Immunological Causes

Immunological Causes

 

Alloimmune Etiology : The conceptus acquires genetic material from both its parents. Thus the conceptus inherits and express on the surface of its cells its father’s histocompatibility antigens that are foreign (i.e., allogeneic & alloantigenic) to the mother.

Defence mechanisms

The pre-implantation embryo expresses only low levels of paternal histocompatibility antigens. Which include products of major histocompatibility gene compress such as HLA and non-MHC or minor histocompatibility (H) transplantation antigens. (65).

(i) This pre-implantation embryo is protected by its small size which reduces the probability of encounter with any maternal effecter cells that have strayed into tubal or peritoneal fluid.

(ii) by lack of direct contact with lymphatic-containing, maternal tissues

(iii) by its zona pellucida which is shed just before implantation. (66)

However if cells such as macrophages in tubal or peritoneal fluid become activated-secretion of cytokenes such as interleukin-1, tumor necrosis factor alpha and granulocyte macrophage colony stimulating factor (GM-CSF) can lead to embryo damage and ... failure may occur e.g. in endometrosis (67-69).

Radio graphic contrast dye used for HSGs may paralyse activated macrophage sand this might explain why some couples unexpectedly achieve pregnancy after-this type of investigation.

At the time of implantation expression of H antigens is shut off so that only embryonic antigens are expressed.

During first 5 post implantation days, there is re-expression of minor paternal H antigens followed on the fifth post-implantation day by MHC expression (65, 70). There’s paternal MHC expression on the human embryo from 6-20 days post implantation (71) and this is confirmed by immuno-histological study of first trimester embryos (72).

The conceptus is in fact 2 grafts in one. The fetal tissue (graft # 1) is enclosed within a sac of membranes lined by fetal trophoblast cells that form the feto-maternal interface and placenta. Conceptus behaves in a manner different from conventional allgrafts and this is primarily due to its trophoblast (graft # 2).

Fetal trophoblast is a unique tissue the development of which is dependent upon presence of paternal genetic material. Where the genes of the trophoblast are entirely paternal, Hydatidiforcce moles and choricarcunoma can develop (73). These neoplastic growths are not rejected by the female even when high levels of paternal HLA antigen are expressed by the tumor. (74).

Trophoblast may be divided into

(1) Non MHC expressing cells founds primarily at the interface between the fetal placental capillaries and maternal blood (75-76).

(2) MHC expressing interstitial and chorionic membrane trophoblast in contact with deciduas expresses a modified from of class I MHC antigen that lacks individual HLA determinant.

Defence mechanisms protecting the fetal trophoblast and blood supply

An important feature of most trophoblast tissue is its extreme resistance to rejection by antigen specific immune effector mechanisms (76) Trophoblast cells are highly resistant to killing by antigen specific cytotoxic (76) cells and by antibody + cyto lytic null type cells (antibody dependent cell-mediated killing).

Null type cells include

(i) Natural killer cells (NK) that type transformed and virus-infected cells selectively and without antigen specificity.

(ii) Natural cytotoxic (NC) cells that lyse cells of solid tumors resistant to NK cells.

(iii) Macrophages

(iv) Lymphokine activated Killer cells (LAKs).

The spontaneous activity of NC and NK cells may be boosted by cytokines released by T cells that mediate delayed type hypersensitivity and generation of LAKS is dependent upon such factors.

—Trophoblast, while resistant to killing by NK & NC cells, is quite sensitive to killing by LAKS (77-79).

—NK, NC and activated macrophages produce a cytotoxin called tumor necrosis factor-alpha (TNF-a) that damages a trophoblast cell line (Clark et al, unpublished data).

Stimulation of TNF-a release can also occur via a non T cell dependent mechanism through exposure of macrophages to bacterial products such as endotoxin (80).

TNF-a acts on vascular endo-thelium to promote clotting (the thromobosis produces nutritional death of the conceptus).

 

Role of Decidua — A Suppression

—Prior to implantation, a novel population of hormone induced suppressor cells develops (82, 82), in the uterine lining. There is no antigenic specificity and these cells can’t release any soluble suppressor factors unlike classic suppressor T cells (81). The relevance of these cells to spontaneous abortion is three fold viz.

(i) They persist during first 4 days after implantation.

