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WRITE UPS - RECURRENT PREGNANCY LOSS - Recurrent Spontaneous Abortions

INTRODUCTION:

As many as 5% of all couples trying to conceive have two consecutive miscarriages and 1% have three or more consecutive losses. Uncertainties regarding the cause and controversies surrounding management of recurrent pregnancy loss are two reasons that recurrent pregnancy loss remains particularly frustrating problem for physicians and patients. Although recurrent pregnancy loss has been well published in the news media and women’s magazines, some articles are misleading and encourage couples to seek unproved diagnostic tests and controversial treatments. Recommendations in the medical literature are also conflicting and have done little to clarify the situations. We shall consider various causes associated RSA in depth.

MORPHOLOGIC AND GENETIC ABNORMALITIES: -

Because most embryos from first trimester spontaneous abortions are chromosomal or morphologically abnormal treatable maternal or paternal factors are not involved in most cases.

CHROMOSOMAL ANOMALIES AND R.S.A.: -

Structural Chromosomal Anomalies & Recurrent Pregnancy Loss:

· Seen in 3% of cytogenetically abnormal conceptus.

· Commonest type-Robertsonian translocations.

· Other types: Inversions, Ring Chromosomes

· Structural translocations: relatively more common in RSA.

· Higher in couples with H/o both RSA and anomalies or SB infants.

· Carriers of ( Pericentric inversion ) : high risk ( abnormal offspring)

· A large chromosomal segment involves early embryonic lethality.

Reproductive Risk In Structural Abnormalities:-

· Risks studied from Robertsonian translocation between chromosomes 14 & 21. (N) gametes of other partner)

When chromosomal anomalies are found

• over 49% are autosomal trisomies

• 20% chromosomal monosomies

• 19% Polyploidy

• 3.8% structural anomaly

• Rest are mixoploidy

Most common anomalies are autosomal trisomies.

Trisomies 13,16,18,21,22 and X are most commonly found. Others probably do not allow embryonic development. Their contribution to pre-implantation loss is uncertain. Numerical abnormalities are result of non-disjunction and uneven distribution of chromosomes at cell division. Most abnormalities arise from errors in meiosis and advancing maternal age is associated with an increased risk of autosomal trisomy.

 Recurrent Aneuploidy: Role In RPL

• Chromosomal anomalies of the embryos are the most common cause of early pregnancy loss

• 50% of early spontaneous abortions are cytogenetically abnormal as against 5% in still births and 0.5% in live births. Most chromosomal abnormalities result in disordered development incompatibility a prolonged intra uterine survival and live birth.

• The most common type of parental chromosomal abnormality is a balanced translocation C a reported prevalence of 2.5% in couples within unselected population.

• An increased number of chromosomes breaks and eccentric fragments pericentric inversions in seen in recurrent abortions group. This presumably would lead to broth, the loss of motility unstable elements during cell divisions and an increased rate of aneuploidy contributing to early embryonic loss.

• Increased number of chromosome breaks and eccentric fragments seen in RSA group.

• Some chromosome bear heteromorphisms such as large heterochromatic centromeres, pericentric inversions, large or double satellites and fragments have been implicated in mitotic instability and a tendency towards increase risk for aneuploidy.

Embryonic aneuploidy is responsible for sporadic and recurrent miscarriages, and a molecular study indicates that the mechanism of aneuploidy is more complicated than previously appreciated. Preliminary studies using DNA analytic techniques suggest that the total genetic contribution to pregnancy loss has been unclear estimated. For example, abnormalities in the aborted embryo due to single gene mutation or mutations at several loci are not detected by the usual karyotype are probably important in detecting C chromosomal and gene abnormality are clinically significant. Immunogentic factors at the maternal fetal interface are also the subject of intense investigations. These new development and other various scenarios strengthen the suspicion that eventually early pregnancy loss may be determined to be largely genetic.

MANAGEMENT: -

 Relevant Genetic Counseling: -

• Karyotyping of couples will reveal that 3.8% have some abnormality, most frequently a balanced chromosomal rearrangement or a translocation.

• It is important to emphasize that karyotyping uncovers only a percentage of those pregnancies lost due to genetic abnormalities ( e.g. single gene defect are missed)

• If the karyotype is abnormal, nothing can be clove to lesson the chances for another abortion, however C more abnormalities there is a 50% chance that the next pregnancy will be normal.

• Amniocentesis on CV biopsy should be encouraged in any pregnancy in couples C a previous abnormal karyotype because of the risk of an abnormal child.

• If aneuploidy is documented on a previous abortion a centrally timed insemination is advocated based on animal studies relating aneuploidy to again of ovum of sperm. The other choice is of donor insemination.

• If euploidy has been documented on a previous abortion anatomic or endocrine factors should be corrected. 

• Point genetic mutations could be responsible for abortion by causing a gene to become lethal.

