due to an infection of the uterine contents during or after the miscarriage. Septic miscarriage is usually caused by improper evacuation of the fetal contents during a miscarriage, often due to an induced abortion. It is advisable to go for an imaging test to make sure all the contents have left the uterus after a miscarriage has been confirmed and appears complete. If symptoms such as fever, chills, or other signs of infection arise following miscarriage or uterine evacuation procedures, it is important to consult a doctor and get treated immediately.
• Excessive Bleeding. Miscarriage may result in hypovolemic shock due to excessive blood loss. This means that the volume of blood is too low to meet systemic requirements, resulting in cardiorespiratory difficulties, dehydration, and physiological stress. Excess bleeding is rare and is frequently caused by the miscarriage of an ectopic pregnancy, which refers to gestation that occurs outside of the womb (in the fallopian tubes or cervix). Medical attention is urgently required if hypovolemic symptoms are suspected. These include dizziness, disorientation, breathing troubles, loss of consciousness, and arrhythmia when changing positions between standing and sitting or lying down.

Miscarriage Causes and Risks

Miscarriage is often caused by factors outside of the pregnant mother’s control. Despite being common misconceptions, exercise, intercourse, and attending work are not known to cause miscarriage.

The following points describe common causes of miscarriage in the first and second trimesters.[5]

First Trimester: Early Miscarriage Causes

The First Trimester spans 0-12 weeks. Miscarriage in this period is also known as early pregnancy loss. Up to 80-90% of miscarriages occur during this time, with the risk being much lower in the second trimester. Causes of early miscarriage in the first trimester likely pertain to genetic deficits, implantation difficulties, and problems with fetal development.

Common first trimester causes include:

• Genetic Abnormalities are commonly cited as the number one cause of miscarriage. While rare genetic disorders can contribute, up to 40-60% of all pregnancies are the result of aneuploidy[6], where there are less than 46 chromosome sets. Most of these cases result in a condition known as a blighted ovum in which no embryo forms.[7] This is often the result of damage or mutation to the fertilized egg or sperm cell and does not necessarily extend to the rest of either in each parent.
• Older Age. The risk of miscarriage increases with age, likely attributable to increments in age-related metabolic changes and DNA damage or mutations. First-time pregnancy miscarriage risk is less than 9% on average in women aged 20-30 years old. Having a child over the age of 40 is associated with miscarriage in approximately 75% of cases.
• Previous Miscarriage. On average, having a miscarriage prior to getting pregnant a second time is associated with a 20% higher risk for a second miscarriage. The mean risk further increases to 28% after 2 miscarriages and 43% for recurrent miscarriages.
• Lifestyle and Nutritional Factors are often associated with miscarriage and are shown to be common risk factors. These include a high caffeine intake, regular smoking, a sedentary lifestyle, stress, malnourishment, and a diet high in refined, non-nutritive foods. Hormonal and metabolic health plays an important role in ensuring successful gestation. Low progesterone, estrogen, high or low body mass, and hypertension may all contribute to a miscarriage.

Second Trimester: Late Miscarriage

The Second Trimester lasts 13-27 weeks. Late miscarriage or late pregnancy loss occurs in this period from week 13 to 21. This accounts for 10-20% (or less) of all miscarriages.

Miscarriage in the second trimester is most often caused by cervical insufficiency or unknown causes. Frequent second trimester miscarriage causes are briefly discussed below:

• Cervical Insufficiency. Often related to infection, surgery, injury, or damage, a weak cervix may open too early during pregnancy and cause miscarriage. This is called cervical insufficiency and is responsible for roughly half of the late miscarriages.
• Structural Deficits. The shape and size of the womb may be unable to accommodate pregnancy. This could be genetic, disease-related, developmental, or due to unusual growths.
• Chronic Diseases. All inflammatory diseases can increase both early and late miscarriage risk. These include autoimmune diseases and those pertaining to metabolic syndrome in which immune derangement, faulty glucose handling, and dyslipidemia are responsible for interfering with fetal growth.
• Infections. Vaginal infections that spread toward the womb are a prime cause of miscarriage in the second trimester.[8] Other systemic and intestinal infections can also contribute to miscarriage risk. It is advisable to practice impeccable hygiene during pregnancy to avoid miscarriage. Take care to avoid acquiring cuts, bites, scratches, and food poisoning, and opt for any mandatory vaccinations after pregnancy.
• Medications. Various medications may increase the risk of miscarriage in either the first or second term. Misoprostol is used to induce abortion but may be mistakenly prescribed for stomach ulcer treatment before pregnancy is confirmed. Certain retinoids such as Hydroquinone and Tretinoin are contraindicated for miscarriage risk[9], even if topical as part of cosmetic formulations. NSAIDs, antidepressants, and immunosuppressants are other types of medication frequently associated with miscarriage.[10] [11] If you are on a prescription and trying to conceive, triple check with a doctor that any of your medications would not interfere.

