Reccurrent Pregnancy Loss

Recurrent Pregnancy Loss / Recurrent Miscarriages / Recurrent Abortions

Miscarriage is one of the most devastating experiences that can happen to a woman. Having one miscarriage is sadly, not that uncommon. Approximately two out of every ten pregnancies will result in miscarriage. After having one miscarriage most women go on to have a healthy pregnancy.

Still there are a few women that will continue to have two, three or more miscarriages. Women are considered to have recurrent miscarriages when they have two or more miscarriages in a row. According to the American Society for Reproductive Medicine, only about one percent of women will have three consecutive miscarriages or more.

It is a vexing clinical problem and the cause is often unexplained. The treatment options are variable, ranging from masterly inactivity to aggressive management. The psychological implications of Recurrent pregnancy loss or abortions are tremendous. A multidisciplinary approach, involving gynecology, genetics, endocrinology, immunology is mostly required.

What do you mean by recurrent pregnancy loss (RPL)?
Pregnancy loss is synonymous with miscarriage or abortion. A miscarriage/abortion is a pregnancy that ends before 20 weeks from last menstrual period. A recurrent miscarriage is 2 or more consecutive, spontaneous pregnancy losses, under 20 weeks of gestation from the last menstrual period (WHO1977).

Primary recurrent pregnancy loss refers to couples that have never had a live birth Secondary recurrent miscarriage is the loss of at least three pregnancies to miscarriage following one successful pregnancy.

Pregnancy losses at higher gestations are called as Stillbirths or preterm neonatal deaths. However, pregnancy losses after week 20 are rare.

What is the incidence of recurrent pregnancy loss?
Miscarriage in early pregnancy is common. Studies show that about 8 to 20 percent of women who know they are pregnant have a miscarriage some time before 20 weeks of pregnancy, 80 percent of these occur in the first 12 weeks. But the actual rate of miscarriage is even higher since many women have very early miscarriages without ever realizing that they are pregnant.

According to some studies the rate of sporadic miscarriages is 12 -15% clinically and subclinical around 60-70%. 1% of couples trying to conceive have recurrent miscarriage.

The chance of having a second spontaneous abortion with a history of only one isolated spontaneous abortion is 15-20% (for clinically recognized pregnancy). If there have been 2 spontaneous consecutive abortions, there is about a 35% chance (1 in 3) that the next pregnancy will be lost. Therefore, the loss rate is almost doubled. If there have been 3 spontaneous abortions in a row, there is a 45-50% chance that the next pregnancy will be lost. There are reports indicating improvement in future pregnancy success for couples with recurrent pregnancy loss after there has been at least one prior live born for the couple. Therefore, the couple’s prior reproductive history is also important.

Classification of RPL / repeated abortions
classification
Table showing risk of repeat loss after a miscarriage
risk_of_repeat_loss
What are the possible causes of recurrent miscarriage?
Causes of RPL /Repeated miscarriages / abortions
causes_of_rpl
In almost 50% of the cases no cause is found (Idiopathic). Some of the other common causes are as discussed below.

Some of the common causes of repeated abortions are as follows:

Genetic abnormalities:

  • Fetal genetic abnormality (trisomy in particular) is the most common cause of miscarriage before 10 weeks of gestation.

Antiphospholipid syndrome (APS):

  • This is the most important treatable cause of recurrent miscarriage.
  • This is a group of autoimmune disorders wherein the women’s body rejects the fetus leading to abortion.
  • Antiphospholipid antibodies are a family of about 20 antibodies, which include lupus anticoagulant and anticardiolipin antibodies.
  • The prevalence of APS in women with recurrent miscarriage is between 5-15%.

Structural:

  • Uterine anomalies (arcuate or septate) are seen in between 10-25% of cases of recurrent miscarriage. Only 50% of pregnancies where there is a uterine structural abnormality achieve term delivery.
  • Uterine fibroids are present in up to 30% of women, but the way they affect reproductive loss is unclear.
  • Cervical incompetence where there is inherent weakness of the cervix or the mouth of uterus may lead to miscarraige after 13 weeks of pregnancy. These are usually painless. This is frequently cited as a cause of midtrimester recurrent miscarriage.

Infective:

  • Toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus (ToRCH) and listeriosis screening has been abandoned when investigating recurrent miscarriage. Still may gynaecologist believe in doing these tests on a routine basis.
  • As per WHO (World Health Organisation) there is no role of ToRCH test in current pregnancy. There is importance of only recent infections which can be diagnosed by using IgM testing. If there is recent infection, pregnancy has to be avoided during that time. In case of old infections, IgG will be positive, which shows that the woman had the infection some time back and now has antibodies against that infection. Nothing has to be done in such cases. This has no implication in current or future pregnancy.
  • There is poor evidence for bacterial vaginosis as a cause of early miscarriage secondary to endometritis.

Endocrine:

  • The relationship between polycystic ovarian syndrome, insulin resistance and pregnancy loss is now thought to be key.
  • Luteal phase defect where there is inadequacy of hormones needed to support pregnancy after conception is also an important cause.
  • Insulin resistance is common in women with recurrent miscarriage and has been associated with an increased rate of miscarriage.
  • Thyroid disorders and diabetes are also related with increased incidence of miscarriage.

Thrombophilias:

  • These are clotting disorders wherein deficiency of one of the clotting factors leads to abortion because of irregular blood supply to the uterus.
  • Three thrombophilic mutations were first identified in the mid-1990s: factor V Leiden (FVL) G1691A; factor II (prothrombin) G20210A and methylenetetrahydrofolate reductase (MTHFR) C677T.
  • However, women with the FVL mutation can have an uncomplicated full-term pregnancy, but multiple risk factors increase the likelihood of adverse pregnancy outcomes.
  • Excessive smoking or alcohol consumption, also exposure to chemicals like pesticides can also be related to abortion.

