Medical history:

Patient is a 31 year old woman with positive family history of thrombophilia –paternal grandfather with stroke, paternal uncle with myocardial infarction. She has had no significant illness. There is no personal history of thrombotic and autoimmune diseases.

Medical diagnosis and summary of pregnancies:

1) Full term pregnancy with a Cesarean section delivery due to a decrease in amniotic liquid and rupture of membranes at the 38^th week. No complications during pregnancy;

2) Miscarriage due to suspected fetal growth delay - Miscarriage around the 17^th week, with no cardiac activity revealed by ultrasound; no previous threat of miscarriage. Histological examination suggested a cystic lymphangioma in the left lateral-cervical region. Normal karyotype.

3) Miscarriage treated with ASA - Miscarriage around the 12^th week, with no cardiac activity revealed by ultrasound, no previous threat of miscarriage. Histological examination showed decidual tissue infiltrated with lymphocyte elements and chorionic villi. Normal karyotype, female fetus.

In XXX the patient underwent hysteroscopy to remove intrauterine adhesions.

4) Miscarriage around the 8^th week, with no cardiac activity revealed by ultrasound. During the first few weeks of pregnancy, appearance of high fever due to presumed streptococcal pharyngitis, treated with amplital and tachipirina. Normal Beta HCG levels; normal thyroid hormones values. The medical treatment consisted of folic acid and ASA, 75 mg/day, starting at least two months before conception; Seleparina, 4,000 UI/day, starting at conception; and with Benexol. Normal karyotype, female fetus.

Medical diagnosis and tests were done at the Poliabortivity Center, ROME, and at the Polyclinic TOR, Vergata. The results were compared with the previous ones and showed a re-positivation of the ANA (1/180). A cross-match was also performed and gave negative results; the serologic HLA Class I and Class II typing showed the following:

PHENOTYPE AB (serologic): A2, A2, B8, B62(15)

PHENOTYPE DR (serologic): DR3, DR4, DR52, DR53, DQ2, DQ8(3)

The patient’s husband underwent the same HLA typing testing with the following results:

PHENOTYPE AB (serologic) A2, A26(10), B51(5), B35

PHENOTYPE DR(serologic):DR402, DR11, DR53, DR52, DQ7(3), DQ8(3)

In T-lymphocyte test, a reduction of the total number of T-cell subpopulations, with phenotype CD4+ and CD4+/CD8+ ratio, are found to be within normal range.

5) Miscarriage around the 9^th week, with no cardiac activity revealed by the ultrasound. The prophylaxis was: Prefolic, 1 tablet/day; Aspirinetta, 1 tablet/day; Seleparina, 6000 UI/day; Deltacortene 1 and 1/2 tablet of 5 mg/day (total 7.5 mg); Benexol, 1 tablet/day; Ferrograd, 1 tablet/day; the patient started also Prontogest, 1 vial/day.

The histological analysis showed the following: Multiple grey-brownish fragments measuring 4cmx3cm when aggregated. Microscopic analysis shows that the material is composed of residues with blood extravasation and necrosis, chorionic villi of various size, with irregular profile, and some with a cistern-like formation and minor hyperplasia of the throphoblast. The endometrium appears glandular, ARIAS-STELLA type, with nucleated erythrocyte and embryonic residues. Similar histological patterns can be observed also during partial mole. HCG monitoring is recommended. Normal karyotype, female fetus.

In the course of several medical consultations up to date, it has been confirmed to the patient that nothing of significance has emerged to justify 4 miscarriages: Anti-thyroid antibodies, ANA and anti-phospholipids were tested positive but not with high values; mutation in the MTHFR of heterozygotes is fairly common; there isn’t a particularly clear thrombophilia (though the last two pregnancies were similarly interrupted). Finally, there doesn’t seem to be any incompatibility in the couple since the cross-match result is negative and also in view of the first pregnancy which was carried to full term without any problems.

This case was subjected to a second medical opinion by a specialist doctor online, using the online Medical Opinion doctor consultation service. The online doctor was asked the following questions:

-What other kinds of testing could be performed to identify the causes (autoimmune, alloimmune, thrombophilic, low antigen incompatibility of the couple or other) of the above described interrupted pregnancies?

- Is it possible that during the first full-term pregnancy something happened that has negatively affected the 4 subsequent failed pregnancies?

