Additional reading

Immunotherapy for recurrent spontaneous abortion.

Early Pregnancy 1995 Mar;1(1):13-26 (ISSN: 1354-4195) 
Coulam CB 
Genetics & IVF Institute, Fairfax, Virginia, USA.

Recurrent pregnancy loss is a healthcare concern. Safe and effective treatments are necessary. Since women experiencing recurrent pregnancy loss are a heterogeneous population, specific markers are necessary to identify those who will respond to various treatments. The presence of antiphospholipid antibodies identifies women with recurrent pregnancy loss who are most likely to respond to heparin and aspirin treatment. An elevated concentration of NK cells in maternal blood and a loss of karyotypically normal embryos after detection of cardiac activity on ultrasonographic examination identify women who are most likely to respond to IVIg treatment. An obstetric history of recurrent primary abortion with an absence of maternal antipaternal lymphocytotoxic antibodies and anti-phospholipid antibodies predicts women who are most likely to respond to allogeneic leukocyte immunization. However, the treatment effect is low, with a livebirth rate of 60% which represents an enhancement over no treatment in the range of 8-10%. The difference in livebirth rates between women receiving IVIg therapy as compared to placebo was 28%. Women experiencing recurrent spontaneous abortion who have high, as opposed to low levels of leukocyte antibody do not respond to leukocyte immunization therapy. They do, however, respond to treatment with IVIg--the overall success rate of IVIg being 70%. It is important to be able to identify women likely to respond to various forms of immunotherapy. Chromosomal abnormalities are evident in 60% of recurrent aborters. Women experiencing recurrent aneuploidy in their abortus would not be expected to respond to immunotherapy. At the present time, the only way to identify such women is to have the results of chromosome analysis of previous pregnancy losses available. Having access to this information will require a change in current obstetric practice regarding obtaining karyotyping of all pregnancy losses. The cost-effectiveness of chromosome studies from abortuses is apparent when costs of evaluation and treatment are considered.

Pregnancy outcome in recurrent spontaneous abortion associated with antiphospholipid antibodies: a comparative study of intravenous immunoglobulin versus prednisone plus low-dose aspirin.

Am J Reprod Immunol 2001 Mar;45(3):174-9 (ISSN: 1046-7408) 
Vaquero E; Lazzarin N; Valensise H; Menghini S; Di Pierro G; Cesa F; Romanini C 
Department of Obstetrics and Gynecology, University of Rome Tor Vergata, Fatebenefratelli Hospital, Isola Tiberina, Italy.

PROBLEM:

To compare the use of intravenous immunoglobulins (IVIG) with prednisone plus low-dose aspirin (LDA) in treating pregnant women with a history of recurrent fetal loss having the antiphospholipid antibody (aPL), in terms of live-birth rate and maternal and perinatal morbidity.

METHOD:

A prospective, two-centers trial study included 82 recurrent aborters with aPL syndrome. Twenty-nine were treated with prednisone and LDA in one center, 53 received IVIG in the other center. Maternal and fetal outcomes and pregnancy complications were compared between groups.

RESULTS:

Live-birth rates were equivalent between groups (78 vs 76%). Mean birth weight was higher in the IVIG group than in the prednisone plus LDA group. In the prednisone- plus LDA-treated patients, gestational hypertension and gestational diabetes were found significantly more often than in the IVIG-treated group (14 vs 5% and 14 vs 5%, respectively).

CONCLUSION:

In patients with aPL syndrome, IVIG treatment improved pregnancy outcome, with significantly lower pregnancy complication rates, when compared with prednisone plus LDA therapy. Medscape Medline Abstract

Canadians Find Gene Tied To Late Miscarriage

Discovery raises possibility of screening women at risk, developing treatment

By CAROLYN ABRAHAM Globe and Mail 
Tuesday, July 19, 2005

Ottawa researchers have discovered the molecular glitch that explains why so many women lose their babies late in their pregnancies -- a condition that is also the second leading cause of infant deaths in the developed world.

Scientists at the Ottawa Health Research Institute have found that a particular gene can produce an underactive enzyme that interferes with the proper growth of a woman’s placenta, the crucial organ that forms within the walls of the uterus to feed a developing fetus.

Too many times, obstetrician and scientist Andrée Gruslin felt helpless and heartbroken watching excited mothers-to-be with "big bellies" and big plans miscarry more than 20 weeks into their pregnancies. In one case, a woman lost eight babies in a row.

"This is a lot more dramatic than [an early-stage] miscarriage," which usually happens within the first trimester, Dr. Gruslin said. "These are pregnancies that can end in a delivery room or the neonatal intensive-care unit."

But finding the condition’s cause -- a gene that can also result in the birth of underweight babies who battle health problems all their lives -- may make it possible to screen pregnant women at risk and develop a treatment.