Unknown or idiopathic:

  • About in 50 % of cases the cause may not be found at all. And this is most difficult to manage.

Can one predict the cause of RPL depending upon the week of gestation?
Yes, sometimes the period of gestation at which the previous miscarriage or abortion occurred points to the cause of abortion. This is summarized below.

RPL2

How is an early pregnancy diagnosed?

Diagnosis of an early pregnancy is done using:

  • Clinical history and examination
  • Transvaginal sonography &
  • Serum β HCG levels

On transvaginal ultrasonography the presence of Gestational sac is an early marker of pregnancy. It is the 1st definitive finding. It is a small round fluid collection with hyperechogenic rim. The mean sac diameter (MSD) and its position in the mid to upper uterus is important.

Yolk sac is the first anatomic structure within G sac. It is seen when mean sac diameter, MSD is 5-6 mm and always when MSD is over 8 mm. It confirms intrauterine location of the pregnancy. The diameter increases steadily till it detaches itself from embryo and is no longer seen by end of first trimester.

USG of early pregnancy showing Yolk sac

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Some of the common sonographic features of early pregnancy loss are:

  • Bradycardia
  • Large yolk sac
  • Small gestational sac and Subchorionic haematoma

Early pregnancy with yolk sac and subchrionic bleed

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What is the role of Serum Beta HCG levels?

Serum Beta HCG levels and USG are complementary. G sac growth and HCG production are relate to trophoblastic function. There is an excellent correlation between sac size and HCG level.

If HCG > 1000 IU/ml, then an intrauterine gestational sac should be seen on TVS. The HCG levels double every 2 days below 1200 IU/ml and every 3 days below 6000IU/ml.

As the embryo grows on USG there is thickening along the periphery of yolk sac.

The Mean Sac Diameter, MSD is around 5 to 12 mm at 5 to 6 weeks of gestation.

The fetal cardiac activity may be appreciated once the embryo attains a length of 4 to 5 mm and Gestational Age (GA) of 6 to 6.5 weeks. The MSD now reaches about 13 to 18 mm and FHR 100 to 115 beats/min before 6 weeks which further increases to 144 to 170 at 8 weeks and 137 to 144 after 9 weeks.

During the embryonic period (Weeks 6 to 10) , the Crown Rump Length (CRL) increases by approx 1 mm/day. The Ventral folding of cranial and caudal ends of embryo are formed and the limb buds begin to grow around 7-8 weeks.

Absent intrauterine sac on USG suggests either there is no pregnancy OR Very early (normal or abnormal) intrauterine pregnancy OR Ectopic pregnancy (extra uterine pregnancy). In such cases a serum β HCG correlation is required.

What is blighted ovum or anembryonic pregnancy?

Anembryonic pregnancy occurs when there is developmental arrest before formation of embryo or before detection of embryo. In such cases the trophoblastic tissue continues to function. In some cases there may be continued sac growth at lower growth rate.

When the G. Sac is more than 8 mm with no yolk sac, the diagnosis is Blighted ovum.

USG image of Blighted ovum with no yolk sac

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If the G sac is more than 16mm with no embryo, then the diagnosis is Blighted ovum.

USG image of Blighted ovum with yolk sac but no embryo / fetal pole

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What if the cardiac activity is absent on USG?

If there is no cardiac on USG and G sac diameter is 9mm on TAS or 4-5 mm on TVS, an embryonic demise is suspected. A second opinion may be required in such cases. Chromosome abnormality may be present in the fetus.

It is seen that, if cardiac activity is present, risk of subsequent fetal loss is < 5%.

  • If on TVS, the Mean sac diameter > 20 mm with no fetal pole then an ANEMBRYONIC GESTATION should be suspected.
  • If the Crown Rump Length (CRL) is more than 6mm with no cardiac activity then an EMBRYONIC DEMISE should be suspected.
  • If on USG the embryo is more than 5 mm with no cardiac activity, then EMBRYONIC DEMISE should be suspected.

Etiology of RPL / recurrent miscarriages / recurrent abortions:
etiology

Ankoor fertility clinic recommendations:

If there is history of repeated first trimester abortions (early pregnancy, generally less than 8-10 weeks), with no cardiac activity detected on USG, then the most likely cause of miscarriages or abortions is Chromosomal / Genetic.

In such cases a detailed history of the couple is taken followed by karyotyping of the couple if required. Further management depends on that.

Does a woman’s age play a role in recurrent abortion?
Yes.

The spontaneous abortion rate rises as the woman’s age increases, with a gradual increase starting about age 30, more rapid increases after age 35, and much more rapid increases after age 40. As a woman ages, the number of her eggs decreases, and the remaining eggs are more likely to have chromosomal errors. The most common abnormalities are Autosomal trisomies (13,16,18,21) in 50-60%, Monosomy X-20%,Triploidy–15% and Tetraploidy-5%.

When women over 40 or 45 years age are recipients of donor eggs from younger women they do not have this increased spontaneous abortion rate. This suggests that the cause of this increase in loss rate is related to egg rather than uterine factors. However, age can also negatively affect the uterine lining, which needs to be healthy in order to maintain a pregnancy.

As the number of miscarriages increase, aneuploidy plays a decreasing role and maternal factors an increasing role.

25-32% of cases are due to Fetal chromosomal abnormality (Hence the need for karyotype analysis of the products of conception). This may be due to abnormalities in the egg, sperm or both. The most common chromosomal defects are Trisomy, Monosomy, Polyploidy.

Is advanced paternal age a risk factor?

Recently, advanced paternal age was identified as a risk factor for miscarriage. A large multicenter European study reported that the risk of miscarriage is highest for couples in which the woman is 35 years or older and the man is 40 years or older.