(ii) During this period of time, the decidua has the ability to exclude macrophages and prevent the expression of delayed type hypersensitivity. Whereas after formation of the placenta, these suppressor T-like cells disappear and expression of DTH becomes possible (83).

(iii) Rate of loss has been found to be increased after injection of anti-body to CD8, presumably by interfering with the hormone induced suppressor T-like cell population (84).

—By the fifth post-implantation day, a population of small sized suppressor cells replaces the CD8 + suppressor population. These cells are small cells with cytoplasmic qranules, lack conventional T cell markers but possess surface receptor for the Fc end of IgG (85) which are recruited/activated by soluble products from trophoblast cells. These cells release a potent immunosuppresive molecule that is homologous with transforming growth factor beta (TGF-b) (86)—which in turn inhibits NK cell activation, LAK generation and the response of NC cells to activation by inter leukin 3 and inhibits the cytotoxic respiratory burst of monocyte macrophage cells (86, 87). TGF-b has the potential to block all of the natural effector mechanisms capable of attacking the trophoblast. TGF-b and TNF-a antigonize each other with respect to effects on the immune response (88).

B. Stimulation :

Presence of growth factors can stimulate placental trophoblast growth. These are cytokines-viz interleukin 3 (a T cell derived molecule) and colony stimulating factors CSF-1 (89) and CSF-GM (90) produced by T cells and a variety of stromal cells participating in the deicidal response (Thorens et al 1987, Zucali et al 1986).

Role of HLA Sharing in Recurrent Abortion

The major histocompatibility complex (MHC) of which HLA is the human variety consists of several linked loci that code for cell surface proteins important in immune function. Class I antigens (HLA loci A, B & C) serve as targets for recognition by cytotoxic T cells and as co-elements in recognition of viral antigens.

Class II antigens (HLA D Loci) code for surface proteins restricted to a small number of cell-types involved in immune recognition and response. These immune response associated antigens (Ia antigens) associate with a variety of foreign molecules and allow their recognition by T helper/DTH cells.

In allogeneic recognition reactions of which the fetomaternal relationship may be one example, Ia differences cause the strongest proliferation of responding T cells in the host, Assumably, Ia is not expressed on the trophoblast due to this reason (76).

Since HLA antigens represent strong antigens leading to graft rejection—it was rather surprising to find an increased frequency of HLA antigen sharing among couples with reduced pregnancy success (recurrent abortion) (93). It was proposed that the defect in abortion was lack of adequate stimulation of a helpful immune response in the mother due to a hypo antigenic conceptus (94). 25% of habitually aborting couples showed abnormal reactivity of the wife’s lymphocytes against the husband’s cells in vitro.

It has been suggested that HLA-D sharing is a harbinger of sharing at a locus called TLX where TLX represents an antigen shared between lymphocytes and trophoblast. If husband and wife share the same TLX, the conceptus will not be antigenic and will not stimulate a protective immune response in the mother. It is proposed that deliberate immunization with husband or third-party lymphocytes will stimulate the protective blocking antibody response that is missing in aborting patients. (95-100). This antibody inhibits an MLC reaction by recognizing the antigen as the receptor in the responding T cell (101, 102); while it’s called a blocking antibody.

It seems likely that TLX sharing, if it does in fact occur, includes all of the important antigenic determinants (epitopes) on the molecule so that the father and fetus are still foreign but not sufficiently different to elicit an intrauterine immune response. Alternately, what may be shared in an antigen (TLX) which performs a helper function in ensuring an adequate induction of immunity to a minor H antigen on the embryo, possibly an embryonic antigen. Unless the husband is TLX homozygous and shares an antigen in common with his partner in which case a 100% failure rate would be predicated, even after 7-10 recurrent abortions there would still be a 50% or greater chance of success based on simple Mendelion genetics.

Primary Aborters : No live births, abort only with one mate, have significant HLA sharing, and abort due to deficient immune response to antigens on the fetal trophoblast (possibly TLX). The response is humoral (103) (Davies and Browne 1985) and is proposed to stimulate local suppressor cell activity in decidua (104, 105). These antibodies tend to block allorecognition by maternal T cells in vitro.

