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Causes of recurrent pregnancy loss(RPL)

What is recurrent pregnancy loss (RPL)? 

This is a condition when a woman has 2 or more clinical pregnancy losses (miscarriages) before the pregnancies reach 20 weeks. Losses are classified by when they occur. Loss of a “clinical pregnancy” is diagnosed by a health-care provider using ultrasound. In most cases, a pregnancy can be seen with ultrasound as early as 5-6 weeks’ gestational age (or 1-2 weeks after a missed period). A “biochemical pregnancy” loss is one that has been detected only by urine or blood hormone testing before disappearing. Biochemical losses are not usually included in making an RPL diagnosis.

What are the causes of RPL? 

There are a variety of reasons why women may have more than one miscarriage:

Genetic/Chromosomal Causes

A chromosome analysis performed from the parents’ blood identifies an inherited genetic cause in less than 5% of couples. Translocation (when part of one chromosome is attached to another chromosome) is the most common inherited chromosome abnormality. Although a parent who carries a translocation is frequently normal, their embryo may receive too much or too little genetic material. When this occurs, a miscarriage usually follows. Couples with translocations or other specific chromosome defects may benefit from pre-implantation genetic diagnosis in conjunction with in vitro fertilization.

Many early miscarriages (the ones that happen in the rst 3 months of pregnancy) are due to genetic abnormalities in the embryo or fetus. Normally, there are 46 chromosomes that contain the genes for normal development. Many early miscarriages happen because the fetus has an extra chromosome or one is missing. For example, babies with Down syndrome have 47 chromosomes. Chromosome abnormalities occur for no known reason in up to 60% of rst-trimester miscarriages. Genetic abnormalities typically do not allow development into a healthy baby. As women age, the miscarriage risk due to these genetic abnormalities increases — from 10%-15% in women younger than 35 years old to more than 50% in women over 40 years old.

In contrast to the uncommon finding of an inherited genetic cause, many early miscarriages are due to the random (by chance) occurrence of a chromosomal abnormality in the embryo. In fact, 60% or more of early miscarriages may be caused by a random chromosomal abnormality, usually a missing or duplicated chromosome.

Age

The chance of a miscarriage increases as a woman ages. After age 40, more than one-third of all pregnancies end in miscarriage. Most of these embryos have an abnormal number of chromosomes.

Hormonal Abnormalities

Progesterone, a hormone produced by the ovary after ovulation, is necessary for a healthy pregnancy. Persistently low progesterone levels after ovulation, often called ‘luteal phase deficiency’, may cause repeated miscarriages. Treatments include ovulation induction, progesterone supplementation or injections of human chorionic gonadotropin (hCG). There is some evidence to support the effectiveness of these treatments, however their overall benefits are difficult to quantify.Thyroid dysfunction and/or the presence of thyroid antibodies have been associated with recurrent pregnancy loss. Abnormal production of the hormone prolactin can also disrupt normal ovulation and has been linked with miscarriage.

Metabolic Abnormalities

Poorly controlled diabetes increases the risk of miscarriage. Women with diabetes improve pregnancy outcomes if blood sugars are controlled before conception. Women who have insulin resistance, such as obese women and many who have polycystic ovarian syndrome (PCOS), also have higher rates of miscarriage. There is still not enough evidence to know if medications that improve insulin sensitivity lower miscarriage risks in women with PCOS.

Uterine Abnormalities

Distortion of the uterine cavity may be found in approximately 10% to 15% of women with recurrent pregnancy losses. Diagnostic screening tests include hysterosalpingogram, sonohysterography, ultrasound, or hysteroscopy. Congenital uterine abnormalities include a double uterus, uterine septum, and a uterus in which only one side has formed. Asherman’s syndrome (scar tissue in the uterine cavity), uterine fibroids, and uterine polyps are abnormalities that may also cause recurrent miscarriages. Often these conditions can be surgically corrected.

A problem with the shape of a woman’s uterus might be a cause for pregnancy loss. Causes for abnormal shape of the uterus can be genetic or exposure before birth to medications such as diethylstilbestrol (DES).

Other anatomic causes include having a band of tissue inside the uterus, called a septum. This can make the inside of the uterus too small. Women born with a septum may have more frequent miscarriages. Fibroids, benign muscle tumors of the uterus, are also common. These can lead to miscarriages if they grow into or near the uterine cavity.

Antiphospholipid Syndrome

Blood tests for anticardiolipin antibodies, lupus anticoagulant, and B2-glycoprotein 1 antibodies may identify women with antiphospholipid syndrome, a cause for 3% to 15% of recurrent miscarriages. In women who have high levels of antiphospholipid antibodies, pregnancy outcomes can be improved by the use of aspirin and heparin.

Thrombophilias

Inherited disorders that raise a woman’s risk of serious blood clots (thrombosis) may also increase the risk of miscarriage as well as fetal death in the second half of pregnancy. While there is no clear consensus that testing or treatment for these disorders can significantly reduce miscarriages in the first trimester, some evidence demonstrates improvement in outcomes using low-dose aspirin or heparin in patients with specific thrombotic risks or unexplained recurrent pregnancy loss.