Sperm aneuploidy (13,18,21,X,Y ) directly influences the rate of aneuploidy in the conceptus (Carrellet al 2003).

Parental chromosomal abnormality (Balanced chromosomal rearrangements) are seen in 0.2 % of the general population & 4% in couples with recurrent miscarriages.3-5% of couples with RSA are carriers of balanced chromosomal rearrangements

What are the common Parental Chromosomal Abnormalities ?

Translocation is the commonest abnormality (1 in 500).

It is exchange of chromosomal segments between two, non-homologous chromosome. It is most common at 13,14,15,21,22. Women are more likely to be affected than Men.

a & b : . Picture showing translocation of chromosomes

translocation

 

rebert

There may be a Reciprocal (Two non-homologous chromosomes exchange information) [65%] Or Robertsonian (Two non-homologous acrocentric chromosomes break at the centromere and the long arms fuse. The short arms are often lost) [35%] translocation.

Other chromosomal errors are Mosaicism for a numeric aberration [12%] and Inversion.

What happens due to Reciprocal translocation?

Two non homologous chromosomes exchange information. If no genes are broken, no gain or loss of genetic information (normal phenotype) – individuals are translocation carriers t(11,22)

If one of the breaks occurs in a gene -gene can be disrupted (abnormal phenotype )

A & B. Reciprocal ranslocation

reciprocal

 

human_genetics

What is Robertsonian translocation?

The incidence of Robertsonian translocation is 1:1000. It occurs with acrocentric chromosomes. This produces one new large chromosome made from the two long arms of two different chromosomes. Two short arms of each chromosome are lost

For example –Down syndrome. Commonest is rob t(13,14)

Risk of Phenotypically abnormal offspring is 1%. The risk of recurrent miscarriages / abortions /RPL is up to 30%.

A& B Robertsonian translocation

robertsonian

Robertsonian Translocation

Are any life style factors related to recurrent abortions/ miscarriages?

Yes. Studies have shown that certain lifestyle factors are associated with recurrent miscarriages like :

  • Obesity -PCOS
  • Occupation
  • Alcohol
  • Caffeine consumption
  • Smoking –Aggravates thrombophilic factors

What is meant by genetic/chromosomal cause of miscarriage?
Up to 70% of miscarriages are caused by chromosomal errors. Chromosomal abnormalities are more common in women who are over 35. In most cases chromosomal defects are a random occurrence and are not likely to reoccur in subsequent pregnancies. Although chromosomal errors are the cause of the majority of miscarriages, they are not usually caused by an inherited trait from mother or father. Which means that both eggs and the sperms are normal but the embryo formed may be genetically abnormal.

Less than five percent of couples tested will have an inherited genetic cause of such chromosomal defects. Which means that either of the parents are having some genetic defect which is transmitted to the fetus making it genetically unstable liable to pregnancy loss. Sometimes, recurrent miscarriages do have a chromosomal cause. Women (and men) older than 35 have a greater tendency to produce eggs or sperm with chromosomal abnormalities.

In few cases, one or both partners may have a balanced translocation or other silent chromosomal abnormality that gives the couple a statistically increased odds of miscarriage in each pregnancy.

Ankoor clinic recommendations for genetic testing or evaluation :

If there is a history of RPL, clotting disorder , still birth/neonatal death, babies with dysmorphic features, mental retardation /developmental delay in previous baby, or other history of inherited disorder a genetic evaluation & testing is recommended.

How is genetic testing done?
Research suggests that after a couple has had 2 or more unexplained miscarriages, there is a 2-5% risk that one member of the couple is a carrier of a balanced chromosome rearrangement.

Chromosomal analysis of the products of conception (the miscarried fetal tissue) and of the woman and her husband (blood test) may provide additional important information that will affect future reproductive decisions and additional testing recommendations.

The “largest single class” of fetal chromosomal abnormality found in spontaneous abortions are the autosomal trisomies (roughly 50% of abnormal specimens), some of which reveal a maternal age effect. Monosomy X is the “single most common” chromosomal abnormality found in spontaneous abortions (roughly 25% of abnormal specimens), which usually occurs due to a loss of the paternal sex chromosome (Y chromosome) and is not more common with advancing maternal age.

Certain chromosomal abnormalities are universally accepted by infertility specialists as a cause for recurrent pregnancy loss. Fortunately, these major chromosomal abnormalities are uncommon. They may occur within either the maternal or paternal chromosomes. The overall incidence of chromosomal abnormality as the cause of recurrent pregnancy loss is low (less than 5% of couples with recurrent losses).

What are the common Single Gene Disorders in RPL?

These may lead to 2nd and 3rdtrimester losses. Common causes are Alpha Thalassemia, Myotonic dystrophy, X linked Dominant disorders, Incontinentia Pigmenti,Chondrodysplasia punctata, Focal dermal hypoplasia of Goltz, Rett Syndrome and Aicardi Syndrome.

The woman may give a history of previous child with blood abnormalities leading to repeated transfusions. This clue may be pointing towards thalasemia in the baby. In such cases genetic testing will help us to know whether one or both the parents are carriers of the gene. This will help us in planning the modality of treatment for the next baby.
What if a genetic abnormality is found?
If an abnormality is identified, prompt consultation with an experienced human geneticist is indicated since the theories and actual experiences in this field are complex and constantly changing. Preconception counselling and planning with respect to prenatal diagnosis is also important. Unfortunately, there is no available treatment to “fix abnormal chromosomes” at this time.

To increase the likelihood of subsequent successful pregnancy, preimplantation genetic screening of biopsied blastomeres during IVF has been recommended in order to prevent the transfer of karyotypically abnormal embryos in couples with normal karyotypes. Donor gamete can be used if any one of parent is chromosomally abnormal with the help of IUI or IVF.