Secondary Aborters : One or more live births, no HLA sharing, may abort with several partners and may possess antibody to paternal cells as detected by a variety of methods (106-108). Abortion is attributed to a toxic effect of the antibody. These patients may have second rather than first-trimester losses, possess anti-phospholipid antibodies that interfere with coagulation (so called lupus anticoagulant) and occasionally have clinically diagnosable autoimmune disease (109, 110). It has been suggested that some first trimester aborters and primary aborters may also have such antibodies, and if blocking activity is already present, treatment with aspirin and prednisone (as is done for patients with lupus anticoagulant) is more effective than immunization. (100). Antibody to blood group antigen p has also been linked to abortion of p+ fetuses (111).

Revised classification may be :

1. Primary aborters without evidence of autoantibodies or blocking factors.

2. Secondary aborters without evidence of autoantibodies or blocking factors, but possibly possessing antibodies against antigens of the husband.

3. Primary and secondary aborters with evidence of autoantibodies or blocking factors (113, 114).

4. Genetic aborters (Mowbray 1988, Gill 1987).

First two groups may be suitable for immunotherapy.

Immunotherapy :

Success rates as high as 95% has been noted with immunotherapy when patients with pre-existing blocking antibodies (100) were excluded.

Atternative forms of treatment for recurrent abortion

Treatment    Success Rate    Reference

1. Human Placental trophoblast        75%      Jolmson et al (1988)115

2. hCG        94%      Harrison (1988)116

3. Corpus lutum extract        84%      Potter (1938)117

4. Progesterone      84%      Shearman & Garrett (1963)118

5. Tender loving care           72%      Stray-Pedersen (1984, 1988)119

6. Cerclage 85%      Edmonds (1988)120

Recurrent Abortions

Antiphospholipid Syndrome

Antiphospholipid antibodies comprise a family of autoandibodies which have a well-established association with fetal loss (121, 122). They are most commonly associated with fetal loss, thrombo cytopenia or thrombotic events without evidence of auto immune disease viz. the antiphospholipid syndrome.

Primary Antiphospholipid Syndrome—must include one clinical and one serological feature.

Clinical features

1. Recurrent venous or arterial thrombosis

      2. Recurrent fetal loss

      3. Thrombocytopenia

Serological features

1. IgG aCL>20 GPL

      2. LA

      3. IgM aCL>20 MPL + LA

1 MPL or GPL is equivalent to 1 ug of affinity purified aCL IgM or IgG.

Diagnostic Tests : The antiphosphalipid antibodies are a diverse family of autoantibodies which share in common a reactivity with negatively charged phospholipids. There are three clinically significant members—viz.-biological false positive test for syphilis.

—Lupus anticoagnlant

—Anticardiolipin antibodies.

I Biological False Positive Test For Syphilis :

A biological false positive test can result from—

1. Antibodies produced in response to infection by a number of non treponemal pathogens (123). In this situation the BFP is likely to be transient, reflecting recent activity of the pathogen. These antibodies are not associated with thromobosis or fetal loss.

2. Autoantibodies produced by patients with autoimmune discuses, particularly patients with APS and/or SLE. These autoantibodies can persist for many years and are associated with both thrombosis and fetal loss.

The BFP reaction requires :

1. That on phospholipid based screening assay such as the VDRL is persistently positive for 6 months.

2. That the absence of treponemal infection is confirmed by a non-phospholipid-based assay such as the TPHA (124).

II Lupus Anticoagulant :

It comprises autoantibodies of either IgG or IgM class which prolong phospholipid-dependent coagnlation assays by reacting with negatively charged phospholipids (125).

Coagulation assays used to screen for LA include the activated partial thromboplastin time (APTT), Kaolin clotting time (KCT), dilute Russell Viper venom test (dRVVT) and dilule tissue thromboplastin assay (dTta)6 Triplett & Brandt 1989).

The minimum criteria for the detection of LA proposed by Triplett & Brandt (1989) are :

1. A prolongation of a phospholipid-dependent screening test such as the APTT.

2. Demonstration that the abnormality is due to an inhibitor rather than a factor deficiency.

3. Proof that the inhibitor is directed against phospholipids (126).

In order to confirm the presence of an inhibitor the screening test is repeated using a mixture (1 : 1) of the patient’s plasma with normal plasma. If the abnormality is due to an inhibitor the test will remain prolonged. If the abnormality is due to a factor deficiency the normal plasma will act as a senses of the factor and the test result will correct to normal.

