Recurrent Pregnancy Loss-Distressing Condition

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RECURRENT PREGNANCY LOSS

INTRODUCTION

Miscarriage is defined as loss of pregnancy before the foetus reaches viability.Recurrent  loss is defined as loss of three or more consecutive pregnancies , it affects 1% of couple trying to conceive( RCOG). When the cause is not known, each pregnancy loss needs careful review to determine where specific evaluation is appropriate and more than two losses needs thorough evaluation.

WHAT COULD BE THE CAUSE?

-Genetic & Chromosomal Factors    (Role of sperm , oocyte and embryo)

-Uterus and Cervical Factors

-Endometrial Factor-Immunological Factor

-Epidemiological Factor

-Infective Factor

-Medical Factor

-Environmental Factor

GENETIC AND CHROMOSOMAL FACTORS

In couples with recurrent miscarriage chromosomal abnormalities of embryo account for 30-57% of miscarriage. In 2-5 % cause of miscarriage one of the partner carries a balanced structural chromosomal anomaly mostly Balanced reciprocal or Robertsonian translocation.Aneuploidy of conceptus is responsible for upto 50% of early pregnancy loss. Risk of aneuploidy increases with both maternal and paternal age. To understand this we need to understand the role of Sperm, Oocyte and Embryo.

SPERM

Male partner also contributes half the genetic material of embryo, so evaluation of paternal factor is necessary for insight in RPL. Assessment of sperm  DNA fragmentation should be done. Sperm DNA can be susceptible to oxidative damage and increase sperm DNA fragmentation may lead to abnormal embryonic development. Incase of high SDF , IVF with ICSI can help rather than conventional Insemination. In couples with RPL 2.7 times rate of sex chromosomes aneuploidy and 3-6 times rate of chromosome 13,18 &21is there.Sperm sorting can be done for optimal sperm function from ejaculate or testicular biopsy.  Several techniques include Microfluidics: which uses small fluid streams to sort cells.Magnetic activated cell sorting(MACS): Uses magnetic charged water column for sorting antibody cell surface antigen tagged cells during fertilisation which plays vital role in embryo development .Fluorescent activated cell sorting (FACS):Fluorescent labelled cells are sorted based on scattering from laser source.Spermatozoa provides genetic and epigenetic materials during fertilisation which plays vital role in embryo development. Certain epigenetic signature may be associated with altered fertilisation and embryogenesis. These include nuclear protein composition , DNA methylation and spermatozoa RNA`s.In mature sperm nearly 90% of histone proteins are replaced with protamines that protect with oxidative DNA damage and assist in sperm motility. Histone modification and retention at deliberate location through sperm genome may impact fertilisation and embryogenesis.Methylation is important for silencing transcription at certain points in spermatogenesis. Sperm RNA plays important role in regulating gene expression in embryo.

OOCYTE

Oocyte abnormality can be intrinsic and functional. Both can cause problem to developing foetus. Most of intrinsic problem can be genomic. These include single gene mutation , insertion, deletion, structural rearrangement or abnormal genetic complement ( trisomy or monosomy). Since these are intrinsically abnormal, there is high risk for repetitive abnormality in conceptus. Structural abnormality of chromosome may also produce intrinsically abnormal oocytes and predisposing too infertility. One in eight couples with RPL has chromosomal rearrangement including inversions and balanced rearrangements. 40 % of the rearrangement cannot be detected in karyotype.Mitochondrial abnormal both number and function can lead to oocyte abnormalities.Quantitative high density assessment of parents genome is necessary which includes high density single nucleotide polymorphism arrays or genomic sequencing with quantitative analysis.

EMBRYO

Most prevalent abnormality in embryo is Mosaicism. Whole chromosome mosaicism occurs in 25% of cases and segmental mosaicism occur in 7-10% of embryo. Balanced translocation is also seen in 4-8% of couples with RPL. It can be either Reciprocal or Roberstonian translocations. In such cases PGT-M combined with PGT-SR to determine if embryo is balanced or normal allowing selecting embryo which will produce healthy offspring and eliminating translocation to pass to future generation.

