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Recurrent Pregnancy Loss Association Awareness. Advocacy. Answers.
Causes of Recurrent Miscarriage
Endocrine Factors
Certain hormonal factors can contribute to recurrent pregnancy loss. In particular, your doctor may check your thyroid function and prolactin levels. Metabolic factors that may be associated with increased risk of miscarriage include polycystic ovarian syndrome (PCOS), mismanaged diabetes and obesity. Luteal phase defects or MTHFR mutations may also relate to RPL, though disagreement about their contribution exists between medical experts.
Immune Factors
Antiphospholipid syndrome (APS) is an autoimmune condition that can cause blood clots and is associated with recurrent miscarriage. The impact of other immune factors like antinuclear antibodies (ANA), human leukocyte antigens (HLA), cytokines, or natural killer cells on pregnancy are still widely debated within the medical community.
Anatomic Issues
Uterine issues like congenital anomalies, fibroids and polyps, or adhesions may have no negative impact on pregnancy, but sometimes they can block the opening(s) to Fallopian tubes, hinder implantation, or increase risk of miscarriage. Many of these can be corrected surgically. Other issues such as cervical insufficiency can lead to second term miscarriage, or premature birth.
Genetic Factors
It is believed the majority of miscarriages are caused by chromosomal abnormalities (genetic issues) of the embryo, or what's called aneuploidy. This could be caused by poor egg or sperm quality, errors in early cell division after fertilization, or something called a "translocation" where one or both parents has all the right genetic material, but some of it is located in the wrong place.
Infectious Causes
There is evidence that women with recurrent pregnancy loss are at an increased risk of chronic endometritis, an inflammation of the uterine lining. Chronic endometritis can be detected with an endometrial biopsy and is treated with a course of oral antibiotics. While there has been increasing literature on the association between chronic endometritis and miscarriage, a routine endometrial biopsy is not yet part of the standard evaluation for RPL.
Lifestyle Factors
Cigarette smoking, alcohol and drug use, and caffeine intake are all associated with increased risk of miscarriage. Medical guidelines state that during pregnancy smoking, alcohol and drug use should stop and caffeine should be limited to less than three cups of coffee per day.
Detailed Descriptions
Thyroid Function
The thyroid is a butterfly shaped gland at the base of your neck and it plays a role in our metabolism. Both hyperthyroidism (having too much thyroid hormone) and hypothyroidism (having too little thyroid hormone) are correlated with increased risk of miscarriage, though hypothyroidism is a more commonly cited factor for RPL.
Doctors test your thyroid function by checking the level of TSH (thyroid stimulating hormone) in your blood. TSH is produced by the pituitary gland. It tells your thyroid to make hormones T3 and T4. If your TSH level is high, it means your pituitary gland is telling your thyroid to make T3 and T4 because you don't have enough (hypothyroidism). If your TSH is low, it means your pituitary gland is telling your thyroid not to make T3 and T4 because you have too much (hyperthyroidism). Your doctor may test the levels of free T3 or T4 in addition to TSH.
The normal TSH range is between 0.5-4.0 mIU/L, but this is for all adults - male and female of all ages - and many fertility doctors believe a TSH below 2.5 mIU/L is ideal for women of childbearing age. A level between 2.5-4.0 mIU/L may be called "sub-clinical hypothyroidism." Sub-clinical and clinical hypothyroidism may be treated by prescribing a hormone replacement medication called levothyroxine.
Learn More
The American Thyroid Association has great patient resources.
The Office of Women's Health also has some easy to understand information about thyroid disease.
Hyperprolactinemia
Prolactin is a hormone produced by the pituitary gland that stimulates breast development and milk production. However, some women have high levels of prolactin outside of pregnancy, a condition called hyperprolactinemia, which can impact ovulation or suppress progesterone production. Hyperprolactinemia can be associated with increased risk of miscarriage.
Prolactin levels are measured through a blood test. If elevated, your doctor may repeat the test to check for consistency since certain foods, stress, and sexual activity can cause a temporary prolactin increase. Your doctor may also recommend an MRI to rule out a rare, but possible pituitary tumor.
If no tumor or other cause is identified, hyperprolactinemia may be treated with medicine; usually cabergoline or bromocriptine.
Learn More
The American Society for Reproductive Medicine (ASRM) has a great fact sheet about hyperprolactinemia if you want to learn more.
Polycystic Ovarian Syndrome (PCOS)
PCOS is a multi-faceted hormonal and metabolic disorder that is the leading cause of infertility among women. While PCOS does not directly cause miscarriage, some data have shown that women with PCOS have higher rates of pregnancy loss.
