The definition of recurrent miscarriages, or habitual abortion, is usually described as having had at least three consecutive spontaneous miscarriages. However, a history of only one spontaneous miscarriage clearly increases the risk for subsequent miscarriages.
In women who have not had at least one live birth, there is a 40% risk of loss after 2 or more miscarriages. The risk of miscarriage in older women increases with advancing age, rising to around 40% by age 44. The definition of recurrent miscarriage must be made on the basis of prognosis for future pregnancies, and patients who have had two or more miscarriages probably should be evaluated.
All patients with recurrent miscarriages should have either hysteroscopy or saline ultrasound. The first procedure consists of placing a small fiberoptic instrument in the uterus to allow direct visualization of the cavity of the uterus. The second procedure, saline ultrasound, is done by placing a small amount of saline solution in the uterus and doing an ultrasound examination at the same time. Either allows good visualization of the uterus. Most uterine abnormalities can be repaired with surgery.
Immunologic Factors (antiphospholipid antibodies, aPL)
Immunologic factors proven to be related to recurrent miscarriages include anticardoilipin antibodies and lupus anticoagulant. Either of these may be related to early miscarriage, fetal growth retardation or late fetal death. While the exact mechanism by which these factors cause miscarriage or fetal damage or death is unknown, many investigators have described extensive placental clotting.
The following tests should be obtained in all patients with recurrent miscarriage:
- Lupus anticoagulant
- Anticardiolipin IgM, IgG, IgA
If either of the above tests are positive, therapy consists of one low dose aspirin daily and either heparin, 5000 IU bid, starting when pregnancy is diagnosed, or preferably, low molecular weight heparin (Enoxaparin,lovenox) 10 mg. daily in one dose. Women with a history of three or more first trimester miscarriages and the presence of aPL and who are not treated have at least an 80% probability to lose a subsequent pregnancy.
Possible complications of heparin or lovenox include reduced platelet counts and bone loss. The latter almost always occurs to a limited extent, reduced platelet counts rarely.
Patients taking heparin or lovenox should have platelet counts about once monthly, and bone scans of the lumbar spine, femoral neck and forearm at 16 weeks and at 34 weeks. Postpartum bone scans also should be done.
When to stop the heparin and aspirin is problematic. Most investigators suggest that if the problem is early pregnancy loss, treatment may be stopped at about 20 weeks gestation, while women with late pregnancy loss should continue treatment to near term.
While there are other causes for thrombophilia, by far the most common are factor V Leiden mutation and prothrombin DNA mutations . Therefore, assessment of recurrent miscarriage should include evaluation for these mutations. Patients who are positive are treated with low dose aspirin and heparin, 5000 IU daily from the time of diagnosis of pregnancy.
Approximately 70% of miscarriages are a result of chromosomal abnormalities, most commonly triploidies, but other abnormal chromosomal changes include 46 X0 and various other chromosomal rearrangements.
Parental chromosomal abnormalities account for between 5 and 10% of recurrent miscarriages. These are most commonly balanced translocations, sex chromosome mosiacism, inversions and ring chromosomes. Therefore, parents who have experienced 2 or more miscarriages should have karyotypes on both partners, since abnormalities can occur in either partner. In most couples in whom one of the parents have chromosomal abnormalities, there is a 50% chance that the next pregnancy will be normal. Pre-implantation genetic screening (PGS) can eliminate embryos with many of these abnormalities. Genetic amniocentesis can also be done, since the children of continuing pregnancies with such abnormalities may have severe congenital abnormalities.
Hypothyroidism is associated with an increased incidence of miscarriage and it is probably worthwhile to measure TSH and T-4.
Luteal phase defect has been a subject of debate for many years. While some early data suggested that low levels of progesterone in the luteal phase might be responsible for pregnancy loss, there is as yet no solid proof, despite many published studies. Diagnosis is by endometrial biopsies on two occasions or persistently low serum progesterone (<10 ng./ml) in two or more cycles.
While there is no definite proof of the efficacy of therapy, empiric treatment is often used in the form of progesterone vaginal suppositories, 50 mg. twice daily.
- Clifford, K. et al Future pregnancy outcome in unexplained recurrent first trimester miscarriage Human Reprod. 12: 387, 1997
- Speroff, l. et al Clin. gynecologic endocrinology and infertility, Lippnicott, Williams and Wilkins 1999
- ZJ Foka, et al Factor V Leiden and prothrombin G20210A mutations are associated with recurrent miscarriages, Human Reprod. 15: 458, 2000
- Brenner, B et al Gestational outcome in Thrombophilic women with recurrwent pregnancy loss treared with enoxaparin, Throm. Haemostat. 83: 693, 2000
- Daya, S et al Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage, Human Reprod. 5: 475, 1999
- Backos, M et al, Pregnancy complications in women with recurrent abortions associated with antiphospholipid antibodies treated with low dose aspirin and heparin, Br J Obst and Gynec, 106:102, 1999
Antiphospholipid Antibodies – relation to IVF and pregnancy loss
Luther M. Talbert, M.D.