Uncommon Causes and Novel Insights

Hydrops Fetalis. This is a condition in which the health of the mother affects the fetus, leading to fluid accumulation in the fetal soft tissues. This can lead to fetal heart failure and mortality[12]. There are two types:

• Immune-Mediated Hydrops. In this type, the mother and fetus have mismatched blood antigens, usually with respect to Rh types, yet several other antigens have been implicated as well. If different, the mother may make antibodies that can cross the placenta and promote cardiac failure in the fetus. Immune hydrops constitute approximately 10% of cases and is treatable with the use of an anti-D immunoglobulin if detected early on.
• Non-Immune Hydrops. This is usually the result of a rare genetic disorder, chronic disease, or abnormality that interferes with the fetus’ ability to adequately manage fluids.[13] It usually causes a back pressure that interferes with the vascular or lymphatic supply of the fetus. This condition may be treatable before miscarriage ensues if diagnosed early on and not caused as a result of genetics or deformity. However, survival rates are usually as low as 10%, and infants born with this condition tend to have neurodevelopmental deficits later on.

Microchimerism. During every stage of pregnancy, cells are exchanged between the mother and fetus. These cells are known to circulate the fetus and remain after birth, known to be present for at least 30 years in all individuals. In women with recurrent miscarriages, there is evidence to suggest that microchimerism may be able to either increase or decrease the risk of miscarriage. Leftover cells from previously miscarried fetuses can negatively influence the growth of new ones moving forward. Similar effects have been documented for microchimeric cells that are still present from the mother’s mother and are capable of interacting with the fetus.[14] These are known to influence fetal immune function and may increase the risk of miscarriage if the mother or her mother gives the fetus reactive immune cells.[15]

Immune and Stem Cell Deficits. New research is highlighting the role of both stem cells and immune cells in a successful pregnancy and how deficits of either may be partially responsible for miscarriages in the context of maternal disease and aging. Faulty or lost stem cells and immune cells can substantially affect the ability of the fetus to develop in the womb by reducing adequate growth and protection measures. Disease and aging can both detract from bone marrow stem cell reservoirs and affect immune function in ways that can directly cause miscarriage. In this respect, radiotherapy, bone marrow transplantation, and other surgeries performed close to conception are also likely to increase miscarriage risk in tandem with aging and disease.[16]

Antioxidant Imbalance. A low level of the cellular antioxidant glutathione and its necessary cofactors have been linked to miscarriage in both the first and second trimesters. Low antioxidant status may be caused by chronic disease, genetic deficits, consuming a diet low in nutrients, or being exposed to environmental factors with pro-oxidant effects (e.g., radiation, pollution, etc.). [17]

Miscarriage Can Potentially Increase Late-Life Disease Risk

While disease can promote miscarriage, recurrent miscarriages can equally increase the risk of contracting disease later on in life. Women who have suffered multiple miscarriages tend to develop cardiometabolic diseases more often and at earlier ages than other women. These include Diabetes, coronary heart disease, and Atherosclerosis.[18] [19] [20]

On a psychological level, the stress of miscarriage is a risk factor in and of itself. Women often become depressed and anxious for months afterward and may require therapy to avoid psychological morbidities. Surveys state the importance of education to minimize the risk as women often feel guilty and ashamed of miscarriage, despite it being a relatively ordinary occurrence that most likely is unrelated to them, their habits, or their state of health.

More research is required to clarify to what extent recurrent miscarriage is physically involved. In some cases, miscarriage can be caused by reproductive abnormalities or disorders that may irrespectively increase the risk for early cardiovascular conditions. However, fetal cellular exchange (microchimerism) is known to promote disease risk in both miscarriage and pregnancy. The outcome is likely to depend on genetic interactions, metabolic factors, and the health of the fetus.

Miscarriage- A Protective Mechanism?

Miscarriage is likely to be a protective mechanism that prevents future complications and preserves the overall health of a species. Over the course of the lifetime, some of the genes in the complete pool of reproductive cells can become faulty due to any major or minor changes. Most miscarriages occur in response to these genetic defects that are usually not caused by the baseline genes of the parents or any health problems they may have.

