A research group led by Associate Professor TANIMURA Kenji from the Department of Obstetrics and Gynecology at Kobe University Graduate School of Medicine, Professor YAMADA Hideto, Director of the Center for Recurrent Pregnancy Loss at Teine Keijinkai Hospital, and Professor ARASE Hisashi from the Osaka University Research Institute for Microbial Diseases has demonstrated, ?for the first time in the world, that novel autoantibodies which had been found to cause thrombosis and other conditions in joint research conducted by Kobe and Osaka universities in 2015, are also implicated in pregnancy disorders, including hypertensive disorders of pregnancy and fetal growth restriction.

It is expected that this result will help illuminate the mechanisms underlying hypertensive disorders of pregnancy, fetal growth restriction, recurrent pregnancy loss, and infertility, for which the causes are not fully understood, as well as contribute to the development of drugs to treat these conditions.

These findings were published in the International Journal of Molecular Sciences on June 30.

Main Points

• In 2015, the group published a paper reporting the discovery of novel autoantibodies that cause a disease called antiphospholipid antibody syndrome, which can cause thrombosis and miscarriage.
• In 2020, they reported that around a quarter of women with recurrent pregnancy loss tested positive for these autoantibodies, and that they are a leading cause of recurrent pregnancy loss.
• In their new 2023 study, they reported that these autoantibodies were present in 18% of women suffering from infertility and 28% of women who had suffered repeated implantation failure.^*1
• The team carried out a multicenter research project to measure these autoantibodies in women with recurrent pregnancy loss, hypertensive disorders of pregnancy, fetal growth restriction, or premature birth at five Japanese hospitals, including Kobe University Hospital and three other university hospitals.
• They found that in addition to recurrent pregnancy loss and infertility, autoantibodies are also a cause of hypertensive disorders of pregnancy and fetal growth restriction.
• The results of this study are expected to lead to the identification of the mechanisms at the onset of conditions including hypertensive disorders of pregnancy, fetal growth restriction, recurrent pregnancy loss, and infertility, and to the development of treatment methods, which could be key to resolving the issue of Japan’s low birth rate.

Study Background

There is a disease specific to pregnancy called hypertensive disorders of pregnancy, where high blood pressure, along with damage to vital organs such as the brain, liver, and the kidneys can endanger the life of the pregnant mother or the baby. In another specific condition during pregnancy known as fetal growth restriction, unborn babies weigh much less than normal for their gestational age, and in the worst case may die in the womb or soon after birth. On the other hand, even women who successfully become pregnant may run the risk of having to undergo a cesarean section at an early stage of pregnancy once hypertensive disorders of pregnancy or fetal growth restriction occurs to protect their own life, losing their baby or having a surviving child with severe disabilities. This exacerbates the issues posed by Japan’s declining birthrate. Currently, however, almost nothing is understood about the mechanisms underlying these disorders of pregnancy (adverse obstetric outcomes), and there are no effective methods of treatment.

Research undertaken jointly by Professor ARASE Hisashi of the Osaka University Research Institute for Microbial Diseases (RIMD) and Associate Professor TANIMURA Kenji of the Kobe University Graduate School of Medicine discovered novel autoantibodies that cause a condition called antiphospholipid antibody syndrome, which can trigger disorders such as cerebral infarction and other forms of thrombosis as well as miscarriage and hypertensive disorders of pregnancy , etc. A paper describing the results of that project was published in 2015. Subsequently, a multicenter research project led by Kobe University that involved five university hospitals found that around a quarter of 227 women suffering from recurrent pregnancy loss, who had repeated miscarriages after becoming pregnant and were unable to carry a healthy baby to term, tested positive for these autoantibodies. This suggested that the autoantibodies could be a leading cause of recurrent pregnancy loss, a result reported in a paper published in 2020. A recently published multicenter study involving Teine Keijinkai Hospital, Yamanashi University, and Kobe University found that the autoantibodies are also associated with infertility, endometriosis-associated infertility, and repeated implantation failure.