• Empirically, the birth of a trisomic infant places a woman at an

• approximately 1% increased risk for a subsequent trisomic conceptus. There is a small but statistically insignificant increased risk for women who have had a trisomic abortus to have a subsequent trisomic abortion.

•  There is a stronger tendency for ensuring abortion to be cytogenetically normal when index abortion has a normal karyotype. If atleast some of the antecedent abortions are trisomic, There probably is an increased risk for recurrence.

ANATOMIC DEFECTS: -

The two most common congenital malformations of the uterus associated with a recurrent pregnancy loss are Subseptate and bicornuate anomalies. Hysterosalpingography is still the best and most practical way to detect these anomalies, but Laparoscopy and hysteroscopy are needed to distinguish the septate from the bicornuate uterus is simplified by hysteroscopic resection of the septum, but an abdominal metroplasty may be required for the bicornuate uterus. After either technique, the pregnancy success rate is about 70% to 90% and most physicians are convinced of this value. However, no randomized trial has ever been done, and some any patients with these anomalies have successful pregnancies. Each patient should be evaluated carefully and the selection for surgical correction must be individualized, because surgical treatment not always necessary.

 Considering the anomalies one by one: -

UNICORNUATE UTERUS: -

- Rare anomaly

- Fetal pregnancy lost within the first 2 trimester. Prematurity –20%.

UTERUS DIDELPHYS: -

· Fetal Survival rate 64% (without surgical correction)

· Best prognosis

· Surgical procedures to treat pregnancy losses-rarely indicated

· Benefit of metroplasty-not certain

BICORNUATE UTERUS: -

- 14% of women with poor reproductive performance can have this.

- 28% abortion rate

-  20% prematurity rate in partial bicornuate uterus

-  66% prematurity rate in complete bicornuate uterus

-  Cervical incompetence incidence is increased. timely cervical encerclage recommended.

SEPTATE UTERUS: -

·  Reports of 28% to 75% live birth rates in different studies.

· Diagnosis: H.S.G., USG., laparoscopy

·  Abdominal metroplasty or hysteroscopic guided septum transection: Advantages-simple procedure and avoids pelvic adhesions, reduced post of morbidity. No requirement for caesarian section

 ACQUIRED UTERINE DEFFECTS: -

Ashermann’s Syndrome:

-Pregnancy resulting in abortion- 40%

-Diagnosis : -USG-HSG-HYSTEROSCOPY

-Hysteroscopic surgery

Value of Treatment in recurrent pregnancy loss:

The optimal treatment for uterine anomalies is still a matter of debate. Open surgical correction of congenital anomalies has been reported to give successful subsequent pregnancy outcome but may be associated significant postoperative infertility of pelvic adhesions.

Majority of studies of RPL on uterine anomalies are without control, comparing miscarriage rate before and after treatment in the same woman. Interpretation of such results can be flawed. Hysteroscopic techniques are attractive, but results from randomized control studies are lacking.   Cervical incompetence is probably over diagnosed.

ENDOCRINE: -

The role of endocrine factors as a cause of recurrent spontaneous abortion is controversial. Diabetes mellitus and thyroid diseases do not represent pregnancy loss. Luteal-phase defect has been questioned because there are no accurate methods for diagnosis and no convincing evidence of correction with treatment exists.

The corpus luteum is an unusual endocrine gland, highly diverse in function and important for successful reproduction in all mammalian species. Much controversy exists about the luteal function in human and hour defects in luteal function affects reproduction. Disagreement has been due to lack of accurate diagnosis and controlled studies to determine whether correction of the luteal phase defect is worthwhile when treating female reproductive problems. The donor egg recipient model from assisted reproductive technology programs has shown that corpus luteum. The mechanism by which these steroids stimulate a uterus to be receptive to implantation of the embryo is not known. Several proteins produced by the endometrium are the markers for uterine receptivity. Furthers work needs to be done to correlate these markers C sub sequent pregnancy outcome. A noninvasive marker for uterine receptivity is ultrasonographic evaluation of the endometrium. But the sensitivity is low (only 20% - 60%).

AUTOMMUNE DISORDERS :-

 The failure of self tolerance or evoking of a humoral or cellular immune response directed against self-antigens is known as autoimmunity.

· It has been known service decades that a systemic autoimmune condition such as SLE is associated with a risk of pregnancy loss.

· Antiphospholipid antibodies comprise a family of autoantibodies that have a well-established association with fetal loss, which share in common reactivity with negatively charged phospholipids.