"If we can find out about the women at risk very early on, we can monitor a baby a lot more closely and possibly save the baby," said Dr. Gruslin, co-author of the report published in the current issue of the Proceedings of the National Academy of Sciences.

The Ottawa team is now setting up a study to run blood tests on roughly 2,000 pregnant women for signs of the underactive enzyme, to ensure the discovery can translate from research into clinical practice.

Known as fetal-growth restriction, the condition strikes 3 per cent of all pregnancies and is the second leading cause of infant deaths in industrialized countries, after premature birth.

Carole Aylwin and her husband Dominique Ratté knew nothing about fetal-growth restriction when last year they saw the troubling ultrasound images of their first child, 17 weeks into the pregnancy.

"At the hospital, [doctors] realized the baby was looking very small. At first, they thought they had mixed up the dates . . . that the baby was two weeks younger than they thought," Ms. Aylwin said.

But after ruling out a genetic problem with the baby and a maternal infection, the doctors realized during regular ultrasound scans that her placenta looked "weird" and "dense," she said, and the baby’s growth was discouraging. By the 24th week, Ms. Aylwin -- nearly six months pregnant -- and her husband learned their tiny baby could be severely handicapped if he or she survived at all.

"So then it was a matter of what would happen and when would it happen," said Ms. Aylwin, describing a nearly unbearable level of stress during what was to be such a happy time.

Last October, their baby was delivered stillborn at 26 weeks.

"All the time, you are asking how come this is happening," Ms. Aylwin said. "Knowing now that they have discovered this molecule that could offer a preventative treatment . . . would be a relief."

Dr. Gruslin teamed up with OHRI researchers Qing Qiu, Ajoy Basak, Majambu Mbikay and Benjamin Tsang to study the molecular biology behind the growth of placentas.

Earlier research had shown that a gene producing a protein known as insulin-like growth factor 2, or IGF2, was critical.

This growth factor invades the muscle cells of the uterus to allow blood and oxygen in to feed the fetus, and helps fetal cells divide and grow. Mice born without the IGF2 gene were very tiny and also grew abnormally small placentas.

But the Ottawa research showed that the normal form of this IGF2 protein has a very long chemical structure.

However, to function properly when helping to build the placenta, another molecule has to effectively cut it down into a smaller form.

That molecule, a so-called PC4 enzyme, is produced by a gene known to be active in the ovaries, the testes and now the placenta.

Dr. Gruslin said it acts like scissors, which cut down the growth-factor protein to a length that is crucial to a healthy pregnancy.

"We have found the scissors in some women are just not sharp enough, or they just don't have enough scissors," Dr. Gruslin explained.

The team tested its theory in a study that found seven pregnant women who suffered from fetal-growth restriction carried longer, or "uncut" forms of the IGF2 protein in their blood.

Eight women without the condition carried shorter forms of the protein.

"This is pointing to a gene that is not active enough in these women," Dr. Gruslin said of the women who suffer from fetal-growth restriction.

There are no immediate medical or genetic therapies to treat the condition and screening for it still remains in the research phase.

Dr. Gruslin has found some success with certain interventions, but she stresses that she can offer no scientific research to explain their effectiveness at this point.

In the case of the women who suffered eight consecutive miscarriages, for example, she prescribed a high-dose of folic acid and a baby Aspirin daily.

That woman has since given birth to a healthy child.

Now Ms. Aylwin who is once again pregnant, currently 14 weeks along, is trying a similar regimen. "They are following me closely," Ms. Aylwin said, "So far everything is fantastic."

WEB SITES AND BOOKS WITH MORE INFORMATION

Grieving Reproductive Loss: The Healing Process by Kathleen Gray and Anne Lassance

www.apsfa.org 
A site about Antiphospholipid Antibody Syndrome. APS is also called APLS or APLA in the United States and Hughes Syndrome or Sticky Blood in the UK

www.chinaivf.com 
Recurrent Pregnancy Loss, by Barry Jacobs, M.D.

www.jem.org 
Complement C3 Activation Is Required for Antiphospholipid Antibody-induced Fetal Loss

MedlinePlus 
Further information on recurrent pregnancy loss

www.nature.com 
Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation

www.rialab.com 
Reproductive Immunology Associates - solutions for immune related miscarriages

www.rialab.com 
About Antinuclear Antibodies

Obstetrics and Gynecology UCLA 
What causes recurrent miscarriage? A discussion of

  • Genetic Causes
  • Hormones
  • Thrombophillic/Blood Clotting Disorders
  • Infection and Recurrent Miscarriage
  • Structural abnormalities of the uterus and cervical Incompetence
  • General

www.surgeryencyclopedia.com 
A discussion of cervical cerclage - a minor surgical procedure in which the opening to the uterus (the cervix) is stitched closed in order to prevent a miscarriage or premature birth.