The antiphospholipid syndrome has been known for many years and is associated with thromboembolism in non-pregnant and pregnant women. While most thrombotic events are venous, cerebral thromboses also occur, even in very young people. It has been known for many years that antiphospholipid antibodies (Lupus anticoagulant and anticardiolipin, aPL) are related to recurrent miscarriage. The data linking aPL and failure to conceive, either naturally or during in vitro fertilization, is much less secure. (1,2)
While first trimester abortion is the most commonly reported pregnancy complication associated with aPL, second trimester loss, small for gestational age infants, preeclampsia and intrauterine death also have been shown to be related to the presence of aPL. Untreated women with three or more first trimester abortions and the presence of aPL have a pregnancy loss rate of up to 80-90% in subsequent pregnancies,
The mechanism by which aPL causes pregnancy loss is not entirely clear. But many investigators have noted extensive placental thromboses, a decrease in vasculo-syncytial membranes and hypovascular villi. (3) In vitro studies suggest that the presence of aPL may increase the production of thromboxane by placental tissue without affecting prostacyclin synthesis.
The fact that aPL is not a rare cause of recurrent miscarriage is attested to by the findings in most studies that approximately 15% of all recurrent miscarriages are due to aPL.
In 1994, Sher et al reported that the presence of aPL reduced the pregnancy rate in patients having IVF, and that treatment with heparin and aspirin restored rates to normal. (5) Since that time, several well-designed studies have refuted this hypothesis. Denis, AL et al studied 793 patients having IVF, and found no correlation with the presence or absence of aPLs. (6) Birdsall, MA et al studied 240 women having IVF, and found no correlation between pregnancy rates and the presence of aPL, but did find a strong correlation with intrauterine growth retardation. (7) Hill and Scott have also studied the presence of aPLs, and found no effect of these antibodies on the outcome of IVF. (8) Thus, it seems established that the presence of aPLs does not negatively impact pregnancy rates in IVF.
While there is no clear evidence that the presence of aPL affects the outcome of IVF, there is overwhelming evidence of its deleterious effect on pregnancy.
There is a high rate of recurrent miscarriage, most common during the first trimester, but may occur later in pregnancy. It has been estimated that about 15% of recurrent pregnancy loss is due to aPLs, and in future pregnancies without treatment, the probability of a live birth is about 10%. (4) In addition, there is increased probability for intrauterine growth retardation and preeclampsia. Therefore, women with unexplained recurrent miscarriage, intrauterine growth retardation or fetal demise in later pregnancy should be investigated for the presence of aPL. Specifically, testing for lupus anticoagulant and anticardiolipin should be done, even if another cause has been elucidated.
Treatment is with low dose heparin, 5000 IU twice daily and aspirin 75 mg.daily. Since pregnancy loss is rare in the first six weeks of pregnancy, many investigators recommend that aspirin be started when the pregnancy test is positive, and that heparin be started when a fetal heart is visible at about six weeks.
There are serious side effects when using heparin. Perhaps the most common of these is bone loss, which amounts to approximately 1% loss of mineral density in the femoral neck monthly, but may reach as high as 12% during the entire pregnancy. Thrombocytopenia has also been reported with heparin therapy, and most authors suggest a platelet count weekly for the first three weeks, and every six weeks thereafter.
Since pregnancy loss may occur late in pregnancy, when to stop becomes an important question. Discontinuation at 34 weeks seems reasonable in women who have experienced early pregnancy loss, but in those with late pregnancy complications (growth retardation, intrauterine death), it may be advisable to continue therapy to term.(1)
- Based on the data presented above, NCCRM patients will follow the protocol below:
- Patients with positive aPL will start aspirin 81 mg. daily when pregnancy is diagnosed.
- Heparin, 5000 IU BID will be started when a fetal heart is present or at 6 weeks gestational age.
- PTT, PT and platelet count will be determined before heparin treatment is initiated.
- Platelet counts will be done at weekly intervals during the first three weeks of heparin therapy and every six weeks thereafter.
- PTT and PT will be done before starting heparin and at six weeks.
- Women with early pregnancy loss will stop both heparin and aspirin at 34 weeks. Those with late pregnancy loss will continue therapy to term.
- Guidelines on the investigation and management of antiphospholipid syndrome, British J. Hematology, 109:704, 2000
- Kowalik, A et al Midfollicular anticardiolipin and antiphosphotidylserine antibody titers do not correlate with IVF outcome. Fertil. Steril, 68:298, 1997
- Levy, RA et al, Placental pathology in antiphospholipid syndrome Lupus, (1998) Suppl 2, S 81-S 85
- Backos, M et al, Pregnancy complications in women with recurrent miscarriage associated with antiphospholipid antibodies treated with low dose aspirin and heparin, British J. Obstet. Gynec. 106:102-107, 1999
- Sher, g, et al, High fecundity rates following in-vitro-fertilization and embryo transfer in antiphospholipid antibody seropositive women treated with heparin and aspirin, Human reprod. 9:2278-83, 1994
- Denis, AL et al, Antiphospholipid antibodies and pregnancy rates and outcome in in vitro fertilization patients, Fertil. Steril, 67:1084-90, 1997
- Birdsall, MA et al Antiphospolipid antibodies in women having IVF, Human Reprod. 11:1185, 1996
- Hill JA and Hill, RT, Immunologic tests and IVF: “please, enough already” Fertil. Steril. 74:439, 2000