 ANTIPHOSPHOLIPID ANTIBODY SYNDROME: -

These are essentially missed abortions. Treatment protocols are many. All give good results. But the main stay is Aspirin, Corticosteroids and Heparin. We got working in this field about 15 years ago. Initially we investigated only recurrent missed abortions of late I-trimester and II trimester. Nearly 80% of such carefully selected cases tested positive. We then enlarged the scope of these investigations to other areas as well. We found association of APA syndrome with other obstetric condition notable amongst these was pre-eclampsia remote from term. Treatment protocol established in these cases was according to the degree of positivity. We classified <10 GPL as negative, 10-20 as weakly positive, 20 to 100 as moderately positive and more than 100 as strongly positive. For weak and moderate positive cases, we gave low dose aspirin 1.2 mg/kg./day in the interval period. Than allowed a conception. We restarted aspirin at 12 weeks and went on to give for 36 weeks. In strong positive cases we gave prednisolone in a dose of 10-20 mg/day for three months in the interval period allowed a conception and then started aspirin in the some dose from 12 weeks to 36 wks. Our published data showed very satisfactory results in the otherwise furious looking conditions.

ANTINUCLEAR ANTIBODIES:-

 ·Modest elevations are common, nonspecific and usually of no clinical significance.

·Presently ANA determination is not recommended as part of evaluation for RSA.

ANTITHYROID ANTIBODIES :-

• Presence of these antibodies may reflect a nonspecific activation of the immune system.

OR

• Antithyroid antibodies may be the result of pregnancy loss. ( or impending pregnancy loss).

• Role in RSA has not been established presently.

LUPUS ANTICOAGULANT:-

• Lupus anticoagulant comprises of autoantibodies of IgG or IgM class that prolong phospholipids dependent coagulation assays by reacting with negatively charged phospholipids.

• Prevalence : 3-4%:-

Mechanism of action: -

· 1) Platelet activation with a lower threshold for aggression induced by interference with phospholipids part of prothrombin activation complex.

· 2) Inhibition of prostacycline formation in vessel walls by inhibiting release of arachidonic acid from membrane phospholipids.

· 3) Pre-kallikrein inhibition

· 4) Prevention of physiological charges in the spiral arteries which results in decreased blood supply to the decide culminating the fetal hypoxia.

· 5) Impaired fibrinolytic system.

ENVIRONMENTAL FACTORS:-

Environmental causes from both the medical and psychological perspectives.

We are less certain about the contribution of environmental, physical, and chemical agents to the incidence of spontaneous abortion. Although we realize that spontaneous abortions are a significant medical and emotional burden to a family a surviving malformed infant can be greater burden to that family.

We do not have an accurate picture of the contribution of environmental agents to the incidence of spontaneous abortion. At the present time it would appear that only a very small proportion of abortions could be attributed toxicants during pregnancy. Conversely, it is the scientific and medical community’s responsibility to prevent the introduction and use of agents that cause unwanted embryonic and fetal loss. Because the teratogenic and abortgenic effects of environmental agents differ, one can not conclude that an agent is an abortifacient because it is not teratogenic.

INFECTION: -

The best evidence suggests that infection is an occasional cause of sporadic spontaneous abortion, and consistent with statistical probability, recurrent miscarriage due to infection occurs with a frequency that is much lower. In the medical literature, the limited evidence linking infection and recurrent pregnancy loss in humans remains largely anecdotal and generally cannot be reproduced in prospective studies.  

Exposure to a microbe that can establish chronic infection that can spread to the placenta in an immuno-compromised patient is probably the most obvious risk situation for habitual abortion. In routine medical practice, it is not necessary or efficient to screen universally for the unexpected but pt is necessary to be aware of the rare possibilities.

PSYCHOLOGICAL FACTORS: -

Unfortunately there has been little formalized research with respect to the psychological causes and reactions to multiple pregnancy loss. Although at one time it was thought that substantial psychopathologic disorders accounted for many early pregnancy losses, little data support this concept. Although emotional responses to miscarriages have been documented for persons experiencing a single miscarriage., little information is available about the premorbid personality or psychological reactions of couples who experience repeated pregnancy loss. Much of what we know is not based on quantitative prospective studies but is theretic and based on anecdotal observations.

Finally there is also an absence of prospective, well-designed studies that evaluate the value of the sorts of therapies that are commonly used to manage the psychological consequences of repeated pregnancy loss. None the less several principles exist that patients and this their therapists have found useful. Soon we hope to see more interest in prospective, randomized trial of various therapeutic options for these couples.

CONCLUSIONS: -

A sympathetic attitude is essential in caring for patients with pregnancy loss. Trust and support is best established by tactful and though discussions between the physician and the couple. The table before summarizes recommendations for an efficient and cost effective diagnostic work-up in patients with recurrent miscarriage. Treatment of maternal non-immunology factors cases. When the clinical and laboratory evaluation is negative, approximately 60% of those couples will achieve a successful pregnancy with no treatment. Therefore further attempts at pregnancy without treatment is often justified depending upon the age and wishes of the couple. Lack age immunizations seems best reserved for carefully selected patients who have no other options and who understand the risks, cost, and pregnancy success rates with and without treatment.

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