Similarly a platelet neutralization procedure (PNP) is used to confirm the antiphospholipid nature of an inhibitor, Lysed platelets are added to the abnormal plasma, and the screening test (APTT or dRVVT) is repeated. An abnormality caused by LA will correct in a PNP whilst an abnormality due to a factor inhibitor will not.

III Anticardiolipin Antibodies :

It is detected by solid phase immune assay (enzyme-linked immuno sorbent assay (ELISA) or radio immuno assay (RIA) (127-128). The aCL assay has proved to be 200-400 times more sensitive than the VDRL test and detected 90% of LA in a population (127).

IV Antibodies to other phospholipids :

Phospholipid antigens other than cardiolipin have been used in solid-phase assays for aPL because cardiolipin being found exclusively in the mitochondria is unlikely to be the physiological antigen for aCL as it is not exposed to circulating aPL (129).

Phosphatidyl serine as been used as an alternative antigen as it is located in membranes of endothelial cells and platelets. However, PS is found in the interior leaflet of non-activated cell membranes and is only exposed to circulating antibodies after cell activation causes its transfer to the exterior leaflet. Some use phosphatidyl ethanol amine which is in both the exterior and interior leaflets of cell membranes and thus is exposed to circulating aPL.

Anticardiolipin Antibody cofactor, B2 Glycoprotein :

The requirement of a cofactor to facilitate the binding of aCL to phospholipids has been described recently (130-132). The cofactor, which is present in normal serum, has been identified as B2-glycoprotein (B2-GP1 - also called apolipoprotein H) (131).

The invitro properties of B2 - GP1 are :

1. Inhibitor of intrinsic phase of coagulation.

2. Inhibitor of platelet activation.

3. Phospholipid binding protein (134-136).

The formation of a trimolecular complex involving B2 - GP1, aCL and phospholipid prevents the normal function of B2 - GP. Also, 132 Matsuura et al (1990) have demonstrated that, unlike aCL of autoimmune origin, aCL resulting from syphilitic or other infection bind to phospholipid in the absence of B2 - GP1. This difference in the cofactor requirements of aCL from various origins explains why only aCL of autoimmune origin are associated with thrombosis and recurrent fetal loss.

Prevalence of aPL, both LA and aCL, in the general obstetric population is 2%.

There is a definite correlation between the presence of aCL and LA. Among patients with SLE and LA, 59% will have aCL and in those with SLE and aCL, 45% will have LA. Incidence of aPL in women with three or more first trimester miscarriages varies between 14% (137) and 42% (138). Parke et al (1991) 139 found a positive frequency of aPL in women with recurrent miscarriage as 16% women who had undergone normal pregnancy as 7% and women who had never been pregnant as 3% Late fetal losses are also associated with aPL-incidence being 30-40%. Parazzini et al (1991)140 concluded that there is no apparent justification for considering aPL to be a risk factor for fetal loss among women who present with spontaneous miscarriage or fetal death and have no previous spontaneous fetal loss. Lockshin (1987)141 noted that fetal death occurred in 77% women with SLE with aCL alone versus 50% patients with LA alone. He concluded that aCL was more sensitive and specific for predicting fetal death than LA.

 

Pathogenesis

I. Effect on Platelets :

Early workers described thrombocytopenia as a frequent finding in patients with aPL(142). Also thrombosis associated with APS is congruent with aPL binding to and disrupting the function of platelet membrane phospholipids. However, the negatively charged phospholipids, with which aPL react, are present only in the inner leaflet (143). Therefore, non activated platelets should not be antigenic for aPL. Upon activation the distribution of Phospholipids in the platelet membrane is altered with the transfer of the negatively charged PS to the exterior leaflet of the membrane. This permits the platelet to participate in the processes of coagulation and may make them antigenic for aPL.

II. Effect on the Vascular Endothelium :

1. Inhibition of prostacyclin production :

aPL which react with membrane phospholipid would inhibit the production of prostacyclin by the vascular endo-thelium and promote thrombosis (144). aPL inhibits the release of arachidonic acid from membrane phospholipid (144).

2. Inactivation of the protein C/protein S/Thrombomodulin pathway. Protein C acts as an anticoagulant by inhibiting the activated coagulation factors Va, VIIIa and platelet bound Va-Xa complex 145 (Kwaan 1989). Two steps in this pathway are phospholipid dependent and may be inhibited by aPL.

