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Uncovering reasons for recurrent pregnancy loss.

Recurrent pregnancy loss can have a significant emotional impact on women or couples who are attempting to have a baby.

Unfortunately, we are able to determine the reason for recurrent pregnancy loss (RPL) only 50% of the time, and there is minimal evidence-based guidance available for the evaluation and management of this distressing obstetric complication.

Although there are many areas of uncertainty regarding the etiology of RPL, some potential causes - from anatomical, genetic, and molecular abnormalities to endocrine disorders and antiphospholipid syndrome - can and should be investigated.

In all situations, our psychological support is essential, and when a likely cause can be found, we then are able to provide the woman or the couple with a reason and hopefully support their next pregnancy in a way that will result in a live birth.

There are various definitions for RPL and, therefore, evaluation can occur after differing numbers of losses. The American Society for Reproductive Medicine defines RPL as disease distinct from infertility that involves two or more failed pregnancies. It recommends some evaluation after each miscarriage of unknown etiology, and a thorough evaluation after three or more losses (Fertil. Steril. 2008; 89:1603).

Many experts believe, however, that a work-up should occur after two consecutive losses. The incidence of spontaneous miscarriage in all pregnancies is 0%-15%. Overall, the risk of further miscarriages increases after each successive pregnancy loss. However, the recurrence rate after the loss of three pregnancies is only marginally increased, compared with the increased risk after two losses. This is why I and many other experts in the field now consider two consecutive losses sufficient for a thorough investigation.


RPL has been associated with many factors and pathologies. Most women with RPL have early first-trimester losses, although some have recurrent losses in the second trimester. The causes of these first - and second-trimester RPLs are often different and require different types of investigations. Here, we focus on recurrent first-trimester loss.

Structural abnormalities of the uterus have been associated with RPL in many cases. In one recently published study, postabortal evaluation of the uterine anatomy with hysteroscopy revealed approximately 20%-40% with congenital or acquired abnormalities of the uterus. These included congenital uterine abnormalities such as partial or complete uterine septum or arcuate uterus, as well as acquired uterine abnormalities, such as intrauterine adhesions, myomas, or polyps (Eur. J. Obstet. Gynecol. Reprod. Biol. 2011;156:101-4).

The investigators did not find any statistically significant differences between hysteroscopic findings and the number of miscarriages. Intrauterine causes are important to evaluate, as many of these conditions can be surgically corrected and often result in successful subsequent pregnancies.

It is well known that chromosomal abnormalities are the predominant cause of miscarriage, and that the rate of chromosomally abnormal specimens from pregnancy loss increases with age. It has been reported across numerous investigations that 50%-70% of abortuses have a karyotypic chromosomal abnormality. Given the increased incidence of nondysjunction in women as they age, the incidence of recurrent miscarriage in women older than 35 years may be explained by this phenomenon.

For some couples, one partner may carry a balanced chromosomal rearrangement, and thus a karyotypic evaluation of each partner may reveal a cause. Karyotypic evaluation of the products of conception may be helpful as well. If the karyotype is normal, then other causes of recurrent miscarriage may be considered more likely to be contributing factors.

Certain endocrine disorders also are associated with RPL, although routine testing has not been recommended in the absence of clinical symptoms. Poorly controlled diabetes, for instance, increases the risk of first-trimester miscarriage, and if diabetes is not controlled in a subsequent pregnancy, miscarriage may occur again. There is no established norm for progesterone levels in the first trimester, but luteal phase defect or progesterone deficiency also have been implicated in RPL.

Thyroid dysfunction has been implicated in RPL as well, and recent reports on thyroid autoimmunity and miscarriage in women with normal thyroid function also are worthy of consideration. In one meta-analysis, 28 of 31 studies evaluating miscarriage showed a positive association between the presence of thyroid autoantibodies and miscarriage (BMJ 2011;342:d2616). The authors of another recent meta-analysis similarly found that the presence of thyroid autoimmunity was associated with an increased risk of miscarriage in euthyroid women, although the investigators also pointed out that the relationship is not necessarily causal (Clin. Endocrinol. [Oxf.] 2011;74:513-9).

