Recurrent Pregrnancy Loss

Recurrent Pregnancy Loss (RPL) or habitual abortion or recurrent miscarriage was defined as three or more consecutive miscarriages before 20 weeks gestation but recently the ASRM updated the definition of RPL to 2 or more clinical pregnancies losses documented by either ultrasonography or approved in a histopathologic examination.
About 1% of couples trying to have children are affected by recurrent miscarriage.

There are various causes for recurrent pregnancy losses but about 50-75% cases are unexplained.

I. Uterine Conditions - A uterine malformation is considered to cause about 15% of RPL. The most common abnormality is a uterine septum a partition of the uterine cavity. Also bicornuate or unicornuate uterus may result in RPL. Also uterine fibroids could also result in recurrent pregnancy losses besides polyps, intrauterine adhesions etc.
II. Cervical Factors - In the second trimester a weak cervix can become a recurrent problem. Such cervical incompetence leads to premature pregnancy losses or preterm deliveries.

I. Translocations - Parental chromosomal anomalies account for 2-4% of RPL in couples. Translocations are the most common aberrations, followed by inversions, insertions and mosaicism.
II. Aneuploidy - Aneuploidy may be a cause of a random spontaneous as well as recurrent pregnancy loss. Aneuploidy is more common with advanced reproductive age reflecting decreased germ cell quality.

Endocrine abnormalities affect both the implantation and maintenance of an embryo, and are the source of 17-20% of all RPL.
I. Women with hypothyroidism are at increased risk for pregnancy losses.
II. Unrecognized or poorly treated diabetes mellitus leads to increased miscarriages. Diabetes mellitus must be evaluated in patients with RPL using HbAIC since uncontrolled DM increases the risk for foetal loss. However, once controlled DM is no longer a risk factor for RPL.
III. Women with polycystic ovary syndrome also have higher loss rates possibly related to hyperinsulinemia or excess androgens.
IV. Inadequate production of progesterone in the luteal phase may also result in RPL.

Thrombophilia may explain upto 15% of recurrent miscarriages. The most common problem if Factor V Leiden and prothrombin G20210A mutation. Other thrombophilia's include prothrombin gene mutation, protein C deficiency, protein S deficiency and antithrombin III deficiency.

A common feature of immune factors in causing recurrent pregnancy loss appears to be a decreased maternal immune tolerance towards the fetus.
Antiphospholipid Syndrome - Around 15% of the women who have recurrent miscarriages have high levels of antiphospholipid antibodies. The clinical criteria for the diagnosis of Antiphospholipid Syndrome (APS) include the following:
I. Three or more consecutive unexplained miscarriages before the 10 wk of gestation.
II. One or more unexplained death of a morphologically normal fetus at 10 wks of gestation or later.
III. One or more premature births of a morphologically normal fetus at 34 weeks of gestation or earlier, associated with severe preeclampsia or placental insufficiency. Women Diagnosed with antiphospholipid syndrome generally take asperin or heparin in subsequent pregnancies.
Thyroid antibodies - Anti-thyroid autoantibodies are associated with an increased risk of recurrent miscarriage. The most prevalent thyroid autoantibody is thyroid peroxidase (TPO) antibody.
Increased uterine NK cells - Natural Killer cells are a type of white blood cells present in uterine tissue. High levels may be linked to recurrent losses but these levels are not the actual predictors of pregnancy loss in women who have not had a miscarriage.
Parental HLA sharing - Inconclusive studies.
Male specific minor histocompatibility - Immunization of mother against male specific minor histocompatibility (H-Y) antigens has a pathogenic role in many cases of secondary recurrent miscarriage occurring after a previous normal live birth.

Luteal Phase Defect -
Luteal Phase Deficiency (LPD) is affected by several factors including stress, exercise, weight loss, hyperprolactinemia and menstrual cycles at the onset of puberty or perimenopause; however the exact mechanism for this disorder is unclear. The theory behind the concept suggests that an inadequate amount of progesterone is produced by the corpus luteum to maintain the early pregnancy. LPD can be diagnosed by measuring serum progesterone or by performing an endometrial biopsy. Luteal phase serum progesterone levels between 2 - 10ng/ml and serum progesterone levels below 15ng/ml in the first 10 weeks of gestation are considered diagnostic of corpus luteum dysfunction.

Smoking, alcohol and caffeine are three of the most common environmental factors associated with single spontaneous abortion. In addition, obesity may have a role in the field of RPL due to its increasing prevalence and association with PCOS, type II diabetes mellitus and hormone abnormalities.

A number of maternal infections can lead to a single pregnancy loss, including listeriosis, toxoplasmosis and certain viral infections (rubella, herpes simplex, measles, cytomegalic virus, cox sickie virus). However, malaria, syphilis and brucellosis can cause recurrent miscarriage. Chronic endometritis due to common bacteria has been found to be prevalent in some women with a history of recurrent miscarriage. Unexplained RPL -
Although it is commonly recognized that unexplained RPL (uRPL) occurs in about 50% of all RPL, but they can be separated into two groups -
I. Type 1: RPL actually due to chance alone.
II. Type 2: Truly unexplained RPL includes younger women with clinically diagnosed pregnancy losses and normal karyotypes in POC

1. Transvaginal ultrasonography for assessment of early pregnancy
2. In non-pregnant patients
a) Karyotyping for both the partners
b) Blood tests for thrombophilia
c) Ovarian function tests
d) Thyroid function test
e) Test to rule out diabetes

If the likely cause of recurrent pregnancy loss can be determined treatment is to be directed accordingly.
a. In pregnant women with a history of recurrent miscarriage, anticoagulants may increase the live birth rate in patients with antiphospholipid syndrome and perhaps those with congenital thrombophilia
b. In many women with chronic endometritis, fertility was restored after appropriate antibiotic treatment
c. In certain chromosomal problems, invitrofertilization with preimplantation genetic diagnosis may be able to identify embryo with a reduced risk of another pregnancy loss which then would be transferred. There are currently no treatments for women with unexplained recurrent pregnancy loss. The majority of patients are counselled to try to conceive again, and chances are about 60% that the next pregnancy is successful without treatment. However, each additional loss worsens the prognosis for a successful pregnancy.

Close surveillance during pregnancy is generally recommended for pregnant patients with a history of recurrent pregnancy loss.

Every miscarriage is accompanied by a feeling of loss, loss of the fetus, loss of confidence in the integrity of the body and its ability to give birth.
It has been found that about 40% of women after a miscarriage will suffer from symptoms of bereavement. About 43-70% would suffer from repeated bouts of mild to severe depression during the 6 months after a pregnancy loss.
RPL evokes a variety of responses such as anxiety, depression, denial, anger and a feeling of bereavement and loss. The health care system needs to respond to these problems and recommend emotional counselling to these RPL women without the harmfulness of a diagnosis of mental illness.

Recurrent miscarriage in itself is associated with later development of coronary artery disease, cardiovascular complications etc
Women with a history of RPL are at risk of developing preeclampsia in later pregnancies.