(a) Protein C is activated by thrombo modulin — a protein present on the surface of vascular endothelial cells. Thrombomoduln must be bound to phospholipid to yield optimum protein C activation (146). It has been demonstrated that aPL can inhibit the invitro activation of protein C by thrombomodulin (146, 147).

(b) Once activated, protein C requires a co-factor, designated protein. S, which facilitates the binding of activated protein C to the platelet membrane (148). Once bound to the platelet membrane, the protein C/protein S complex then inhibits coagulation factors Va and Xa. aPL can interact with phospholipids and inhibit the proteins dependent anticoagulant activity of activated protein C.

3. Inhibition of antithrombin III anticoagulant pathway

Endothelial cells express upon their surface heparin like molecules—glycosaminoglycans (GAGS)—which activate antithrombin III (149). The GAG heparin sulphate is believed, to be the physiological activator of ATIII and is particularly important as an anticoagulant in the microcirculation (150). It has been proposed that aPL could cross-react with GAGS and inhibit the activation of ATIII.

Clinical Associations with APS.

The hall mark of the presence of aPL is the triad of arterial and venous thrombocytopenia and fetal loss.

Medical Disorders

I. Neurological Disorders     1. Transient ischaemic attacks

      2. Amaurosis fugax

      3. Migraine like headaches

      4. Acute ischaemic encephalopathy

      5. Multi-infarct dementia

      6. Degenerative myelopathy.

II. Cardiac Disorders            1. Valvular lesions

      2. Valvular or chamber thrombosis

      3. Coronary artery occlusion

III. Aderenal gland involvement         1. Addison’s disease

IV. Skin-Live do reticularis

V. Lungs     Pulmonary hypertension

Snedden’s Syndrome comprises the clinical triad of live do reticularis, cerebrovascular occlusion and labile hypertension in the presence of aPL (151). Evidence for an underlying collagen disorder can be found in 30-40% of individuals with aPL.

Drugs such as procainamide, guanidine, phenytoin, chlorpromazine, valproic acid, amoxycillin, hydrallazine and propanolol have been reported to induce aPL but drug induced aPL is generally not associated with thrombotic complications or fetal loss.

Obstetric disorders

1. First trimester miscarriage.

2. Later fetal loss with evidence of growth retardation.

3. Later fetal loss without evidence of growth retardation.

4. Placental abruption.

5. Pre-eclampsia-often severe and early onset.

6. Chorea gravid arum.

152 Bird Sall et al (1992) found that 33% of women who had a shill birth due to placental abrupion had aPL.

INDICATIONS FOR INVESTIGATION OF THE PRESENCE OF ANTIPHOSPHOLIPID ANTIBODIES IN AN OBSTETRIC POPULATION

1. All autoimmune diseases

2. Thrombocytopenia

3. Previous arterial or venous thrombotic event

4. BFP VDRL

5. Recurrent (>3) first trimester miscarriages

6. All fetal losses after 20 weeks of pregnancy

7. Placental abruption (previous or current pregnancy)

8. Fetal growth retardation (previous or current pregnancy)

9. Severe early onset pre-eclampsia (previous or current pregnancy)

10. Chorea gravid arum.

Management Specific Therapy

I. Women with antiphospholipid antibodies without previous loss or significant medical disease.

—Managed with careful monitoring alone

II. Antiphospholipid syndrome with fetal loss

A. Low level antibodies (aCL<60 GPL; KCT<250s)

Most patients of this group deliver a normally grown infant at term without intervention.

These women are treated with low dose aspirin — monitoring their LA level during pregnancy and observe closely.

B. High litre antibodies (aCL>60 GPL; KCT>250s).

These patients require active treatment with close monitoring of fetus and mother.

Treatment is with low dose aspirin + (i) Heparin 10,000 IU s/c BD in patients with previous thrombotic event.

(ii) Corticosteroids to reduce KCT<200 s in patients with no thrombotic event.

Various Therapies for APS

A. Single Agent Therapy

1. Cortricosteroids :

Mechanism of action—Immune suppression by inhibiting the production of Interleukin 2 by T4 cells.

Dosage—40-60 mg/day

The steroid dose is titrated against the KCT value of maintain a KCT value below 200s, usually commencing with prednisone 40 mg and measuring KCT values monthly. For maintenance low dose prednisone 10-20 mg/day is used. Administration of coticosteroids will suppress the LA but not aCL.