UTERINE AND CERVICAL FACTOR

Congenital uterine anomaly is associated with 7-28% of cases of RPL. This includes Septate, Arcuate or Bicorpeal uteri. Acquired uteri anomaly include submucosal myomas, Intrauterine adhesions, Endometrial Polyps.In Congenital malformations Septate uterus is the most common malformation  it occurs in 6-16% of cases. It occurs due to failure of resorption of medial septum. It can be arcuate or septate uterus depending upon indentation of medial septum from 10-15mm. Miscarriages occur due to inadequate implantation of embryo on poorly vascularised septum.Fibroids are associated with infertility due to implantation failure. Fibroids are classified according to the position submucosal, intramural or subserosal. Fibroids lead to alteration in anatomy of uterine cavity, leads to chronic endometrial inflammation, abnormal vascularisation, increase uterine contractibility  and abnormal endometrial pattern. Submucosal fibroids have strongest association with low pregnancy rates. Intramural fibroid are also related to increased risk of RPL where myomas are more than 4 cm.Presence of endometrial polyp related to RPL ranges from 1.6-6 %. It can interfere with pregnancy due to mechanical interference and release of molecules with relevant evidence of increased level of inflammatory markers. There is reduced level of HOXA 10 and mRNA.Intrauterine adhesions referred as Ashermans Syndrome characterised by fibrotic tissue developing from opposing walls of uterine cavity or cervix that alter the quality of endometrial mucosa. It occurs mainly due to uterine curettage, infection, intrauterine surgery, post obstetrical complication mostly due to retrained fragments of placenta. It can also occur post hyteroscopy , myomectomy and lysis of adhesion.

Cervical weakness is a recognised cause of 2nd trimester miscarriage where spontaneous rupture of membrane or painless cervical dilatation occur.

ENDOMETRIAL FACTOR: ENDOMETRIOSIS, ADENOMYOSIS & CHRONIC ENDOMETRITIS

ENDOMETRIOSIS

It is estsrogen dependent chronic condition defined as presence of ectopic endometrial like tissue causing local inflammatory response and pain leading to infertility. Endometriosis affects 40% of patients with infertility and has been associated with poorer ART outcomes including decreased yield of mature oocyte and lower implantation rate and decreased pregnancy rate. RPL results due to different mechanism:Toxic pelvic factors altering oocyte quality through direct and persistent effect on gametes and and embryo during temporary exposure while passing through distant segment of fallopian tube . This can also increase the risk of embryo aneuploidy.Secondly it can cause inflammatory dependent alteration of ectopic endometrium. This results in altered endometrial changes during window of implantation, impaired predecidual transformation and ultimately defective placentation. These can lead to early pregnancy loss and RPL.

ADENOMYOSIS

It is defined by presence of endometrial glands and storms developing in myometrium. It causes inflammatory process within ectopic endometrium including cellular and biochemical alterations. Adenomyosis can alter the normal response to progesterone. It can led to progesterone resistance  and decrease progesterone receptors and methylation defect. HOXA 10 Gene is also decreased in endometrium and there is increase in inflammatory markers. The uterine contractility and endometrial peristalsis can lead to implantation disorder and defective deep placentation and interim miscarriage and RPL. There is also thickening of junctional zone in Adenomyosis and this causes altering in pregnancy chances and and placentation quality and there by increasing the risk of miscarriage.

CHRONIC ENDOMETRITIS

Chronic endometritis is persistent slight inflammation of endometrial lining . CE can lead to altered uterine contractibility and irritability of uterine wall at moment of implantation may improve receptivity.

EPIDEMOLOGICAL

Advanced Maternal age is associated with decline in number and quality of oocytes.

Age related risk (RCOG)

12-19 years  – 13%

20-24 years  – 11%

25-29 years  – 12%

30-34 years  – 15%

35-39 years  –  25%

40-44 years  –  51%

> 45  years   – 93%

Advanced Paternal age is also identified as risk factor. Risk of miscarriage is more in woman >35 yrs and man >40 years.

ENVOIRNMENTAL

Exposure to certain chemicals ,drugs, X-ray may also increase the risk of miscarriage. Some factors are work related and some can be due to sedentary life styleExcess of alcohol , caffeine  and smoking either active or passive can affect pregnancy outcome.Obesity can also be reason for miscarriage

INFECTIVE

Any severe infection that leads to bacteria or viraemia can lead to miscarriage. Certain bacterial infection like Mycoplasma, Hominus, ureaplasma and chlamydia have been identified mostly in individuals with miscarriage. Though role of infection in RPL is unclear.

