“Secondary” Recurrent Pregnancy Loss

04 Nov
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“Early recurrent pregnancy loss (RPL) is defined as two (2) or more failed pregnancies prior to the 13th week of gestation. Less than 5% of women will experience two (2) consecutive early miscarriages, and only 1% experience three or more. About 70% of these are “Primary RPL”, i.e., repeated losses occurring in circumstances where all prior pregnancies were lost before the 26th week (third trimester). The remaining 30% are “Secondary RPL” i.e., where the woman will have had at least one (1) prior third trimester pregnancy before have a series of early losses.

This post will address early Secondary RPL as a distinct entity because the cause is often unique, necessitating special diagnostic and therapeutic considerations.

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To start with, it is important to recognize that most sporadic early (1st trimester) pregnancy loss (>70%) is due to “embryo incompetence” related to chromosomal/genetic factors. However, when early miscarriages recur repeatedly, the cause is more frequently due to an embryo implantation dysfunction, and this likelihood increases with the number of miscarriages experienced.  On the other hand, later (2nd trimester) pregnancy losses (which not discussed in detail here) are most often due to pathologic, post-surgical and congenital (present at birth) uterine conditions. Infrequently, parasitic or viral inflammatory processes also play a role.

The vast majority of early pregnancy losses are caused by embryo chromosomal irregularities (aneuploidy) and tend not to recur over and over. Having had a single miscarriage, the likelihood of a second one occurring is no greater than average. However, after two (2) losses, the chance of a third one occurring is double (35-40%) and after three (3) losses, the chance of a 4th miscarriage increases to about 60%. The reason for this is that the more miscarriages a woman has, the greater is the likelihood of this being due to non-chromosomal, implantation dysfunction.

Knowing this, it makes sense that if following miscarriage, specialized analysis of the chromosomal configuration (karyotyping) of embryonic/fetal products shows this to have been a karyotypically normal conceptus, there would be a strong likelihood that the losses were likely due to “embryo implantation dysfunction” rather than embryonic factors. It would also provide an ominous prediction that if left untreated, miscarriages would be likely to occur in subsequent pregnancies as well. To me, such a disaster is thus potentially remediable and this is precisely why I strongly advocate that all miscarriage specimens be karyotyped.

Late pregnancy losses occur far less frequently (1%) than do early pregnancy losses. They are most commonly due to anatomical abnormalities of the uterus and/or cervix. Weakness of the neck of the cervix rendering it unable to act as an effective valve that retains the pregnancy in the uterus (i.e. cervical incompetence) is in fact one a very common cause of 2nd trimester pregnancy loss. So also are developmental (congenital) abnormalities of the uterus (e.g., a uterine septum), uterine fibroid tumors, and inadequate thickening of the uterine lining.

Secondary Early RPL

When this occurs it should be a “red flag” to the treating doctor, suggesting an underlying anatomical or immunologic implantation dysfunction (IID). Important contributing factors are:

1. An inadequate uterine lining, that is either too thin (<8mm at the peak of estrogen stimulation) or whose receptivity has been compromised by post-inflammatory/post-surgical scarring or surface lesions such as fibroids or polyps, and sometimes (rather infrequently) due to prenatal exposure of the woman to diethyl stilbestrol (DES).  Irregularity in the contour of the uterine cavity can also result from polyps, fibroid tumors in the uterine wall encroaching on the uterine cavity, intrauterine scarring (post-inflammatory or post-surgical).

2.  Immunologic implantation dysfunction (IID) causing early RPL: For this to be a factor there must be associated activation of uterine natural killer cells (NKa)

  • Autoimmune Implantation Dysfunction: Most immunologically caused early, “primary RPL” miscarriages are autoimmune in origin and are due to auto-antibody (anti thyroid/antiphospholipid antibodies)-induced, uterine natural killer cell activation (NKa). Here, timely initiation of the correct dosage of Intralipid/steroids/heparinoid (Clexane or Lovenox), sufficient to down-regulate (NKa/APA) through the first trimester, in my opinion constitutes optimal and effective treatment.
  • Alloimmune Implantation Dysfunction:  Here, reaction to antigens derived from another member of the same species (the man’s sperm) causes activation of the woman’s uterine NK cells resulting in local release of excessive TH-1 cytokines that damage the root system (trophoblast) of the implanting embryo leading to subsequent loss. Alloimmune implantation dysfunction is a relatively common immunologic cause of recurrent pregnancy loss, and even more so…of secondary early RPL. The cause is believed to be alloimmune incompatibility in DQ alpha/HLA genotypes between the male (sperm) and the recipient’s uterus. Required treatment is much more complex than with autoimmune RPL. Here, treatment depends on whether one or two DQ alpha genes are involved (since each person has two such genes). If only one DQ alpha gene of each partner matches (a “partial match”), treatment with Intralipid and steroids can be effective. Since in such cases the likelihood of any embryo matching is 50:50, and once an embryo matches, it is highly unlikely that any treatment (Intralipid/steroids/IVIG/LIT) will avoid it being rejected, it is my opinion that in cases of a “partial match” +NKa, only one embryo should be transferred at a time to avoid one matching embryo from sealing the fate of both. I also recommend full embryo karyotyping (CGH) to selectively facilitate the transfer of a “competent” embryo and so double the chance that a single transferred blastocyst (provided of course that it is not a “matching” embryo) will propagate a viable pregnancy.