Side effects : Cushioned features, acne, adernal insufficiency, diabetes mellitus, oral candida, hypertension, osteoporosis.

Overall live birth rate—44%.

2. Heparin :

Mechanism of action—Facilitates the action of ATIII.

Dosage—Subcutaneous heparin sufficient to increase APTT to 1.5-2 times normal in those with normal APTT, or if APTT prolonged already heparin dose sufficient to achieve thrombin time of >100s.

Usually a dosage of 10,000 IU twice daily is used in women with previous thromboembolis or those with aPL in high titre.

Side effects : Bruising, thrombocytopenia, osteoporosis, overall live birth rate 77%.

3. Aspirin :

Mechanism of action—Inhibits cyclooxygenase in the platelet which prefentially lowers platelet thromboxane, leavning endothelial prostacyclin synthesis relatively intact.

Dosage—75-80 mg per day.

Overall live birth rate 83%.

 

B. Combination therapy

1. Coricosteroid + low dose aspirin

Over all live birth rate 68%

2. Heparvin plus low-dose aspirin

Overall live birth rate 88%

3. Azathioprine plus corticosteroid

(75-100 mg)

4. Immunoglobulin prednisone plus low dose aspirin

Overall live birth rate 71%.

General Care :

Woman with APS is at significant risk of hypertension, venous thrombosis, pulmonary embolism or thrombocytopenia. Besides she may develop activation of her autoimmune disease.

III. Asymptomatic Antinuclear Antibodies :

Significantly greater prevalence of low-titer antinuclear antibodies (ANA) has been reported in patients with unexplained fetal losses before viability than in normal control subjects 153 high frequency of positive ANA titres also occure in patients with fetal losses caused by nonimmunologic factors such as uterine anatomic malformations and luteal phase defect. 154, 155 ANA titre is between 1 : 20 and 1 : 160 and the tuorescent pattern is usually speckled or homogenous. Occasionally there will be a positive history of vasal or oral ulcerations, skin sensitivity, or unexplained recurrent musculo-skeletal pain. A positive ANA tites in a patient with prior early pregnancy losses indicates the need for further investigations of autoimmune factors viz. LAC; ACA and BFP-ST. If any of these tests is positive, autoimmunity is most probably responsible for pregnancy losses.

(E) Clinical Features :

The clinical types of abortions which obstetrician usually encounters regarding early pregnancy losses are

1. The patient with first trimester vaginal bleeding sub grouped into

a. Threatened abortion

b. Inevitable abortion :

Complete

Incomplete

2. The patient with fetal death or second trimester abortion — Missed Abortion

3. The patient that has a history of multiple early pregnancy losses — Recurrent Abortion.

Threatened Abortion :

The most common symptom of a patient with impending abortion is vaginal bleeding. In most patients here is an interval of several days between the onset of symptoms and the actual miscarriage. However, in some the symptoms progress rapidly so these patients should be examined within a reasonable time.

At the time the ovum is becoming embedded in the uterus, that is, at the time the first menstrual period is missed or soon after, a slight implantation hemorrhage is not uncommon. This diagnosis can only be made in retrospect and the safe rule is to regard any bleeding, no matter how little, which is not explained by a lesion on the vagina or cervix as evidence of threatened abortion. The bleeding is indicative of some degree of separation of the chorine from the decidua and it varies in amount, duration and type. At first the discharge is bright red. when it changes to dark brown it means that active bleeding has ceased and that old blood in the uterus is undergoing dissolution.

Sometimes the patient also complains of backache and mild lower abdominal discomfort due to uterine contractions. However the pain is usually mild in these cases.

Inevitable Abortion :

Abortion becomes inevitable if, in addition to the clinical features of threatened abortion, there are painful uterine contractions, dilatation of the cervix, or extrusion of some part of the conceptus through the as. Ballooning of upper vagina, tenderness of the uterus and pyrexia are other suggestive signs.

Many abortions occur with a minimum of warning and upset, others are characterized by recurrent haemorrhage and this may produce serious shock. Retention of the canal can itself produce shock.

Incomplete Abortion : The bleeding does not get progressively less but varies from day to day, becoming heavy from time to time. It continues intermittently for weeks and months and may be accompanied by periodic uterine colic. A normal menstrual rhythm is not re-established.