Male factor

Some evidence suggests that abnormal integrity (intactness) of sperm DNA may affect embryo development and possibly increase miscarriage risk. However, these data are still very preliminary, and it is not known how often sperm defects contribute to recurrent miscarriage. 

Lifestyle/Environmental

Smoking increases the risk for RPL. Using certain recreational drugs, such as cocaine, can also lead to miscarriage. Being overweight has been linked with RPL as well as other pregnancy complications. Excessive alcohol or caffeine intake might be linked with RPL.

Medical

Untreated medical conditions, such as thyroid disease or diabetes, can increase the risk for miscarriage. Abnormalities of the immune system or blood-clotting system (thrombophilia) can also cause RPL.

Unexplained 

In over half of RPL cases, doctors cannot find the cause for losses. However, many of these may be due to genetic abnormalities. No explanation is found in 50% to 75% of couples with recurrent pregnancy losses.

Are there tests to discover causes of RPL? 

Blood tests can show if a woman has certain medical, immune, or blood-clotting conditions that might cause RPL. The chromosomes of women and their male partners can be studied using a special blood test called a “karyotype.” Some healthy people have differences in the way their chromosomes are arranged. This can increase their risk for genetically imbalanced pregnancy losses. A special x-ray (hysterosalpingogram) or ultrasound (sonohysterogram) can show if a woman has a problem with the shape of her uterus. If available, the tissue from a miscarriage can be tested for genetic abnormalities.

Are there treatments available for RPL? 

With certain conditions, medical or surgical treatment can lower a woman’s risk for future miscarriage. 

Will I be able to have a baby even with a history of RPL?

Even after having 3 miscarriages, a woman has a 60%-80% chance of conceiving and carrying a full- term pregnancy.

Many women have a miscarriage at one time or another. Miscarriages can happen for many reasons. Having a miscarriage doesn’t mean a woman will have another miscarriage if she tries again. But some women suffer more than one miscarriage. This is called recurrent pregnancy loss (RPL). Women and families often grieve these losses deeply. Women may also worry that they are sick or did something to cause the losses. RPL, however, is often a natural process. Less than half of recurrent miscarriages have an obvious or treatable cause. Almost two-thirds of women with RPL will eventually have a healthy pregnancy — often without any extra treatment.

If you have suffered two or more miscarriages, you should talk with your doctor. Often, women decide to continue trying to get pregnant naturally. However, in certain situations, your doctor might suggest treatments to help reduce your risk for miscarriage.

Surgery 

Surgery can x some problems in the uterus (womb), like extra tissue that divides the uterus (septum), some broids (benign tumors), or scar tissue. Correcting the shape of the inside of the uterus can often lower the chance for miscarriage. The surgeon uses a tool with a camera (hysteroscope) passed through the vagina to repair the inside of the uterus. 

Blood-thinning medicines 

Women with autoimmune or clotting (thrombophilia) problems may be treated with low-dose aspirin and heparin. These medicines can be taken during pregnancy to lower the risk of miscarriage. You should talk to a doctor before using these medicines because they increase the chances of serious internal bleeding problems. 

Correcting other medical problems 

Recurrent pregnancy loss may be related to some medical problems. These include abnormal blood sugar levels, an over- or underactive thyroid gland, or high levels of the hormone prolactin. Treating medical conditions such as diabetes, thyroid dysfunction, or high prolactin levels can improve the chances of having a healthy, full-term pregnancy.

Genetic screening 

In about 5% of couples with RPL, one of the parents has a rearrangement (translocation) of their chromosomes. If one parent has a translocation, this can cause fetuses with chromosome imbalances that are more likely to miscarry. The parents’ blood can be studied (karyotyped) to see if they have a translocation. If a chromosomal problem is found, the doctor might recommend genetic counseling. While many couples with translocations eventually conceive a healthy pregnancy naturally, your doctor might suggest fertility treatments, such as in vitro fertilization (IVF).  After IVF, before the embryos are returned to the uterus, they can be tested (preimplantation genetic screening). This allows embryos without translocations to be chosen to increase the chance of a healthy pregnancy.

Lifestyle Choices 

In general, whatever is healthy for a woman improves the chance of a healthy pregnancy. Stopping cigarette smoking  will lower the risk for miscarriage. Limiting alcohol and caffeine intake may also help. Being overweight has been linked with increased risk of miscarriage, so healthy weight loss might also help pregnancy outcomes. There is no proof that stress, anxiety, or mild depression causes RPL. However, these are important problems that go along with RPL. Psychological support and counseling can help couples cope with the emotional pain of miscarriage and create a healthy environment for a pregnancy.

Controversial treatments 

There is no proof that intravenous (IV) infusions of blood products (such as intravenous immunoglobulin [IVIG]) or medicines (such as soybean oil infusion) decrease the risk of miscarriage.

Credit: reproductivefacts.org