Ankoor clinic recommendations :

If there is history of repeated late first trimester or second trimester abortions (12 to 24 weeks), with cardiac activity detected on USG, then painless abortion follows, the most common cause is an anatomical defect like cervical incompetence or uterine defects (septum etc). In such cases simple investigations, like discussed below, can diagnose the condition.

For eg.

  • USG for cervical length and internal os diameter or uterine malformations.
  • HSG (Hysterosalphinography) can also diagnose these uterine anomalies.
  • Hysteroscopy can help to diagnose as well as treat the condition.

If there is cervical incompetence ie. Weakness of cervix, then a simple stitch taken over the cervix (mouth of the uterus) will be needed.

Uterine abnormalities can mostly be corrected during operative hysteroscopy.

What are the anatomical factors associated with RPL?
Uterine abnormalities:

Uterine abnormalities account for ten to fifteen percent of repeated miscarriages. Some women are born with a double uterus or an abnormally shaped uterus. Uterus abnormalities may cause problems with proper implantation, create problems with blood supply to the uterus, or there may not be room for the baby to develop and grow.
Sometimes, something is physically different about a woman’s uterus in a way that reduces her chances of a successful pregnancy. This might mean her uterine shape is abnormal or her cervix is weakened in a way that reduces her odds of a successful pregnancy. Multiple intramural and submucosal fibroids are associated with an increased risk of pregnancies ending in miscarriage.

Anatomical factors that may cause recurrent miscarriages include:

  • Uterine septum (or other congenital problems)
  • Cervical insufficiency
  • Fibroids (submucosal)
  • Uterine scarring (Post surgery or infection)

Incidence of Uterine anomalies leading to RPL:

General population 6.3%
Infertile women 7.6%
Women with recurrent miscarriages 16.1%

 

Most common anomaly is a septate or subseptate uterus. Other common conditions are T-shaped uterus, fibroids, intrauterine adhesions.

Incompetent Cervix:

  • Incompetent cervix may cause second trimester miscarriages (between 12-24 weeks of pregnancy) or premature labor.
  • Usually associated painless cervical dilation and usually requires emergency cervical cerclage operation.
  • There are certain uterine abnormalities like septate or bicornuate uterus associated with cervical weakness which is congenital.
  • There are certain uterine surgeries like recurrent curettages or removal of cervical fibroid which can traumatize the cervix and lead to weakness.
  • Incompetent (or weakened) cervix may require a surgical procedure called cerclage. Cerclage is a surgical stitch placed around the cervix at around 14-18 weeks of pregnancy to help keep it from dilating prematurely.

If there is a history of painless abortion in the late first or second trimester, it can be due to cervical incompetence. Sometimes these women give history of preterm vaginal deliveries or history of cervical stitch been taken in the previous pregnancy. This also points to cervical incompetence.

These abortions can be prevented by taking a simple stitch over the mouth of the uterus (cervix). This helps us to continue the pregnancy till term and avoid miscarriages.

How do anatomical causes lead to RPL?

Smaller uterine cavities have fewer suitable implantation sites. They also have aberrations of vascularisation. Sometimes they may be accompanied by cervical incompetence. This leads to both early & later pregnancy losses.
How do you evaluate the Uterine Cavity abnormalities?
Transvaginal ultrasound can only diagnose a few of the important uterine anomalies, and frequently further testing is required. It is sometimes possible to see abnormalities inside the uterus at the time of a scan, especially a vaginal scan. A scan will also enable the ovaries to be examined at the same time. Occasionally polycystic ovaries are diagnosed by ultrasound scan.

USG images of Uterine cavity malformations

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Testing the uterine cavity can be done with a hysteroscope, a small camera place into the uterine cavity through the cervix.

Other testing such as hysterosalpingogram (HSG), saline infused sonogram or MRI can also be used.

Hysterosalpingography

  • The routine use of hysterosalpingography as a screening test for uterine anomalies in women with recurrent miscarriage is questionable.
  • It is associated with patient discomfort, carries a risk of pelvic infection and radiation exposure and is no more sensitive than the non-invasive two dimensional pelvic ultrasound assessment of the uterine cavity with (or without) Sonohysterography when performed by skilled and experienced personnel.

HSG images of uterine malformations and abnormalities

subseptate-uterus-5

 

septum

Saline installation sonography (SIS)

  • A small plastic tube is passed through the cervix and a water-like solution injected through it.
  • The scan can determine whether there is any abnormality inside the uterus.
  • Three-dimensional ultrasound
  • The diagnostic value of three-dimensional ultrasound has been explored and appears promising.
  • Since three-dimensional ultrasound offer both diagnosis and classification of uterine malformation its use may obviate the need for diagnostic hysteroscopy and laparoscopy.

Hysteroscopy

  • This investigation, performed under general anesthesia, examines the inside of the uterus with a thin telescope (3-5 mm in diameter).
  • By inserting this telescope through the cervix and into the uterus, the doctor can see the shape of the uterus and examine its lining.

Hysteroscopic pictures of Uterine malformations and abnormalities

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During hysteroscopy, if there is a uterine septum or polyp which may be the cause of repeated abortions, then these too can be removed hysteroscopically.

Classification of Mullerian Anomalies
Classification of Mullerian Anomalies

What is the treatment of Uterine Anomalies?
Most experts recommend hysteroscopic resection of a uterine septum in women with recurrent miscarriage; since most women with bicornuate or unicornuate uteruses have good obstetrical outcomes, and surgical repair of these abnormalities is more invasive than septum resection and associated with a higher risk of complications, repair of these abnormalities is not generally advised.