In long standing cases, the attachment of the chorion to the uterus becomes organized into fibers tissue and becomes a placental polyp.

On examination the uterus is slightly enlarged and often softened. Internal as is patulous — a very important sign indicating that there is something within the uterus.

 

Complete Abortion :

The bloody discharge decreases progressively and usually ceases within 7-10 days. The first menstrual period occurs 4-6 weeks later.

Clinical assessment of patients with first trimester vaginal bleeding :

Firstly the gestational age of the pregnancy should be estimated by clinical dating and by assessment of uterine size. A large for date uterus may indicate a Hydatidiforcce-mole whereas a small uterus suggests a blighted ovum. Presence of a tender adrenal mass suggests an entopic pregnancy. Also, the pelvic examination may show cervical changes if the process is advanced.

For pregnancy of less than 6 weeks GA, serum hCG is done to decide whether an ultrasound should be done and how to interpret its results. It is possible to see a gestational sac inside the uterus using TVS only when s.hCG is 1000 MIU/ml or more.

Patients with first trimester bleeding and serum hCG levels below this critical value should have a repeated quantitative hCG evaluation 3 days later.

—If the hCG value doubles—pregnancy is likely to be intrauterine and there is a high probability of a normal outcome.

—If the hCG value does not double and initial protestation and estradiol concentrations are 1000 (progesterone < 15 mg/ml eotradiol < 200 mg/ml), then the pregnancy is abnormal, either a blighted ovum or an ectopic.

The predictive accuracy of low values for hCG, progesterone, and estradiol is 90-95% and most patients exhibiting this combination have spontaneous abortions or tubal pregnancies. The prediction of a normal outcome based on favorable hormone concentrations early in gestation is accurate in 80% of the cases. Also sonographic evidence of normal fetal cardiac activity in these patients indicates a low risk for abortion. Simpson et al 156 demonstrated that the fetal loss rate after documenting the presence of fetal heart motion by USG at 8 weeks is only 3.2%. This finding has been confirmed by other investigators.157

Patients with first trimester vaginal bleeding as well as reassuring ultrasound and hormonal findings should be told that the possibility of spontaneous abortion is small (2.5% to 3.2%). Bed rest + progesterone supplementation in cases with serum value < 15 mg/ml is recommended in these cases.

Patients with blighted ova need karyotyping of the products of conception. If the karyotype of the blighted ovum reveals an autosomic trisomy, the patient will be at higher risk for a subsequent trixomy offspring and genetic amniountesis should be recommended in subsequent pregnancies. If the karyotype shows strimutural rearrangement of the chromosomes, parents should go for karyolyping to rule out the possibility that one is a carrier of a translocation or an inversion.

Cases with inevitable abortion require evaluation of the uterus under general anesthesia. However patients in shock should be resuscitated first.

Missed Abortion

Sometimes the fetus dies in utero but the uterus fails to respond normally by expelling it. The fetus then becomes maturated or mummified, the liquar amnii is absorbed and the placenta becomes pole and thin. Carneous (Blood) Mole is one variant caused by multiple hemorrhages in the choriodecidual spare. A mass of pantly organized blood clot and chorion is formed eventually after absorption of the dead fetus.

Patient usually has complained of slight uterine bleeding following symptoms and signs of a normal pregnancy. The discharge clear up temporarily and pregnancy. The discharge cleare up temporarily and this pregnancy is apparently progressing normally until it becomes clear after some weeks of observation that the uterus is not growing, indeed it becomes smaller and harder in consistency. Sooner or later hemorrhage recurs or there may be an intermittent brown discharge. Breast signs retrogress and symptoms such as nausea disappear. Diagnosis is usually made by ultrasound.

Complication include disseminated, intravascular coagulation caused by products of placental degeneration but is unlikely to occur for at least 3 weeks after he death of the pregnancy. Stimulation of the uterus can precipitate the trouble presumably by raising the intrauterine pressure to drive thromboplastin into the intrauterine pressure to drive thromboplastin into the circulation. So blood tests for fibrinogen content and for clot stability before and during the induction of abortion are must normal level of fibrinogen is 350-450 mg%. The danger level is < 100 mg%.

Treatment of afibrinogenaemia is only evaluation of uterus — which causes correction in 12-14 hours.