The role of inherited thrombophilias in RPL is rather controversial, with a recent shift away from the belief that all thrombophilias put women at risk for RPL. Initial case-control studies were suggestive of increased risk for women with inherited thrombophilias, including factor V Leiden deficiency, prothrombin gene mutation, antithrombin III deficiency, protein C deficiency, and protein S deficiency. However, subsequent prospective evaluations have shown that these genetic disorders are more likely to be associated with later pregnancy loss and not early recurrent loss.

Antiphospholipid syndrome (APS) continues to be considered a major contributor to RPL, causing up to 15% of recurrent miscarriages. This disorder is an autoimmune disorder that manifests itself in vascular events or adverse pregnancy outcome in addition to the presence of antiphospholipid antibody. The diagnosis is made with the presence of one or more clinical scenarios and the presence of antibodies when the patient is tested on two occasions, at least 12 weeks apart.

Evaluation and Management

Given the wide array of potential causes of RPL, evaluation can be lengthy and potentially unfruitful.

On the other hand, because a significant number of uterine abnormalities are correctable, hysterosalpingogram, sonohysterography (also known as hysterosonography), or hysteroscopy are often worth performing. In a study of 60 nonpregnant patients with a history of at least three previous recurrent miscarriages, hysterosonography was found to have higher diagnostic accuracy in the detection of uterine cavity anomalies and was better tolerated by the patients, compared with the other two methods (Arch. Gynecol. Obstet. 2006;274:284-8). In the event that there is a congenital uterine malformation or an acquired abnormality, these can be managed with surgical correction of the abnormality.

Furthermore, if karyotype is available from any of the products of conception involved in the miscarriages, then karyotypic evaluation may be possible. An aneuploidy result in the setting of advanced maternal age may lead the clinician to suspect that nondysjunction is a factor in the RPL. In the event that the karyotype is normal, further investigation into other causes may be fruitful.

Parental karyotyping will reveal a balanced translocation 3%-6% of the time. However, as the authors of a case vignette point out, such karyotyping is expensive, and treatment options (in vitro fertilization with preimplantation genetic diagnosis) have not been shown to improve outcome over spontaneous conception (N. Engl. J. Med. 2010;363:1740-7). These realities lead some couples to forego this type of testing.

Testing for diabetes and thyroid disease is not recommended as a screening measure in RPL unless the patient has symptoms suggestive of either condition. Although some experts might recommend testing for thyroid autoimmunity, the value of routine screening for thyroid autoantibodies in euthyroid women with RPL is unclear at this point. There is some evidence that treatment with levothyroxine can significantly reduce the risk of miscarriages (as described in the two previously cited meta-analyses) so for now, the reported association between thyroid autoimmunity and miscarriage is at least worthy of our consideration.

With regard to thrombophilias, the focus is increasingly on screening specifically for APS, and treating accordingly, rather than on screening more broadly for thrombophilias. Although some providers continue to evaluate for inherited thrombophilia in women with RPL, others now recommend that evaluation for inherited thrombophilia not take place outside a research setting.

Most people with inherited thrombophilias do well with pregnancies, and research thus far has not shown any clear benefit to heparin thromboprophylaxis (with or without aspirin) in women with inherited thrombophilia and RPL.

A 2009 Cochrane review concluded that there is insufficient evidence to recommend the use of anticoagulants in women without antiphospholipid syndrome (Cochrane Database Syst. Rev. 2009 [doi:10.1002/14651858.CD004734. pub3]).

Two more recent, controlled, randomized trials of women with unexplained RPL similarly showed no improvement in live-birth rates with the use of either low-dose aspirin or low-dose aspirin combined with low-molecular-weight heparin (N. Engl. J. Med. 2010;362:1586-96; Blood 2010; 115:4162-7).