- Was the prophylaxis appropriate, in regard with the dosage administered?

-Which other medical treatments or other therapy would be recommended before and /or during another pregnancy?

- Given the age of the patient, should she still be hopeful or would it be better to accept the idea of not trying anymore?

Response from Medical Opinion online medical services:

Thank you for the referral and the copy of the patient´s medical records. This is an online second medical opinion based on the attached clinical information. I have not performed a clinical examination of the patient. This second opinion has been requested on behalf of the patient by Medical Opinion. The patient is a young woman, 31 years old, suffering from secondary recurrent abortions. During a 2 year period, she underwent 4 miscarriages at 17, 12, 8 and 9 weeks´ gestation with a thorough investigation, including genetic, anatomic, immune and thrombophilic testing.

I agree with the conclusions in her medical records that "nothing significant has emerged to justify the 4 miscarriages", and I do not see any medical problem and don´t believe that we will be able to identify a cause that is related to her first full-term pregnancy. I would suggest more testing (Christiansen et al. 2005): fasting glucose and HbA1c, paternal karyotypes (which will probably be normal), repeated diagnostic hysteroscopy. The patient underwent hysteroscopic adhesiolysis, with no mention of the extent and degree of adhesions or the presence of any other intrauterine pathologies. Since we are actually dealing with idiopathic secondary recurrent miscarriages (the patient has one child), the risk of miscarriage in her next pregnancy is around 25% (Speroff and Fritz, 2005). Therefore, it would be reasonable to try to conceive. During her fifth pregnancy, the patient was treated with a combined prophylactic therapy (Prefolic, Aspirinetta, Seleparina, Deltacortene, Benexol, Ferrograd and Prontogest) which resulted in miscarriage. This combination includes several medications, covering a wide spectrum of pathophysiologic abnormalities that prevent us from isolating the specific benefit or detrimental effect of each of the medications used. Moreover, there are two medications that were not used and should be considered in this specific patient:

Human chorionic gonadotropin (HCG) - A Cochrane meta-analysis (Scott and Pattison, 2000) found that HCG was associated with a reduced risk of miscarriage for women with a history of recurrent miscarriage (odds ratio 0.26, 95% confidence interval 0.14 to 0.52).

Intravenous Immunoglobulins (IVIG) - The Practice Committee of the ASRM (2006) has concluded that "the results summarized from the five RCTs indicate that …In secondary RSPL, there was a higher proportion of successful pregnancies with IVIG, but the number of patients was insufficient to rule out a chance finding (2.19, 95%CI 0.65, 7.39)" ( see also, Hutton et al 2007).

In light of the aforementioned observations, I would suggest the following prophylactic therapeutic strategy:

• Repeat the aforementioned suggested testing including diagnostic hysteroscopy, and treat accordingly.
• The patient should start taking folic acid, 5 mg/day.
• A beta-hCG test should be done every month, on the day of missed menses.
• If positive, the patient should start taking aspirin - 75-100 mg/day and repeat the beta -hCG test two days later.
• If the 2^nd beta -hCG test rises appropriately, the patient should start receiving I.M HCG 2500 IU twice a week (until 12 weeks gestation).
• Low molecular weight heparin (Clexan, 40 mg/day) should be started with the ultrasonographic appearance of fetal hearth beats (6+ weeks gestation).
• Regarding IVIG, It might be added in the next pregnancy, or only if the aforementioned strategy fails (due to its high cost).

Good luck

If I can be of any further help to you, please contact through Medical-Opinion

Sincerely,

MD,

Director

Infertility and IVF Unit

REFERENCES:

Christiansen et al. Evidence-based investigations and treatments of recurrent pregnancy loss. Fertil Steril_ 2005;83:821–39

Hutton B, Sharma R, Fergusson D, Tinmouth A, Hebert P, Jamieson J, Walker M. Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review. BJOG. 2007;114:134-42.

Scott JR, Pattison N. Human chorionic gonadotrophin for recurrent miscarriage. Cochrane Database Syst Rev. 2000

Speroff and Fritz, Eds. Clinical Gynecologic Endocrinology and Infertility. Lipincott, Williams and Wilkins, 2005

The Practice Committee of the ASRM. Intravenous immunoglobulin (IVIG) and recurrent spontaneous pregnancy loss. Fertility and Sterility 2006;86:S226-S227