There is no single test for PCOS because it manifests as a cluster of symptoms which can include irregular or no periods, excess hair growth or thinning hair, acne, weight gain, or skin tags. Your doctor will probably conduct a physical, a pelvic exam to look for cysts on your ovaries (though not all women with PCOS have these), and a blood test to rule out other issues and check your androgen levels (these are the "male hormones" that are sometimes elevated in women with PCOS).
Unfortunately, there is no cure for PCOS, but your doctor may recommend various treatments depending on your specific symptoms. As it relates to pregnancy, you may be encouraged to lose weight to lower your BMI. If you are not ovulating, you may be prescribed clomiphene (Clomid) or letrzole (Femara) to induce ovulation. Many women with PCOS are diabetic, prediabetic, or have insulin resistance, so your doctor may prescribe metformin to help control your blood sugar. Some studies have shown that metformin can improve pregnancy outcomes for women with RPL, though other studies did not find any benefit.
Learn More
The PCOS Challenge is the National Polycystic Ovary Association. They have groups you can join and resources you can access for more information about living with PCOS.
The CDC also has a PCOS Fact Sheet
The Office of Women's Health also has some easy to understand information on PCOS.
Luteal Phase Defect
The luteal phase is the second half of your menstrual cycle, after ovulation and before your next period. During the luteal phase, your progesterone level rises and prepares your endometrium (the inner lining of your uterus) for implantation. If you have a luteal phase deficiency or defect (LPD), you may not have enough progesterone to support implantation or sustain early pregnancy.
The challenge is that because women's bodies are so unique, two healthy, fertile women might have very different progesterone levels. Moreover, the same woman might have different progesterone levels during different menstrual cycles. These variances make it hard to determine what progesterone level is "normal."
Since tests for LPD are unreliable, some doctors choose to treat patients "empirically" (based on experience, rather than scientific evidence). Often patients will be prescribed supplemental progesterone, to facilitate endometrial development. Progesterone can be given orally, vaginally, or as an intramuscular injection. There is mixed evidence as to whether progesterone supplementation has any positive impact on recurrent pregnancy loss, but there is no known negative impact. There are also no standard recommendations for when to start supplementation, or how it should be administered, so different doctors will follow different protocols.
Learn More
For a detailed explanation of the menstrual cycle and the hormones involved watch this video from Osmosis.org
MTHFR Mutations
MTHFR (methylenetetrahydrofolate reductase) is a gene that helps convert folate (vitamin B9) into its active form, which is necessary in order to break down the amino acid homocysteine. Mutations of the MTHFR gene may result in elevated homocysteine levels, which have been associated with a number of health conditions, including pregnancy loss. However, there is still a lot to learn. MTHFR mutations are very common, and other factors also effect the levels of folate and homocysteine in our body, so the exact role MTHFR mutations play in RPL is unknown. As a result, treatment for MTHFR mutations is not currently recommended by the medical societies to treat recurrent miscarriage.
There is a test for MTHFR mutations but there is no treatment outside of diet modifications and nutritional supplementation. Some providers may may suggest taking a prenatal vitamin with folate or methylated folate rather than folic acid (the synthetic form of the vitamin). You can also eat folate rich foods like green vegetables, nuts, beans and liver.
Learn More
The NIH Fact Sheet on folate contains good information about recommended levels, food and supplements.
The National Library of Medicine has a guide to the MTHFR gene and related health conditions.
Antiphospholipid Syndrome (APS)
APS is an autoimmune condition in which the body produces abnormal proteins that can lead to blood clotting issues. In pregnant women this may disrupt placental or fetal development. APS is associated with early pregnancy loss, repeat miscarriage and other challenges in later pregnancy.
APS is hard to diagnose since the tests for it can give false positives. Testing is usually done only after someone has had clots or multiple pregnancy losses. Blood tests are performed to check for different antiphospholipid antibodies (aPL), usually lupus anticoagulant, anticardiolipin antibodies, and anti-beta-2-glycoprotein I. For a diagnosis, one or more of the tests needs to be positive when tested twice, at least 12 weeks apart and 6 weeks after a miscarriage.
If you have APS and have experienced multiple miscarriages, your doctor may prescribe daily oral low-dose aspirin, often with shots heparin or Lovenox (fractionated heparin), which are both blood thinners.