IMMUNOLOGICAL

DM &THYROID

Systemic maternal endocrine disorder such as Diabetes Mellitus and Thyroid disease have been associated with miscarriage. Women with diabetes who have HbA1C levels increased in first trimester has increased risk of miscarriage and foetal malformation . But well controlled DM and thyroid is not a risk of recurrent miscarriage. Antithyroid antibodies are also linked to miscarriage.

PCOS

PCOS has been linked to increased risk of miscarriage but exact mechanism is unclear. It is basically attributed to insulin resistance , Hyperinsulinemia and Hyperandrogenemia.

APLA

APLA are present in 15% of women with recurrent miscarriage . Antiphospholipid antibodies – lupus anticoagulant, anticardiolipin antibodies and beta 2 glycoprotein antibodies.

Adverse outcomes include:1) Three or more miscarriages before 10 weeks of gestation.

2) One or more morphological normal foetus after 10 weeks of gestation

3) One or more preterm births before 34 weeks gestation owing to placental disease .

Mechanism by which APLA causes pregnancy morbidity are:-Inhibition of trophoblastic function and differentiation-Activation of complement pathway at maternal foetal interface resulting in local inflammatory response  and in later pregnancy thrombosis of placental vasculature.

THROMBOPHILLIA

Pregnancy itself is a prothrombotic state and pregnant patient are even at higher risk of complication when thrombophillia is present.Many factors contribute to this hyper coagulable stateincrease in clotting factors (VII,VIII,X,Von Willebrand factor and fibrinogen)Decrease in anticoagulant activity(Protein S and acquired protein resistance)There is reduction in fibrinolytic activity . These changes are accompanied by venous stasis in the lower extremities and so results in five fold increase in venous thromboembolism during pregnancy. Inherited Thrombophillia are caused by genetic mutations and acquired Thrombophillia  is associated with APLA syndrome.

MATERNAL ADOPTION TO FOETUS

Uterine NK cells are associated with the establishment of normal early placentation through vascular remodelling at the end of implantation process. This altered vascular conversion and insufficient invasion of the uterine lining by trophoblast have been considered the primary defects in pre-eclampsia and also contribution to RPL. However excessive invasion can also lead to risk like placenta accreta.

DIAGNOSIS AND TREATMENT OF RPL

A couple with history of RPL should undergo through evaluation and testing. Each miscarriage history should be taken including time to conception, gestation age when loss occurred, Any data from USG or genetic testing of foetus. History of previous pregnancy that where viable, H/O uterine surgeries, h/o irregular menses, h/o medical illness/endocrine abnormality or any gynaecological surgeries.

Every couples history should be taken regarding exposure to previously or ongoing to chemical or environmental toxins any history of arterial or venous thrombosis.

In case of APLA syndrome it is mandatory that women have 2 positive tests at least 12 weeks apart for either lupus anticoagulant or anticardiolipin antibodies of Immunoglobulin G or Immunoglobulin M present in medium to high titre over 40g/l or above 99th percentile . They should be considered for treatment with low dose aspirin plus heparin to prevent further miscarriage.

In case of congenital anomalies both hysteroscopy and laparoscopy remains the gold standard for diagnosis of uterine malformation.Pelvic MRI may be helpful in complicated cases associated with complex anatomical defects like rudimentary cavities. Hysteroscpic metroplasty is common in case of uterine septum.

First line diagnosis of uterine fibroid is USG. MRI can also be done to find number of myomas ,size, relationship to serial surface but its expensive diagnostic tool. Submucosal fibroids can be resected by hysteroscopicaly. Intramural Fibroids can be removed either laprocopicaly or abdominal approach.

According to ESHRE & ASRM polyp can be removed by hysteroscope.Intrauterine adhesions can be removed by hysteroscopic adhesiolysis , physical barrier or intrauterine foleys catheter to prevent reoccurrence.In case of

Adenomyosis gonadotropin releasing hormone analogues are given to reduce the thickness of junctional zonne  to help in future pregnancy.

In case of chronic endometritis histology is gold standard . It  can be treated with oral antibiotics.

In case where their is chromosomal rearrangement or abnormality is there genetic counselling should be considered. So these are some causes and its related treatment to distressing condition of RPL.

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