Histologic and microbiologic examination of the placenta is a fundamental part of the evaluation of these patients as the most common reasons for early fetal demise include chromosome abnormalities, antiphospholipid syndrome, ascending infection, subchorionic hematomas and abnormal placentation. Placenta will show extensive acute inflammatory changes in patients with ascending infection and typical lesions in patients with chronic vellitis caused by cytomegalic virus infection. Thromboses of fetal and maternal vessels will be seen in patients with protein C deficiency — possibility of fetal chromosome abnormalities can also be diagnosed.

Fetal autopsy to rule out genetic syndrome fetal blood for karytyping as well as for ??? cultures for mycoplasma, ureaplasma, chalmydia and listevia may be done.

ANA titer, anticardiolipin antibody, lupus anticoagulant and a TORCH titer may also help beaching for the cause. HSG is recommended in unexplained cases a few weeks after their miscarriage to rule out a uterine anomaly induction with laminaria tents for cervical dilation followed by prostaglandin suppositories or high dose oxytocin are preferable over uterine evaluation and curettage — so as to get an intact fetus and placenta.

Recurrent Abortions : Incidence is 1% there consecutive pregnancies ending in spontaneous abortion constitute the definition of recurrent abortion.

Clinical Assessment and Diagnostic Work-up

Majority of patients will have recurrent anceptodic abortions or blighted ova in this group. Following history and findings are suggestive of recurrent blighted ova :

(i) Finding of molar degeneration in the histologicalexamination of the products of conception of a prior abortion is suggestive of triploidy.

(ii) Previous abortions showing empty sacs on ultrasound examination is suggestive of trisomy 16

(iii) History of a malformed infant in the family suggests balanced translocation in one of the parents.

(iv) Interval infertility is again suggestive of balanced translocation in the parents.

(v) History of repetitive abortions occurring before 12 weeks.

(a) The probabily of a successful pregnancy in such cases is 62% 158 without any treatment.

(b) Recurrent abortions with early fetal demise : Need evaluation of following factors.

(i) Anatomic abnormalities of uterus and cervix best assessed by HSG - Hysteroscopic surgery cervical cerelage can correct the defect.

(ii) Corpus luteum deficiency :

Results in progesterone deficiency leading to pregnancy loss in first trimester especially between 8 and 12 weeks when the production of progesterone switches from the corpus luteum to the developing placenta. Typically, these patients have uterine contractions for several days preceding the onset of bleeding and the abortion. Diagnosis is made by endometrial biopsy or serum progesterone estimation during the secretory phase of the cycle.

(iii) PCOD & Hyperandrogenism diagnosed by serum luteinizing hormone/follicle-shimulating hormone (LH/FSH) ratio and total testosterone concentrations. Other endocrinal problems like thyroid gland dysfunction should be treated. GnRH agonists for pituitary suppression followed by induction of ovulation with hCG is helpful in PCOD. For hyperandrogenism prednisone is used.

(iv) Growth retarded but chromosomally normal fetuses. A biopsy of placental implantation area (obtained by curetting at the time of delivery) shows the lack of physiologic changes in the spiral arteries.

(v) Autoimmune disorders diagnosed by ANA titer, lypus anticoagulant, VDRL, anticardiolipin and SS-A antibodies. Testing for HCA sharing or antipaternal antibodies has no role in establishing a prognosis. Low dose aspirin + prednisone 40-60 mg/day or low dose aspirin + subcutaneous heparin 5000 U 12 hrly.

(vi) Repeated ascending infections due to group B streptocoi mycoplasma, ureaplasma and chlamydia can cuase repetitive early pregnancy losses in patients who are carriers of the organism causing the infection and inpatients with some degree of cervical in competence.

Cerclage operation + antibiotic treatment is recommended in these cases.

(F) Conclusion :

Differentiation of all abortion cases into embryonic and anembryonic pregnancies before abortion occurs with the advent of ultrasonography has simplified the counselling of patients with threatened abortions and of patients who had one or more spontaneous abortions. Couples with blighted ova do not require extensive workup, whereas patients who have aborted cytogenetically normal fetuses need as extensive search for nongenetic factors responsible for the pregnancy loss.

Eventually it can be concluded that the obstetrician should investigate each pregnancy loss until the underlying cause is discovered. Otherwise, the diagnosis and management of patients with repetitive early pregnancy losses will be affected by inadequate information about the nature of their prior abortions.