Learn More
The American College of Rheumatology has a great Fast Facts page about APS
Other Immune Factors
The human immune is a complex network which helps our bodies fight off disease and infection. Some doctors and researchers posit that the same immune system components that recognize any foreign cells during an infection, may also view a growing fetus as a foreign entity to be fought off. Specifically:
- Natural Killer Cells: A type of white blood cell that recognizes and kills infected cells
- Cytokines: A group of proteins that play a role in signaling, and therefore regulating, aspects of the immune system
- Human Leukocyte Antigens (HLAs): Proteins that sit on the surface of our cells and that help recognize "non-self" cells
Some studies have shown a correlation between the above factors and increased rates of miscarriage. However, diagnostic tests and treatments for the above are debated among experts and currently not recommended by the medical societies to treat recurrent miscarriage.
If your doctor does believe an immunological component is causing your miscarriages, he/she may prescribe:
- Steroids like oral prednisone, which are used to reduce inflammation
- Intravenous immunoglobulin (IVIG), an infusion of antibodies pooled from the plasma of thousands of donors that is typically used to treat patients with primary immune deficiencies
- Intravenous intralipids, which is an infusion of essential fatty acids, which is typically given to patients who need IV nutrition
- Anti-tumor necrosis factor alpha (anti-TNFα) medications, which are typically used to treat autoimmune diseases
Learn More
NIH overview provides good information about our immune system components
Congenital Anomaly
Congenital means "present at birth" so if you have a congenital uterine anomaly, you've had it your whole life, even though you may only be finding out about it during a fertility workup. Before we are born our uterus grows in two halves that fuse together. Sometimes the two halves don't fuse completely, which impacts the shape of the uterus. This can affect implantation or cervical competence and be associated with miscarriage.
The most common uterine anomalies are:
- Septate or septum: From the outside the uterus looks normal, but inside there is a partial or full band of tissue dividing the endometrial cavity.
- Bicornate ("two-horned"): There are two endometrial cavities coming from their cervix.
- Unicornate ("one-horned"): There is only one endometrial cavity, but it only has one 'arm' or one half.
- Arcatate: From the outside the uterus looks like it has a dent on top or is more heart-shaped instead of rounded.
Uterine anomalies are identified through a sonohysterography (SHG) or saline sonogram (SIS). During this procedure saline is injected into your uterine cavity through your cervix and a 3D ultrasound is performed to view the shape of your uterus.
Depending on the shape of your uterus and pregnancy history, your doctor may recommend surgery to correct the anomaly.
Learn More
The American Society of Reproductive Medicine (ASRM) has Fact Sheets about uterine anomalies and saline sonograms
Fibroids and Polyps
Fibroids are masses of cells that grow in the wall of the uterus. They are common and often don't cause any symptoms. Fibroids differ in size and location, but when they are located inside the uterine cavity, where an embryo would implant, they can increase the risk of miscarriage.
Your doctor may feel fibroids during a pelvic exam or see them on an ultrasound or other imaging procedures. Your doctor may also perform a hysteroscopy and laparoscopy to determine the specific location of fibroids, and may recommend their surgical removal.
Polyps are growths in the lining of the uterus. They are also common, but medical experts disagree on whether or not they have an impact on pregnancy. Similar to fibroids, your doctor might find them during an ultrasound or hysteroscopy, and may recommend their removal or biopsy.
Learn More
The Office of Women's Health has a lot of information about uterine fibroids, their causes and treatments.
The Royal College of Obstetricians and Gynaecologists (RCOG) in the UK, similar to ACOG, has a patient information booklet on hysteroscopies.
Intrauterine Adhesions
Intrauterine adhesions, or scarring, are rare, but can occur after uterine trauma, infection, or surgery (commonly a D&C procedure). The condition, called Asherman's Syndrome, often, but not always, causes absent or light periods and can cause infertility and increase the risk of miscarriage.
Asherman's syndrome is identified through a sonohysterography (SHG) or saline sonogram (SIS). During this procedure saline is injected into your uterine cavity through your cervix and a 3D ultrasound is performed to view the shape of your uterus.
Surgery can remove the adhesions and correct the symptoms, but scars can reform after surgery, and subsequent pregnancies can still have a higher risk of miscarriage and complications.
Learn More
The American Society of Reproductive Medicine (ASRM) has Fact Sheet about intrauterine adhesions.
The International Asherman's Association has information and fact sheets about the condition.
Cervical Insufficiency
The cervix connects the uterus to the vagina. As pregnancy progresses and the body prepares for delivery the cervix begins to shorten (efface) and open up (dilate). If this happens too early, the cervix may be unable to support the weight of a developing pregnancy which can lead to repeat second trimester miscarriages or preterm birth.
There is still a lot that is not known about cervical insufficiency (sometimes called cervical incompetence or cervical weakness) and it can be difficult to diagnose because symptoms first arise during pregnancy.