The benefits of myomectomy are uncertain and supported only by reports of better outcomes after surgery than before surgery. More extensive surgery to remove uterine myomas involving laparoscopy or laparotomy poses hazards for subsequent pregnancies (e.g., a risk of uterine rupture), and its effect on the likelihood of subsequent miscarriage is uncertain.
Hormonal / Endocrinological causes:

Ankoor clinic recommendations:

When the age of the couple is more than 35 years, testing for blood sugars is generally recommended as they have a tendency for increased sugars. Diabetes can be associated with infertility as well as repeated miscarriages as the increased sugar levels affect the egg and sperm quality.

Woman with history of thyroid disorders need to take their medications regularly to avoid miscarriages.

What are the hormonal /endocrine causes of RPL?
A multitude of endocrinological events aid in the implantation & successful growth and development of the fetus. A small number do have certain endocrine alterations that could potentially lead to RPL.

8 to 12% of all RPL are due to endocrine factors.

Common endocrine factors are :

  • Thyroid Dysfunction
  • Diabetes – Poorly controlled Type 1 Diabetes has been associated with miscarriage. Improving blood sugars before conception will improve the outcome during pregnancy.
  • Hyperprolactinemia
  • Luteal Phase Defect
  • Hyper secretion of LH (PCOS)
  • Obesity

Do I have a high risk of miscarriage if I have PCOS?

PCOS has been linked to miscarriage. Women with PCOS have higher levels of male hormones. This has been associated with infertility as well as miscarriage. Insulin resistance is common in women with RPL, and has been associated with an increased rate of miscarriage. Hyperinsulinemia is associated with impairment of the fibrinolytic response, which is important in the tissue remodeling that accompanies embryonic implantation. Over a third of all women who have recurrent miscarriage also have PCOS.

Treatment of PCOS often involves weight loss, insulin-sensitizing medications and ovulation induction. This treatment combination reduces the risk of miscarraige considerably.

How do you evaluate endocrine disorders?

  • The minimum workup includes a complete medical, surgical, genetic, and family history followed by physical examination.
  • On General physical examination look for signs of endocrinopathy (hirsutism, galactorrhea, thyroid), PCOS (hirsutism, hyperandrogenemia, obesity) and Syndrome X (obesity, hypertension, impaired GTT, hyperinsulinemia, hypertriglyceridemia.
  • Most cases can be evaluated with simple blood tests and treated if present.
  • The recommended hormonal testing will depend up on the symptoms experienced, but may include thyroid, prolactin, follicle stimulating hormone, fasting glucose and insulin levels.
  • Because measuring TSH is a sensitive and inexpensive tool to assess thyroid function, it should be considered in the evaluation of RPL for women with any signs or symptoms of thyroid dysfunction
  • Other testing that might be indicated based on the patient’s presentation include insulin resistance testing, ovarian reserve testing and antithyroid antibody testing

Common investigations in cases of RPL

Common investigations in cases of RPL

How does Type 1 Diabetes Mellitus (T1DM) lead to RPL?

Type 1 Diabetes Mellitus (T1DM), is a T-cell mediated autoimmune disease which results in destruction of insulin-producing βcells. There is increased risk of Autoimmune Polyglandular Syndromes (autoimmune thyroid disease, celiac disease, gastritis, Addison’s Disease and vitiligo). 15 to 30% of patients with T1 DM have thyroid antibodies. 50% of patients progress to clinical autoimmune thyroid disease. Women with poorly controlled diabetes, as evidenced by high glycosylated HbA1c levels in the first trimester, are at a significantly increased risk of both miscarriage and fetal malformation. Spontaneous abortion rate increases 3-4 fold with poor glycemic control in early pregnancy.

Screening for occult diabetes in asymptomatic women is not necessary unless the patient presents with an elevated random glucose level or exhibits other clinical signs of diabetes mellitus or if there is an unexplained loss in the second trimester.

What is Autoimmune thyroid diseases ?

It is also known as Hashimoto`s disease. There is destruction of thyroid tissue. Presence of thyroid peroxides (TPO) or thymoglobulin antibodies, and elevated TSH concentrations.

Presence of antithyroid antibodies presents as recurrent pregnancy loss, which is brought about by increased T-cell or natural killer cell activation

When should the screening for thyroid dysfunction done?

Ideally, one should get the serum TSH checked pre conceptionally. If TSH is high, check FreeT3, FreeT4. If it is also high, then treat. If TSH high, and T3, T4 normal ie. subclinical hypothyroidism, then if planning pregnancy then treat otherwise the woman can be observed.

  • For TSH between 2.5-5.0 mU/L: recheck TSH during 1st trimester
  • If TSH is 0.4-2.5 mU/L: No need to recheck during pregnancy
  • If TSH not done pre conceptionally, do at earliest antenatal visit. If 0.1-0.4 mU/L: hCG effect (9% pregnancy), recheck in 5wk. If < 0.1 mU/L: recheck immediately with FT4, FT3, T4, T3.

Hypothyroidism can increased risk of abortion in overt cases. If antibodies are present, sub clinical cases also associated with abortion. IUGR and IUFD is seen in in uncontrolled cases.Rarely neurological deficit and low IQ can occur if thyroid is uncontrolled in 1sttrimester.

What is luteal phase defect?

Luteal phase defects are most often thought to result from inadequate progesterone effect on the uterine endometrial lining. Some researchers believe that Luteal Phase Defect is responsible for up to forty percent of recurrent miscarriage; however, there are some questions as to the accuracy of these studies.

Progesterone appears to have a critical role in implantation and the development of a normal pregnancy. Limited exposure to progesterone may result in infertility (severe) or recurrent pregnancy loss (milder). Characteristically, decreased progesterone results in a shortened (less than 11 day) luteal phase (period between ovulation and the onset of the next menses) or a persistently abnormal endometrial biopsy (greater than 2 days out of phase). When these changes are more severe, the impact on reproduction can be greater.

What is the cause of Luteal Phase Defect (LPD)?