Although this association of autoantibodies with infertility and recurrent pregnancy loss has become increasingly clear, their relationship with adverse obstetric outcomes such as hypertensive disorders of pregnancy, fetal growth restriction, and preterm delivery has not previously been addressed. In this study, joint research conducted in five hospitals (Teine Keijinkai Hospital and four university hospitals including Kobe University) was the first in the world to investigate whether there is any association between adverse obstetric outcomes and autoantibodies.

Research Findings

Autoantibodies were measured in the blood collected from (1) women who had suffered recurrent pregnancy loss, (2) women with past or present hypertensive disorders of pregnancy, fetal growth restriction, or preterm delivery, and (3) postpartum women with no pre-existing conditions or obstetric abnormalities in previous pregnancies who had given birth to full-term infants of normal weight after an uncomplicated pregnancy (women who experienced normal delivery), who were inpatients or outpatients at one of the five Japanese participating hospitals and who had consented to take part in the study. They used statistical analysis to compare the autoantibody positivity rates of these three groups and investigate their association with recurrent pregnancy loss, hypertensive disorders of pregnancy, fetal growth restriction, and preterm delivery.

The autoantibodies were measured by a technique devised and patented by the team members. This involves creating cells that express a complex comprising a protein called β2-glycoprotein I (believed to be the target of the antibodies that cause antiphospholipid antibody syndrome) and an HLA Class II antigen (the HLA type that is more susceptible to antiphospholipid antibody syndrome) on the cell surface. These cells react with the patient’s blood to detect antibodies that bind to the complex on the cell surface.

The results showed that the positivity rates for autoantibodies were 78/462 women (16.9%) with recurrent pregnancy loss, 24/138 women (17.4%) with past or present hypertensive disorders of pregnancy, 19/124 women (15.3%) with past or present fetal growth restriction, 8/71 women (11.3%) with past or present preterm delivery, and 27/488 women (5.5%) who experienced normal delivery. Statistical analysis of the strength of the associations between the autoantibodies and the various adverse obstetric outcomes, taking account of other factors that can affect hypertensive disorders of pregnancy and fetal growth restriction such as the women’s age, body mass index (BMI, an indicator of obesity), and smoking, showed that the autoantibodies were strongly associated with recurrent pregnancy loss, hypertensive disorders of pregnancy, and fetal growth restriction (Table).

Research on autoantibodies may help to illuminate the mechanisms of the onset of recurrent pregnancy loss, hypertensive disorders of pregnancy, and fetal growth restriction, and decrease the number of couples, pregnant women, and children suffering from these conditions and handicaps caused by them. We might even venture to say that they could be key to resolving the issue of Japan’s low birthrate.

Future Prospects

This study has shown that the novel autoantibodies the team discovered are associated not only with recurrent pregnancy loss and infertility, as previously reported, but also with other adverse obstetric outcomes such as hypertensive disorders of pregnancy and fetal growth restriction.

In the future, the group aims to develop drugs that suppress the production of these autoantibodies or block their action, leading to potential treatments for recurrent pregnancy loss, infertility, hypertensive disorders of pregnancy and fetal growth restriction. Similar autoantibodies might also be present in common autoimmune diseases such as rheumatoid arthritis, and this discovery could bring about revolutionary progress in immunology.

Terminology

*1 Repeated implantation failure

For a pregnancy to become established, the fertilized egg must become attached to the endometrium in a process called “implantation.” Repeated implantation failure occurs in infertility treatment when eggs fertilized by in vitro fertilization or intracytoplasmic sperm injection are returned to the womb but repeatedly fail to implant and a pregnancy does not result.

*2 Adjusted odds ratio

The “odds ratio” is an index that expresses the strength of an association between a factor and a disease. In particular, the “adjusted odds ratio” is the odds ratio after the effects of other factors that might also be associated with the development of the disease in addition to the factor under investigation (such as age, sex, or smoking) have been eliminated.

Acknowledgements

This study was supported by the Japan Agency for Medical Research and Development (AMED), a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS), and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT).

Original publication

Tanimura et al.:?Anti-β2-glycoprotein I/HLA-DR Antibody and Adverse Obstetric Outcomes.?International Journal of Molecular Sciences (2023). DOI: 10.3390/ijms241310958