Genetic research has revealed that some of the gene mutations implicated in causing miscarriage can result in mental retardation, physical deformity, or a number of genetic diseases if the fetus is allowed to develop properly[21]. In this sense, miscarriage is a healthy occurrence in the majority of cases and should not be a cause for concern. In the absence of complete infertility, conceiving couples ought to understand that a second or even third attempt may not indicate a problem,and that they can have a healthy child.

Miscarriage Management

Treatment depends on the underlying cause. In most cases, a doctor will monitor the situation rather than intervene, allowing the miscarriage to occur naturally. Medical intervention may include medication or surgery in some cases.

The treatment of recurrent miscarriage may involve:

• Hormonal therapy for regulating imbalances
• Surgical interventions for correcting structural issues in the uterus (like fibroids)
• Preimplantation genetic diagnosis for testing and selecting healthy embryos in vitro
• Immunological treatments for modulating the immune response
• Blood thinners, for patients with thrombophilia or unexplained pregnancy losses

While considerable research has gone into the management of recurrent miscarriage, it remains challenging to treat with further evidence needed on the efficacy of various methods.

Improving Pregnancy Outcomes

General strategies for improving pregnancy success include:

• Leading a Generally Healthy Lifestyle. It is vital for both conceiving and pregnant women to consume a nutritious diet that is not lacking in micronutrients and essential amino acids. Care needs to be taken as well to maintain constant blood sugar levels and prevent hyperglycemia. Pregnant women can still engage in moderate exercise all the way throughout the pregnancy until the third trimester. However, precautions need to be taken to minimize the risk of falls and injuries, as these can promote miscarriages.
• Taking multivitamin and B vitamins. Vitamin D3, B6, and B9 (folic acid) are especially pertinent to help prevent miscarriages, and birth defects before and during pregnancy, as their deficiency promotes elevated homocysteine that can interfere with gestation.
• Quitting Smoking. Smoking affects metabolism in such a way that it lowers blood oxygenation, suppresses hormones and interferes with glucose levels. It may also increase the risk of subclinical nutritional deficiencies. Quitting smoking is important to ensure optimal fetal development.

Platelet-Rich Plasma Therapy may be able to improve outcomes for women battling to conceive or who suffer from recurrent miscarriages. Research is still in its infancy regarding its effectiveness. According to studies, it may reduce the risk of miscarriage by enhancing the outcomes of in vitro fertilization[22] and improving implantation rates[23]. There is limited evidence indicating that it may help to protect the fetus from miscarriage induced by bacterial infections.[24] PRP therapy should not be opted for during pregnancy, yet it may be complementary if undergone prior to conception or IVF.

Conclusion

Miscarriage is the leading complication associated with pregnancy. Symptoms of miscarriage are not confirmation of the condition and warrant diagnostic confirmation. There are many causes of miscarriage, with most of them being outside of the parents’ control. The most common causes involve genetic anomalies within the supply of reproductive cells, the risk of which increases with age and disease. Treatment can resolve some autoimmune causes of pregnancy, yet is mostly tailored to speeding up a miscarriage. Preventive methods include leading a healthier lifestyle.

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Sources:

• [1] https://www.ncbi.nlm.nih.gov/books/NBK560521/
• [2] https://www.nhs.uk/conditions/miscarriage/symptoms/
• [3] https://www.ncbi.nlm.nih.gov/books/NBK532992/
• [4] https://www.ncbi.nlm.nih.gov/books/NBK554460/
• [5] https://www.nhs.uk/conditions/miscarriage/causes/
• [6] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4443861/
• [7] https://www.ncbi.nlm.nih.gov/books/NBK499938/
• [8] https://pubmed.ncbi.nlm.nih.gov/21051848/
• [9] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114665/
• [10] https://pubmed.ncbi.nlm.nih.gov/29890124/
• [11] https://pubmed.ncbi.nlm.nih.gov/27031036/
• [12] https://www.ncbi.nlm.nih.gov/books/NBK563214/
• [13] https://www.ncbi.nlm.nih.gov/books/NBK563214/
• [14] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154341/
• [15] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718967/
• [16] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9244729/
• [17] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10290363/
• [18] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9617475/
• [19] https://pubmed.ncbi.nlm.nih.gov/23536362/
• [20] https://pubmed.ncbi.nlm.nih.gov/30144277/
• [21] https://pubmed.ncbi.nlm.nih.gov/33969392/
• [22] https://pubmed.ncbi.nlm.nih.gov/33872382/
• [23] https://pubmed.ncbi.nlm.nih.gov/35345084/
• [24] https://pubmed.ncbi.nlm.nih.gov/32006776/
• [25] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229790/

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