The Continuing Spectrum of Infertility and RPL

Recurrent Pregnancy Loss (RPL) occurs during the first trimester in 85% of the cases. It is defined as loss of two or more clinical pregnancies, prior to 20 weeks, confirmed by either ultrasound imaging or histopathological examination. Currently, biochemical as well as ectopic pregnancies are not included. However, they often co exist with RPL and we should standardize the criteria for diagnosing biochemical pregnancies prior to including them in the definition of RPL.

RPL is multifactorial with diverse etiological factors, like anatomical, immunological, infective, endocrinal, genetic and unexplained. It is best understood as

• Embryocentric – genetic abnormalities of the embryo
• Uterocentric – anatomical, immunological and infective

There are three kinds of patient subgroups:

• Hyperfertilie - They frequently achieve spontaneous pregnancies, therefore, have a high number of miscarriages. However, if these patients are subjected to repeated evacuations, they may end up with a damaged endometrium and subfertility.
• Subfertile – they usually have long inter-pregnancy intervals and often resort to ART procedures
• Infertile group – Present primarily with infertility but have recurrent implantation failure (RIF), biochemical pregnancies or miscarriages, post treatment

Hence, it has been suggested that the time to live birth from the intent of pregnancy is also important and should be considered, rather than just the number of miscarriages alone.

Factors causing both infertility and RPL are listed below

Uterine causes

• Uterine anomalies like septate uterus
• Intramural and submucous myomas
• Intrauterine adhesions
• Adenomyosis
• Chronic endometritis

Ovarian factors

• Endometriosis
• Poor ovarian reserve

Sperm factors

• Teratozoospermia
• Increased DNA fragmentation

Tubal factors

• Hydrosalpinx
• Intratubal adhesions

Immunological factors

• APLA syndrome
• Autoimmune diseases - SLE, Coeliac disease & Rheumatoid arthritis

Infective causes

• Latent genital tuberculosis

Endocrinal causes

• Polycystic Ovarian syndrome
• Thyroid antibodies and disease
• Luteal phase deficiency
• Hyperprolactinemia
• Uncontrolled Diabetes mellitus

Life Style factors

• Obesity, smoking, alcohol, recreational drugs and intense exercise.

When the abnormality is severe, there will be infertility, where as mild abnormality results in miscarriage.

Patients with RPL may present with the following:

• Biochemical pregnancies,
• Implantation failure during IVF cycles,
• Intrauterine growth restriction,
• Oligohydramnios
• Pre eclamptic toxaemia
• Intrauterine death / Stillbirth

Established treatment modalities are:

• Controlling the endocrine milieu
• Treating endometritis and latent infections
• Optimizing the uterine cavity with hysteroscopic surgery
• Suppressing/ enucleating adenomyoma / endometriosis
• Endometrial evaluation –vascularity, receptivity assay (ERAS)
• Uterine artery Doppler flow studies in mid luteal phase
• Diagnostic IVF / PGS cycle to evaluate the embryos
• Steroids / Intralipid / Intravenous immunoglobulin administration in autoimmune causes

Newer treatment modalities to increase endometrial cytokine production, thereby improving implantation rates, are being tried for both RIF and RPL. These include

• Endometrial scratching
• Administration of Granulocyte Colony Stimulating factor
• Platelet rich plasma
• Stem cells derived from bone marrow / adipose tissue

They appear to hold promise but we await results of randomized controlled trials.