These are mainly chromosomal abnormalities which are seen on average in:

• 50 - 70%  in first trimester loss
• up to 30% in second trimester loss
• 3 - 5% in third trimester loss
• 0.5% of live birth

Problems with the pregnancy environment

Historically cervical incompetence was the most suspected anatomical cause of repeated second trimester miscarriages though the evidence has not always been overwhelming. It is defined as inability of the cervix to support a pregnancy to term due to functional or structural defects. It is prevalent in 0.2 % of the general obstetric population but in 8% of women with history of previous midtrimester miscarriages. Animal studies documented defective tensile strength of the cervix due to rearrangement or disorganisation of the collagen fibres.

Unfortunately there is no objective diagnostic test to be done in-between pregnancies and clinical suspicion is most important as hysterosalpingography and painless passage of size 8 dilator into the cervical canal are not reliable.   

However during pregnancy 3 ultrasound scan criteria are used to help with the diagnosis. Transvaginal scan examination gives good quality images and hence helps more with the diagnosis. The 3 criteria are: 

• A short cervix is a good parameter to use. Shortening of te cervix during repeated examinations could follow increased uterine muscle activity or inherent cervical disease. 
• Dilated internal cervical os leading to the characteristic ultrasound funnelling effect. Together with the short cervix they could facilitate ascending bacterial infection which could weaken the exposed membranes.
• Prolapsed membranes  

Uterine anomalies both major and minor are prevalent in 7-8% of fertile women and in more than 25% of women with recurrent miscarriages. However major anomalies prevalence was estimated to be 3% in fertile and infertile women but 5-10% in patients with recurrent miscarriages. Uterine anomalies are related to mullerian ducts  complete or partial failure of fusion or failed canalisation.

A summary of the reproductive performance of women with uterine anomalies is as follows:

• Arcuate uterus with a concave upper cavity of < 1 cm intrauterine indentation has no impact though contradictory reports have been published suggesting more second trimester and pre term delivery with this anomaly.
• A septate uterus has 25.5 % risk of miscarriage but its impact on infertility is less known. With continued pregnancy there is increased incidence of of malpresentation and caesarean section rates. After incision of the septum there is 2-3 fold improvement in pregnancy outcome but it does not improve pregnancy rates in infertile patients.
• A bicornuate uterus is associated with slightly increased risk of second trimester miscarriages and preterm deliveries problably due to an associated cervical incompetence. It is not recognised as a cause of first trimester pregnancy loss and does not cause infertility. Unlike the septate version surgical treatment is not usually indicated and might be resorted to as a final option. Follow up of the patient with serial transvaginal ultrasound scan examinaions for early detection of cervical incompetence and insertion of a cerclage is the first line of management. Should reconstructive surgery be indicated, it should be transabdominal or laparoscopic but not hysteroscopic. 
• Didelphic uterus is associated with 20% miscarriage rate and 24% preterm delivery rates.
• A unicornuate uterus has significant effect on reproduction due to abnormal uterine vasculature and decreased muscle mass. The ectopic rate is increased to 4.3%,   miscarriage rate 34.4%, preterm labour 43.3% and live birth 54.2%. Moreover there is a high caesarean section rate with this abnormality due to malpresentation and abnormal uterine contractions. It has a banana shape cavity on transvaginal ultrasound scan examination. 

Coronal view of arcuate uterus	Coronal view of a  septate uterus	Coronal view of a sub septate uterus	Unicornuate uterus after saline infusion	Grey scale 2D view of double uterus

 Fibroids

 

The presence of submucous fibroids is widely accepted as a cause of recurrent pregnancy loss. As well recent research showed that relatively large intramural fibroids [> 4 cm in diameter] could compromise reproductive performance.  Lower implantation rate following IVF has been described in such cases even without involvment of the uterine cavity. The best way to assess how much the cavity is affected by a fibroid is through saline infusion sonohysterography which would show how much of the fibroid extends into the uterine muscle as well. This is an important information which could not be asecertained with hysteroscopy yet it is important for deciding the best surgical approach to remove such fibroids.

  

Coronal view of a uterus with a submucous fibroid	A submucous fibroid as seen hysteroscopically

 

Intrauterine adhesions

 

These are scar tissues which form inside the uterus as a result of infection or previous surgery. They could complicate any surgery involving the uterine cavity especially evacuation of retained products of conception. They could reduce or stop menstrual blood loss, cause infertility or repeated miscarriages. Usually patients give history of such procedures during consultation.  As well saline infusion sonohysterography is the best method for diagnosing intrauterine adhesions. In severe cases and with apical synechiae obstructing the isthmic part the uterine cavity would fail to distend with the fluid.  

Intrauterine adhesions shown as filling defects  disturbing the cavity after SIS	Intauterine adhesions with a fibroid seen  hysteroscopically

Large endometrial polyps

These are tumours of the basal endometrium with fibrous stroma and central blood vessels. Large polyps could compromise early pregnancy and would need to be removed.

   

Endometrial polyp in a sagittal view of the uterus	Large endometrial polyps

  

---

2.  Hormonal factors

These are not as common as they were thought to be few years ago. Inadequate luteal phase was thought to be an important factor but treatment with progesterone failed to show significant effect in preventing recurrent miscarriages. The same was true for repeated injections of hCG to stimulate the corpus luteum. Studying luteal serum progesterone level is not helpful in the diagnosis of management of this problem. Even endometrial bipsies which were considered to be most diagnostic of indaquate luteal phase have been shown to be unreliable. Parous women with no fertility issues were shown to have endometrial biopsies 2 or more days out of phase.

