jueves, 25 de enero de 2018

Recurrent miscarriage: treatment

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By Liji Thomas, MD

Due to the uncertainty of diagnosis in such a high percentage of cases of recurrent miscarriage, also known as recurrent pregnancy loss (RPL), the management of RPL is still undergoing evolution.

Credit: Idutko/ Shutterstock.com

RPL, or habitual abortion, is a distressing and often perplexing condition for both patient and physician. While some causes have been identified, such as chromosomal abnormalities, endocrine diseases, hereditary and acquired thrombophilias, and uterine anatomical anomalies, no obvious reason for abortion is identified in about half of all cases.

immunologic research is going on to explore the role of natural killer and T-regulatory cells, as well as many cytokines and antigenic proteins, in the etiology of recurrent miscarriage.

General measures: psychological support

The first step in any woman who has had three or more recurrent abortions is reassurance that the likelihood of successfully carrying the next pregnancy is still higher than the odds of having another miscarriage. Even without any treatment, in the absence of any identifiable cause, research shows that 60-80% of next pregnancies are likely to be carried to term and born alive.

The most important need at this stage for the couple with unexplained RPL in acute emotional distress is to explain their chances of having a live baby and offer emotional support. There should be specific time allotted for discussion with the couple in which they can express their fears and realistic assessments made of their chances of having a baby in future.

Some small studies found that tender loving care, or psychological support and sympathetic counseling, was associated with successful next pregnancies in up to 80% of cases. This may help to break the vicious cycle of miscarriage-associated stress which in turn produces a higher risk of miscarriage.

At the same time, the importance of factors such as obesity, tobacco smoking, alcohol abuse, and caffeine use above occasional level, in the etiology of sporadic abortion, should be explained clearly and the couple encouraged to adopt appropriate lifestyle changes.

This is because all RPL is not a series of miscarriages caused by the same etiologic factor, but may be due to several sporadic abortions occurring as a result of differing causes. For instance, cigarette smoking could cause poor trophoblastic implantation. A most convincing approach could be that changing one’s habits to a healthier lifestyle cannot cause any harm and may most probably push up the chances of having a successful pregnancy.

Genetic testing

Though some cases are due to aneuploidy caused by Robertsonian translocations, genetic testing is not recommended as a routine measure. It is probably best reserved for those with a strong family or personal history of fetal anomalies or if aneuploidy has been identified in the last abortion.

When a couple has had RPL and chromosomal anomalies are shown to be present in the parental karyotype, one method of management is to perform in vitro fertilization (IVF) with genetic testing being offered once the pregnancy is confirmed.

Preimplantation testing is now available, with newer techniques which use whole-genome amplification for molecular karyotyping, or laser-assisted blastocyst biopsy, comparative genomic hybridization (CGH) or single nucleotide polymorphism (SNP) arrays. However, all experts do not agree, because some reviews showed that there was no benefit to this approach.

Surgical treatment

Women who have RPL due to uterine anomalies such as septate or bicornuate uteri are often recommended to have corrective surgery, called metroplasty. Evidence shows that this is followed by a good outcome in terms of live births in 65-85% of cases. The relevance of this result is, however, thrown into some doubt by the fact that almost 60% of such patients do carry a successful pregnancy without surgery, and 78% of them give birth to live babies.

It is today thought that minimally invasive surgery would be better suited to these patients. Even standard therapies such as adhesiolysis for Asherman’s syndrome, or surgical removal of uterine fibroids and polyps to boost fertility, are not yet proven to be useful in cases of pregnancy loss.

Cervical cerclage for incompetent cervix is indicated only if a woman has lost one baby at least in midtrimester due to cervical incompetence. In such a case, any future pregnancy should be monitored by a transvaginal ultrasound to detect shortening and widening of the cervix, in which situation an emergency cerclage is indicated by Shirodkar’s technique.

Without such a history, any woman whose cervix is demonstrated to be shortened at midtrimester by ultrasound scanning and with a single live pregnancy should be offered either cerclage, a vaginal pessary, or vaginal progesterone.

Anti-infective measures

There is some evidence that appropriate treatment of bacterial vaginosis or abnormal vaginal flora, even if it not causing any symptoms, with clindamycin, lowers the incidence of late abortion or premature birth, but its relevance to RPL is not yet established.