Since Autoimmune IID is often genetically transmitted, it is not surprising that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as Lupus Erythematosus (LE), Scleroderma, clinical or subclinical hypothyroidism, Rheumatoid Arthritis etc. Reactionary autoimmune IID also occurs in conjunction with endometriosis (regardless of its severity) in about 1/3 of cases.

Managing Secondary RPL

Since “embryo incompetence” due to genetic/chromosomal factors is by far the commonest cause of early miscarriage, all cases of RPL must be so evaluated to start with. This requires genetic testing of both partners’ blood to diagnose and treat balanced translocations or other genetic conditions (rare), full karyotyping (CGH) of embryos to try and exclude aneuploidy of the embryos, and then selective embryo transfers of chromosomally normal embryos.

Evaluation for implantation dysfunction requires timed ultrasound assessment/hysteroscopy and treatment of uterine factors (hormonal/ surgical/ Viagra therapy/ gestational surrogacy).  Treatment of anatomical causes of early implantation dysfunction could involve surgical (usually laparoscopic/hysteroscopic) removal of local lesions such as fibroids, scar tissue and endometrial polyps. Notably, cervical incompetence and uterine congenital abnormalities (septum etc.) are highly unlikely causes of early pregnancy loss. They more commonly result in later loss and premature labor.

Blood Testing is needed to diagnose thrombophilias which, if present, require selective supplementation with folic acid /Clexane/Lovenox

RPL due to Autoimmune IID is diagnosed through blood testing the woman for antiphospholipid antibodies (APA), antithyroid antibodies (ATA), immunophenotype, antinuclear antibodies (ANA), NKa using the K562 target cell test (and/or possibly in the future, measurement of TH-1 cytokine activity). Central to the diagnosis of autoimmune IID is the detection of NKa in the absence of an alloimmune cause (see below). Treatment involves the well-timed administration of an appropriate dosage of Intralipid/steroids/Lovenox or Clexane (selectively) in the 1st trimester. Steroid therapy is commenced with IL therapy 10-14 days prior to anticipated egg retrieval and is ended by the 10th week.

RPL due to a “partial” alloimmune IID is diagnosed by testing the blood of both partners for DQ alpha and HLA genetic matching + NKa. It is essential to understand that alloimmune matching WITHOUT NKa IS NOT associated with an increased risk of failed IVF or pregnancy loss and does not require treatment. In my opinion, treatment of a “partial DQ alpha match”/NKa requires 2-4 weekly Intralipid infusions well in to the 2nd trimester. Steroids therapy is commenced with IL therapy 10-14 days prior to anticipated ET and ends by the 10th week.  Sequential (cyclical) single blastocyst FET of chromosomally normal embryos is recommended for reasons mentioned above.

Cases of early RPL due to a total DQ alpha/HLA match + NKa have a dismal chance of a viable pregnancy unless the embryos are transferred to  a non-matching gestational surrogate or non-matching donor sperm is used along with  the embryo recipient being treated with Intralipid/steroids for her NKa.

Use of IVF: IVF is recommended in order to optimize the timing for good quality blastocysts being transferred into an optimally prepared intrauterine environment.

Important Post Script:

Whenever a patient presents with a history of having had a previous pregnancy that advanced into the second or third trimester (whether a viable or non-viable gestation) and thereafter started to lose pregnancies repetitively in the 1st trimester, two causes must immediately come to mind:

a) Endometritis with her prolonged pregnancy compromised her uterus (lining thickness or scarring) or

b) The woman has an Immunologic Implantation Dysfunction (often due to alloimmune DQ alpha/HLA matching). The mechanism of the latter is that she conceived the 1st time before NK cell activation occurred and thereupon, either during the prolonged pregnancy or with subsequent exposures to her partner’s sperm, she developed NKa. A similar sequence of events often will also explain why a woman was able to have a baby in a prior relationship and then started to experience repeated miscarriages (or unexplained infertility/IVF failure) with a new partner (who possibly shared DQ alpha/HLA similarities with her.

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