On the other hand, trials of women with antiphospholipid antibody syndrome have shown that pregnancy outcomes are improved with the use of aspirin plus heparin. A Cochrane review that covered 13 qualifying studies concluded that combined unfractionated heparin and aspirin may reduce pregnancy loss by 54% (Cochrane Database Syst. Rev. 2010 [doi: 10.1002/14651858. CD002859.pub2]).

Investigators are still exploring the potential differences between unfractionated and low-molecular-weight heparin (LMWH) in the setting of antiphospholipid syndrome. However, these formulations are used interchangeably so frequently in other settings that either can be selected for treatment of RPL. We favor the use of LMWH because dosing is once daily, as opposed to the twice-daily dosing schedule required for unfractionated heparin.

Luteal phase defects and progesterone deficiencies are difficult to diagnose.

Although endometrial biopsy was once used to attempt to assess progesterone function, this has been not been shown to be beneficial in the evaluation of couples with RPL.

However, a recent Cochrane review of progesterone for preventing miscarriage found that although there is no evidence to support the routine use of progesterone to prevent miscarriage in general, there appears to be evidence of benefit in women with a history of recurrent miscarriage (Cochrane Database Syst. Rev 2008 [doi:10.1002/ 14651858.CD003511.pub2]).

Regardless of the route of administration, progesterone supplementation was associated in this review with a statistically significant decrease in the miscarriage rate compared with placebo or no treatment in women with RPL (odds ratio, 0.38).

An Individualized Approach

In order to appropriately counsel and care for these patients, a thorough obstetric history is important and should help to guide evaluation and management. It is important to be sensitive to the emotional factors that come in to play for many couples who are going through the evaluation of pregnancy loss. I often reassure these women that this is a common problem and that even with repeated miscarriages they may still have successful pregnancies in the future without any intervention.

I give them a thorough explanation of the etiology of RPL, and emphasize that a cause might not be found. If a patient has any symptoms suggestive of diabetes, then I consider a fasting glucose or hemoglobin [A.sub.1c] test to confirm a diagnosis. Evaluation of the uterine cavity should be undertaken for all women with RPL.

I also recommend evaluation for antiphospholipid syndrome with lupus anticoagulant, anticardiolipin antibodies, and [beta.sub.2] -glycoprotein I antibodies. (See box.)

In addition, I generally discuss with patients the controversy over testing for inherited thrombophilias. If there is any family history suggestive of thrombophilia, I will test for these. Otherwise, I discuss the potential for this testing and will often leave this up to the patient to decide.

After all the testing is complete, management is driven by the results, and when there are no positive results, progesterone supplementation can be offered.

Referral patterns likely vary by community, with either reproductive endocrinologists or maternal fetal medicine specialists providing consultation for these patients.

It is important to appreciate, however, that general ob.gyns. - armed with the proper time and information - are also in the position to evaluate and work up an RPL case, and to provide the supportive care, empathy, and encouragement that patients need.

RELATED ARTICLE: Criteria for the Diagnosis of Antiphospholipid Syndrome

Clinical Scenarios (any one of these present):

* Thrombosis in any organ.

* Intrauterine embryonic or fetal death at greater than 10 weeks' gestation.

* Delivery before 34 weeks' gestation because of eclampsia, preeclampsia, or other sign of placental insufficiency.

* Three or more recurrent miscarriages unexplained by other conditions.

Laboratory Findings (any one of the following found on two occasions 12 weeks apart):

* Lupus anticoagulant present.

* Anticardiolipin IgG and/or IgM at medium values or high (greater than 40 GPL or MPL, or greater than 99th percentile).

* [Beta.sub.2]-glycoprotein I of IgG and/or IgM (in titer greater than 99th percentile).

Note: 1 GPL (lgG phospholipid) unit = 1 mcg lgG antibody; 1 MPL (IgM phospholipid) unit = 1 mcg of IgM antibody.

Source: J. Thromb. Haemost. 2006;4:295-306

Dr. ATKINS said she had no relevant financial disclosures.
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Title Annotation:OBSTETRICS
Author:Atkins, Kristin
Publication:OB GYN News
Date:Feb 1, 2012
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