 

However certain endocrine problems are important in causing pregnqancy loss but they are usually clinically manifest beforehand. Thyroid problems could be related to pregnancy loss but only when the condition is very severe. The presence of thyroid antibodies without manifest hormonal defects has no bearing and the patient should not be treated accordingly. 

 

Similarly diabetes mellitus is not a risk factor by itself unless it is  not well controlled. However patients should be advised not to get pregnant unless the HBA1c level is < 7.5%.

 

On the other hand the increased risk of pregnancy loss with PCOS is thought to be related to high levels of insulin and androgens but not to luteinising hormone. High androgens levels have been shown to affect both oocyte quality and endometrial receptivity. Reduction of LH level by GnRH analogues did not improve miscarriage rate in women with high LH.  On the other hand metformin which is a category B drug has been found to reduce the miscarriage rate in patients with PCOS and insulin resistance. Accordingly its use during the first trimester should be considered and discussed with patients with PCOS who had repeated pregnancies loss.

 

---

3. Immunological factors

 

Different immunological problems are being implicated as important causes of recurrent miscarriages and different investigations and treatment protocols are being used to address them. Two main theories have been put forward to explain how these factors could affect pregnancy outcome:

• Impairment of ‘angiogenesis’ or development of blood vessels leading to occult or very early miscarriages.
• Increased clotting in preformed placental blood vessels leading to miscarriage and late pregnancy loss .

Thrombophilia with hypercoagulable conditions could be due to congenital defects in the colagulation pathway resulting in increased thrombin formation. The most common defects include mutation in factor V Leiden, a mutation that results in resistance to activated protein C which is necessary to control thrombin formation. Prothrombin gene mutation and hyperhomocysteinaemia are also common. Less frequent causes include protein S, protein C and antithrombin deficiency.

 

Autoantibodies to phospholipids are responible for the well known antiphosphplipid syndrome. It is associated with both early and late pregnancy loss including early miscarriages, stillbirth and neonatal death. Furthermore it has non-reproductive effects secondary to the increased coagulation tendency associated with the syndrome. 

 

It is important not to forget the role of endometrial receptivity and blood flow in the uterine artery and subendometrium in facilitating or hindering implantation of embryos. An adverse immunological effect on the uterus could lead to a thin endometrium with low uterine and subendometrial blood flow. Recent research showed that even at 4-5 weeks gestation age uterine artery resistance index was higher in women who had recurrent miscarriages than a control group. This was suggestive of the detrimental effect of poor uterine perfusion at such an early stage.  

 

Women with recurrent miscarriage were reported to have high peripheral and endometrial natural killer cells or activity and reduced expression of alpha-1 and -4 integrins in their blood vessels, high T-helper-1 and low T-helper-2 cytokines and reduced concentration of endometrial proteins glycodelin and MUC1. These are examples of the vast load of literature building up in this field in addition to the antiphosphplipid syndrome effect.

 

A personal or family history of autoimmune problems might be present including thyroid disease, rheumatoid arthritis, endometriosis or even repeated pregnancy wastage .

---

 

 4. Life style issues  

This is a vague area which is difficult to measure. However maternal smoking, use of illicit drugs and excessive alcohol intake are known to increase the risk of pregnancy loss. Few other environmental factors are incriminated with no good evidence. However tetrachloroethylene which is used in dry cleaning and accutane need special mentioning here.

 

Body weight extremes have also been associated with adverse pregnancy outcome. Accordingly women should be advised to follow a healthy life style with healthy dieting and excercise to attain a BMI as near to normal as possible before getting pregnant.

 

Few years ago pelvic infection was considered an important cause of repeated miscarriages. This view is no longer valid and routine detailed investigations for this entity are not warranted. However infection could contribute to sporadic miscarriages. This could be caused by such organisms as toxoplasmosis, bacterial vaginosis, primary infection with rubella and cytomegalovirus. On the other hand untreated endometrial ureaplasma infection could be associated with repeated miscarriages. Syphilis should not be forgotten as a cause of second trimester miscarriages in certain areas of the world.

  

---

 

Management

 

A structured investigation programme is needed to make a diagnosis before offering any form of treatment. This would include a detailed medical history and examination. Tailored investigations would include the following: 

 

Transvaginal scan examination and Saline Infusion Hysterography would be necessary to exclude all the anatomical causes mentioned above. A monitored cycle with Doppler studies would help in documenting the maximum thickness of the endometrium and the echogenic pattern just before ovulation. As well Doppler studies of the uterine artery and subendometrial blood flow would give valuable information as to the perfusion of the endometrium necessary for adequate receptivity. All these tests are designed to reflect endometrial receptivity which is defined as the maturation state of the endometrium at the time of blastocyst implantation. This is a simplistic way of assessing the complex interaction between the endometrium, ovary and embryo which results in increased endometrial vascularity and oedema, enhanced glandular secretions and development of pinopodes on the luminal epithelium at the time of blastocyst implantation.

 

Endocrine tests would include day-3 of the cycle FSH, oestradiol and inhibin B to test for the ovarian reserve. This could be supplemented with transvaginal scan examination to measure the volume of the ovaries and to count the number of antral follicles in each ovary. Occasionally early follicular scan examination could reveal rapid recruitment of multiple follicles which is a biological evidence of incipient ovarian failure especially in women with short follicular phase. Recently anti-mullerian hormone assessment bacame available as a more reliable measure of ovarian reserve. Unlike FSH or inhibin it does not need any special timing during the cycle. Patients with very low ovarian reserve produce low quality eggs liable to pregnancy failure if fertilised and implanted. For patients with a suspected PCOS diagnosis the profile would include fasting insulin and glucose, LH, testosterone and SHBG.