Poor follicular phase leads to inadequate Luteal phase. Premature LH causes stimulation of immature granulose cells. Abnormal patterns of LH secretion in the Luteal phase can Attenuated “LH” & “FSH” ovulatory surge. There may be decreased endometrial nuclear progesterone receptors. In some cases LPD can also be found with normal levels of progesterone.

How are endocrine disorders treated?

  • DM should be controlled at least 6/12 prior to conception. HbA1c should be in normal range.
  • Treatment for Luteal Phase defect includes taking progesterone supplements or suppositories, Usual routes of administration of progesterone is Oral, Intramuscular, Vaginal Capsules, Gel.
  • Luteal Phase Support (LPS) like hCG injections , Progesterone, Estrogen + Progesterone tablets.
  • Thyroid – Hyper and Hypo thyroid should be controlled. Euthyroid with ↑ peroxidase antibody may benefit from treatment. Levothyroxine therapy should be administered for subclinical and overt hypothyroidism.
  • Poorly controlled hypo / hyperthyroidism, Subclinical hypothyroidism and Euthyroid women with high serum (TPO) are at increased risk of miscarriages.
  • Treated thyroid dysfunction is NOT a risk for RPL.
  • Therapy with insulin-sensitizing agents for the treatment of RPL in the presence of PCOS has recently gained popularity.
  • Treatment of documented hyperprolactinemia with Bromocriptine & Cabergoline shows benefit in terms of successful pregnancies, as well as prevention of ectopic pregnancy

What is the role of Progesterone in RPL?

Progesterone support in pregnancy has been in use for nearly 60years, dating back to the 1940s. Its initial use was inpatients who had habitual spontaneous abortion caused by Luteal phase deficiency (LPD). This is due to a failure of the function of the corpus luteum in the production of progesterone, which is indispensable during the first seven weeks of pregnancy. Surgical removal of the corpus luteum during this period of time results in pregnancy loss and progesterone replacement can help maintain the pregnancy. There is evidence of support in the concept that progesterone given in early pregnancy may be useful in some women with recurrent miscarriage and that the measurement of serum progesterone levels in early pregnancy can be an adjunctive marker for the further assessment of pathologic pregnancies.

Progesterone levels are based on her menstrual cycle and in the stage of pregnancy.

Before Pregnancy

  • Prior to ovulation: Progesterone levels tend to be < 2 ng/ml
  • After Ovulation: > 5 ng/ml

In Pregnancy

  • Progesterone levels rise with pregnancy. This can often indicate the health of a pregnancy.
  • First Trimester:9-47 ng/ml
  • Second Trimester: 17-147 ng/ml
  • Third Trimester: 55-200 ng/ml

Low progesterone levels are associated with increased risk of miscarriage in the first trimester. There are many forms of treatment or supplementation that help to increase and maintain the production of progesterone. The treatment options listed below are generally followed for the first trimester of pregnancy. Dosages vary based on specific need or deficiency.

  • Intra-muscular progesterone injections-self administered for the first trimester of pregnancy
  • Oral progesterone capsules (standard or sustained release)
  • Progesterone vaginal pressaries
  • HCG-Human chorionic gonadotropin

Immunological causes:

Ankoor clinic recommendations:

If there is history of repeated abortions after cardiac activity seen on USG with:
History of thrombosis of the vessels or premature birth with normal fetal morphology due to severe pre-eclampsia , or severe placental insufficiency.

In such cases the most common cause is immunological, Anti phospholipid antibody syndrome (APS).
In these cases abortions can be avoided by using blood thinning agents in the form of oral tablets (aspirin) or injections (Heparin). Good results are seen after using these agents before and during pregnancy.

How does the immunological disturbance lead to RPL?
Two major categories of immunologic causes of recurrent pregnancy loss are autoimmune, in which the woman’s immune system attacks her own organs and tissues, and alloimmune, in which the immune system attacks tissues considered foreign.

Immunomodulation occurs during pregnancy

The Embryo / Fetal antigens produce two types of antibodies:

  • T Helper I Cell response
  • T Helper II Cell response

 

fetus

 

embryo

Thus, if T helper I cell response is activated it produces harmful cytokines and fetus is rejected.

Exact alignment between binding surfaces of the paternal antigens and maternal antibodies causes activation of the complement cascade leading to abortion of the fetus.

Interferon’s (IFNs) Type I and /or Type II are important in establishing uterine receptitivity to implantation in mammals. Uterine receptivity to implantation is progesterone dependent. Hence IFNs and progesterone activate complimentary cell signaling pathways to modulate expression of genes for attachment of trophectoderm to uterine luminal and superficial glandular epithelia .

What is meant by autoimmune?

An important feature of the immune system is its ability to distinguish foreign (unwanted) material from its own (desired) self. If this ability to distinguish non-self from self fails, then the system produces an immune response against itself (or its own tissues). This is called “autoimmune” disease.

Autoimmune disease or dysfunction may play a role in up to 10% of recurrent pregnancy loss.

Anti-phospholipid syndrome (APS) is the autoimmune dysfunction that is classically associated with recurrent pregnancy loss. APS is associated with pregnancy loss in any trimester, placental thrombosis (blood clots), and small placentae.

There may be thrombosis of the venous (may be unusual sites)/ arterial/small vessel.

Adverse pregnancy outcome in the form of ≥3 consecutive miscarriage (<10weeks), ≥1 fetal death (>10 weeks normal morphology) and ≥1 premature birth (<34 weeks with normal fetal morphology) due to severe pre-eclampsia or severe placental insufficiency are see in Anti-phospholipid syndrome (APS)

In APS there is inhibition of trophoblast function & differentiation. It affects the activation of complement pathways at the maternal-fetal interface resulting in a local inflammatory response. In later pregnancy, thrombosis of the uteroplacental vasculature

The interruption of the circulation to the fetus via these blood clots is a possible reason for the fetal losses. Establishing the diagnosis of APS is important since most of the treatment options involve considerable expense and some added risk. All couples with recurrent pregnancy loss should be screened for APS.