Endocrine treatment

A careful evaluation of diabetes, hypothyroidism and hyperprolactinemia should be done in every case of RPL and any abnormalities should be treated appropriately. However, elevated LH levels have not been proved to play any significant role in RPL and therefore suppression of LH secretion is not known to impact pregnancy outcomes.

Hyperprolactinemia is treated with dopamine agonists, and hypothyroidism with thyroid hormones to achieve TSH level of less than 2.5Mu/l. If antithyroid antibodies are detected careful follow up and supplementation with 50 mcg levothyroxine is suggested to be useful even in euthyroid women. However, the presence of these antibodies is not a risk factor in subsequent pregnancies, so that the value of empirical thyroxine is in doubt.

A randomized controlled trial called the thyroid antibodies and levothyroxine study (TABLET) study is now underway to evaluate the relevance of this treatment in euthyroid women. Careful control of diabetes is also important. Anovulatory disorders are often associated with insulin resistance, and this is also linked to spontaneous abortion.

Thus, both lifestyle changes and medication to reduce blood glucose levels are associated with reduced risk of miscarriage in subsequent pregnancies. Metformin is not, however, recommended as such for the treatment of RPL.

Progesterone supplementation

Progesterone has an anti-inflammatory and immunomodulator effect which is protective in pregnancy. Natural dihydrogesterone acts via progesterone-induced blocking factors (PIBF) to inhibit several cytotoxic lymphocyte actions.

For this reason, patients with unexplained RPL may benefit from progesterone administration in the next consecutive pregnancy, usually as micronized progesterone 400 mg orally or vaginally, in the absence of any known harm. Evidence for actual benefit is being sought in a multicenter trial.

Aspirin and heparin

Aspirin, low molecular weight heparin (LMWH) and other anticoagulants have been studied especially for their benefit in RPL due to antiphospholipid syndrome. A protocol which includes both low-dose aspirin and LMWH has been found to reduce the miscarriage rate and achieve a higher rate of live births in women with a history of RPL and thrombosis due to heritable or acquired thrombophilia.

It is not helpful in women who have heritable thrombophilia and RPL. It is not recommended as such in women without APS either at present.

Such women should be carefully monitored and LMWH should be administered only if a risk of venous thromboembolism is present. Low-dose prednisone is also given if the woman has been diagnosed with systemic lupus erythematosus and not otherwise.

Folic acid

High doses of folic acid and methylcobalamine are given to women with hyperhomocysteinemia as well as in diabetes, especially when the latter is associated with obesity. Evidence for its role in preventing RPL is lacking.

Immunotherapy

Autoimmune mechanisms are important in RPL, and immunomodulation has been investigated in its prevention. Some of them include high-dose intravenous immunoglobulin (IVIG) which is supposed to increase the expression of CD94 and so reduce cytotoxic effects of NK cells.

Paternal cell immunization, donor leukocytes from a third person, and trophoblast membrane donation have all been studied but any possible benefit was only found in secondary RPL. Thus these are not recommended in primary RPL due to the risk of infection with CMV and other viruses, as well as inducing hypersensitivity reactions. In the current situation, these are offered only as part of research trials.

Human chorionic gonadotropin

Human chorionic gonadotropin (HCG) has not been found to be of benefit in the prevention of RPL, and so its use is not recommended.

Other agents

Drugs which inhibit the fibrinolytic activity are not recommended except as part of research, and intravenous intralipid drugs are also not proved to be of clinical benefit.

Conclusion

Despite much study, the etiology of RPL is far from clear in half of all cases, and therefore management of unexplained RPL is also evolving with research. Known causes should be effectively controlled, such as APS, autoimmune rheumatologic and endocrinologic disorders. Karyotyping is useful in selected cases.

Uterine surgery may be of use in a subpopulation of women with uterine anomalies. Most immunologic approaches are yet to be validated. Overall, closer monitoring and the application of standard care measures have led to better outcomes in many women with RPL, as these therapies tend to have multiple benefits apart from the targeted organ system, leading to an overall protective effect during pregnancy.

Reviewed by Afsaneh Khetrapal Bsc (Hons)