If your doctor believes you have cervical insufficiency based on your medical history and physical symptoms, he/she will monitor you closely through regular trans-vaginal ultrasounds. You may also be a candidate for a procedure called a cerclage where the cervix is stitched shut until the last month of pregnancy.
Learn More
Tommy's, a UK based research organization, has helpful information about cervical incompetence.
The Royal College of Obstetricians and Gynaecologists (RCOG) in the UK, similar to ACOG, has a patient information booklet about cervical cerclage.
Aneuploid Embryos
The majority of first-trimester pregnancy losses are the result of chromosome abnormalities or “aneuploidy.” This is when the embryo has an abnormal number of chromosomes (i.e. 47 chromosomes instead of 46). Maternal age is the most common risk factor, as there is an increased risk of a chromosome error in the egg as women age. There have also been studies that show an increased rate of sperm DNA fragmentation in men with recurrent pregnancy loss. Sperm DNA fragmentation (abnormal genetic material within the sperm) is an area of active research in the recurrent pregnancy loss field and not yet part of the recommended work up.
Performing chromosome testing on pregnancy tissue following a miscarriage can help determine if a pregnancy loss was due to a chromosome error. The most common abnormalities found in miscarriages are trisomies (extra chromosomes) or monosomes (too few chromosomes).
Assisted reproductive technologies like IVF with preimplantation genetic testing for aneuploidy (PGT-A) can test embryos before implantation to see if they are chromosomally normal (euploid). While IVF is not indicated for all women with recurrent miscarriage, some women may benefit from IVF and PGT-A.
Learn More
You can read the ASRM committee opinion on preimplantation genetic screening here.
Learn more about assisted reproduction or find a doctor at Fertility IQ
Chromosomal Translocations
Humans have 46 chromosomes in 23 pairs, and each chromosome contains a particular set of genes which tell our body how to structure and function. In people with a translocation, some of the genetic information from a chromosome in one pair is exchanged with some of the information from a chromosome in another pair (imagine chromosome pairs Aa-Aa and Bb-Bb turning into Aa-Ab and Bb-Ba). The person still has all the genes to function properly, but they are not located in the normal places.
A translocation can create problems during reproduction. Gametes (sperm or egg cells) only have 23 chromosomes - half of each pair. So when a person with a translocation makes gametes, some of them will be missing genetic material, which increases the risk of miscarriage.
Translocations are inherited, so if genetic testing is performed on an embryo or fetus after a miscarriage and a translocation is identified, parents should be tested. Translocations can also be identified by "karyotyping" which involves taking a photograph of your chromosomes using a blood sample. If a translocation is found, genetic counselling may be advised.
If you have a translocation, you may still be able to have a normal pregnancy. Depending on the type and location of translocation, if you keep trying, you may naturally conceive a genetically normal embryo, or you may be able to conceive using donor eggs or sperm. Some fertility specialists may recommend pursuing in vitro fertilization (IVF) with pre-implantation genetic diagnosis (PGD) of the embryos before transfer.
Learn More
This video does a good job explaining what happens in a translocation
The NIH Human Genome Research Institute contains a nice description and picture of chromosomal abnormalities.
There's a helpful TEDEd video on IVF
Sources
- Shahine, Lora. Not broken: an approachable guide to miscarriage and recurrent pregnancy loss. Publisher Not Identified, 2017.
- Danielsson, Krissi. After Miscarriage: Medical Facts and Emotional Support for Pregnancy Loss. Read How You Want, 2010.
- “Evaluation and Treatment of Recurrent Pregnancy Loss: a Committee Opinion.” Fertility and Sterility, vol. 98, no. 5, 2012, pp. 1103–1111., doi:10.1016/j.fertnstert.2012.06.048
- Atik, R. B., Christiansen, O. B., Elson, J., Kolte, A. M., Lewis, S., Middeldorp, S., … Goddijn, M. (2018). ESHRE guideline: recurrent pregnancy loss. Human Reproduction Open, 2018(2). doi: 10.1093/hropen/hoy004
- Li, Y. H., & Marren, A. (2018). Recurrent pregnancy loss: A summary of international evidence-based guidelines and practice. Australian Journal of General Practice, 47(7), 432–436. doi: 10.31128/ajgp-01-18-4459
Disclaimer
Material herein is provided for informational purposes only. It is general information that may not apply to you as an individual, and is not a substitute for your own doctor’s medical care or advice. No warranties are given in relation to the medical information provided, and that no liability will accrue to Recurrent Pregnancy Loss Association or any of its board members in the event that a user is damaged in any way as a result of reliance upon the information.
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