The prevalence of APS in normal population is around 2%, and 30-40% of women with SLE have APS. Around 30% of APS have thrombosis, and up to 30% women with severe early onset pre-eclampsia have APS.

15% women with RPL have APS. Live birth rate without treatment is only around 10%.

The tests that we routinely order include one of the coagulation tests (aPTT) that relies on the activation of the “prothrombin activator complex” and which will be appropriately diluted with normal plasma when abnormal, the anti-cardiolipin antibody test (positive in 2-3% of the general population, 7-45% of women with recurrent pregnancy loss- depending on what level is considered abnormal), and the lupus anticoagulant test (positive in 1-2% of the general population, 10% of women with recurrent pregnancy loss) APS is classically defined as a triad of recurrent pregnancy loss, thrombosis and autoimmune thrombocytopenia (decreased platelet concentration).

For diagnosis of APS there should be persisting presence of either Lupus anticoagulant OR Anticardiolipin antibodies OR β-2 glycoprotein 1 antibodies on separate occasions at least 12 weeks apart.

For those couples with recurrent pregnancy loss, the positive finding (on 2 separate occasions) of either an appropriately performed coagulation based test or a direct antibody test is generally all that is required to propose treatment.

Without treatment, couples with APS have a poor chance of carrying a fetus to term. The worst prognosis appears to occur when there is a prior fetal loss and high anti-cardiolipin antibodies.

Treatment options for APS include:

  • Low dose aspirin (75 mg per day) starting prior to pregnancy.
  • Heparin – We usually use low molecular weight heparin at the dose of 1unit/kg/day. This form of heparin has lesser side effects and is equally effective. However there are some side effects associated with taking these injections which one needs to discuss with the doctor.
  • Prednisone (30-60 mg per day) to suppress the immune system. This corticosteroid can have several potentially serious complications. When given during pregnancy for this indication, prednisone has been associated with preterm premature rupture of the fetal membranes, preterm delivery and pregnancy induced hypertension. This medication should only be given by physicians experienced in its use for this indication and typically in a research setting. We do not routinely recommend this medication.
  • Immunoglobulin (Ig) therapy, with intravenous injections of Igs, has been used for several decades in the treatment of immunodeficiency conditions and more recently in the treatment of autoimmune disorders. The mechanism of action is not known, the dosing is not standardized for recurrent pregnancy loss, and this treatment is very expensive. On the other hand, early experience with this treatment has been very encouraging.
APS without previous thrombosis and recurrent early (Pre embryonic or embryonic) miscarriage Low dose aspirin alone or together with either unfractionated heparin (UH) or LMWH
APS without previous thrombosis and fetal death (>10 weeks gestation) or previously early delivery (<34 weeks gestation) due to severe pre eclampsia or placental insufficiency These women at high risk of thrombosis.Low dose aspirin plus:· Unfractionated heparin (UH) to maintain mid interval aPPT 1.5 times the control.· LMWH (usual prophylactic doses)Heparin / Low molecular weight heparin (LMWH) should be started when Fetal cardiac activity is visualized on USG.
APS with thrombosis Low dose aspirin plus:· Unfractionated heparin to maintain mid interval aPPT in the therapeutic range.· LMWH (usual prophylactic doses)· The anticoagulation should continue six weeks postpartum.

 

What is meant by alloimmune dysfunction?
Alloimmune dysfunction resulting in recurrent pregnancy loss has also been proposed. Allogenic antigens are molecular structures that occur in different members of the same species and have the ability to elicit an immune response. Normally, a person will reject dissimilar (non-self) tissues or structures from the body using the immune system. In pregnancy, the placenta and growing embryo are not entirely “self” but rather are a result of both the maternal and paternal genetic heritages (referred to as a semi-allograft). The placenta (and pregnancy) has a “privileged” relationship with the pregnant woman that allows for it to escape rejection.

The mechanism for this privilege is not known. There have been several interesting and complex theories attempting to describe how the normal pregnancy achieves its privileged status in the maternal uterus. None of these theories has been generally accepted and proven.

The diagnosis of alloimmune recurrent pregnancy loss is one of exclusion. That is, when all other tests have been performed and the findings have come back normal then some of those with “unexplained” losses are thought to fall into this category.

Several physicians refuse to treat alloimmune recurrent pregnancy loss since there are no direct diagnostic tests, treatment options are expensive and their benefits are largely unproven, and treatment options potentially involve risk. The treatment is largely limited to a research facility with expertise in these therapies.
The two main treatment options include unified leukocyte (white blood cell, WBC) immunization with paternal or donor blood cells, using 200-300 million mononuclear cells from the isolated buffy coat of blood, once the woman is pregnant and prior to 6 weeks gestation on one occasion only immunoglobulin (Ig) therapy, with intravenous injections of Igs. The mechanism of action is not known, the dosing is not standardized for recurrent pregnancy loss, and this treatment is very expensive.

Progesterone favours the development of human T helper cells producing Th2-type cytokines and promotes IL –4 production. Progesterone inhibits in vitro embryotoxicTh1 cytokine production in trophoblast in women with recurrent pregnancy loss.

There is modulation of cytokine production by dydrogesterone in lymphocytes from women with recurrent miscarriage. Dydrogesterone inhibits the production of the Th1 cytokines IFN-γ and TNF–α from lymphocytes and up-regulates the production of the Th2 cytokines IL-4 & IL-6 inducing Th1 to Th2 cytokine shift.

 

What are Cytokines ?

Cytokines are secreted molecules that regulate the intensity and duration of the immune response by exerting a variety of effects on lymphocytes and other immune cells. Cytokines are the messengers of the Immune System (Th1 : TNFα,Il-2, Th2 : IL-4, IL-10) just as Hormones are the messengers of the Endocrine System.

Th-1 cytokines trigger thrombotic / inflammatory processes at the maternal uteroplacental blood vessels by activation of vascular endothelial cell procoagulant.

While, Th-2 cytokine inhibit Th-1 induced tissue destruction by monocytes. TNF-β is supposed to suppress the growth of trophoblasts by inducing apoptotic changes in these cells.

Infective causes:

Ankoor clinic recommendations:

Testing for infections like Toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus (ToRCH) and listeriosis screening has been abandoned when investigating recurrent miscarriage. As per WHO (World Health Organisation) there is no role of ToRCH test in current pregnancy. There is importance of only recent infections which can be diagnosed by using IgM testing. If there is recent infection, pregnancy has to be avoided during that time. In case of old infections, IgG will be positive, which shows that the woman had the infection some time back and now has antibodies against that infection. Nothing has to be done.

Testing for Rubella infection, identifies candidates for immunization. This immunization has to be done when the patient is not pregnant. It is advised to avoid pregnancy for 3 months after vaccination.

Can infections lead to RPL?

  • Certain infections have been linked to miscarriage.
  • Genital infections such as bacterial vaginosis may increase a woman’s risk of having a miscarriage.
  • Although any bacterial or viral infections that spread to the uterus may cause sporadic miscarriage, there is no proven infectious cause of recurrent miscarriage.
  • Testing for infections is not routinely done in women who have no symptom of infection.
  • Thus, screening tests for TORCH, ureaplasma, chlamydia, and other infectious agents are not recommended in the evaluation of recurrent miscarriage.

Unexplained causes:

Ankoor clinic recommendations:

In certain cases even after looking for all known causes of recurrent abortions, no etiology can be found. These are called as unexplained abortions / miscarriages.

In such cases there may be an underlying problem at the level of gametes or endometrium.

For eg. They may have male sperm abnormalities. This can be diagnosed by using special tests like DNA fragmentation of the semen or FISH (Fluorescent in situ hybridization) of the semen.

Sometimes there may be subtle abnormalities in the endometrial blood flow. These can be diagnosed using special Doppler ultrasound imaging before and after ovulation.

Advanced maternal age also causes changes in the egg / ovum which may not be picked up by the usual tests.
All these conditions require specialized testing and management.

Medications can be given to improve the gamete quality of both the husband and wife.

Endometrial blood flow and thickness can be improved by giving drugs like sildenafil citrate vaginally along with blood thinners like aspirin, and drugs like pentoxyphylline and estrogen.

What about the male causes for miscarriage?
There is some evidence that defects in the male’s sperm may cause miscarriage. It is not known how often sperm defects are the cause of recurrent miscarriage. Some studies suggest an effect of male age on miscarriage and other suggest the increased DNA damage in the sperm may contribute as well. Further research is needed in this area.

Sperm quality is dependent on the amount of damage to the sperm DNA or DNA fragmentation. DNA is arranged in a double helix or ladder configuration with side rails and rungs. If the rungs are broken, then the ladder is unsteady and will not function properly. Sperm DNA fragmentation has little or nothing to do with the parameters that we measure on the routine semen analysis like the shape of the sperms or whether the sperms are moving. Men with otherwise normal semen analyses can have a high degree of DNA damage and men with what was called very poor sperm quality can have very little DNA damage.

The degree of DNA fragmentation correlates very highly with the inability of the sperm to initiate a birth regardless of the technology used to fertilize the egg such as insemination, IVF or ICSI. Sperm with high DNA fragmentation may fertilize an egg and embryo development stops before implantation or may even initiate a pregnancy but there is a significantly higher likelihood that it will result in miscarriage.
What is the role of endometrial blood flow in RPL?

  • Successful implantation depends on a close interaction between the blastocyst(developing embro) & receptive endometrium.
  • Each month the human endometrium undergoes a series of distinct cyclical changes in preparation to receive the developing blastocyst.
  • Such changes need well controlled dynamic remodeling of endometrial micro vasculature through the process of angiogenesis & arteriogenesis.
  • Adequately prepared endometrium required for successful implantation.
  • Endometrial development regulated by steriod hormones various growth factor & cytokines.
  • Some of these factors need to be transferred to the endometrium.
  • For this it is essential that adequate blood supply should reach the functional layer of the endometrium.
  • Endometrial and subendometrial vascularity is significantly higher in pregnant patients with live birth following stimulated IVF treatment than in those who suffered a miscarriage.
  • Various studies concluded that Unexplained infertility is associated with a profound impairment of endometrial perfusion that might be amenable to treatment by perfusion enhancers.
  • Some drugs like aspirin, glyceryl trinitrate, angiogenic growth factors & sildenafil citrate have shown good effect on endometrial perfusion.

What if the cause remains a mystery?
Up to 50 % of couples with RPL fail to reveal a cause even after testing. For women with unexplained RPL, empirical treatment with low-dose aspirin, prophylactic doses of low-dose heparin or both have shown to give better results.

Specialists may suggest reasonably safe forms of therapy that may prove helpful, such as low-dose aspirin and/or progesterone. Sometimes patient are also given a try with promising investigational treatment like intravenous immunoglobulin (IVIG). It is a drug which is used to treat many immune disorders and has been found to be useful in RPL by some studies.

Ankoor clinic recommendations:

Apart from this, lifestyle changes such as good diet, weight loss, exercise are highly advocated.

What is needed many a times is repeated assurance, motivation and encouragement by the treating fertility specialist as well as the family members.

Stress reduction therapies such as meditation, yoga, acupuncture etc have also helped some women. (These have been discussed in details in other section.) Understanding and support from health care professionals and family members will keep the woman motivated and will restore her self esteem.