Do antiphospholipid antibodies in amniotic fluid affect pregnancy?

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Consultation

2024-02-16

Author: Willie
Translator: Lydia

About Antiphospholipid Syndrome

Antiphospholipid syndrome (APS), also known as Hughes syndrome, was proposed by Professor Graham Hughes in the UK in 1983. It is mainly due to a hypercoagulable situation caused by autoimmunity in the body. Anti-phospholipid antibodies can cause a series of clinical lesions such as arteriovenous thrombosis. APS is mainly divided into primary and secondary. Primary refers to patients who are not accompanied by other related diseases; while secondary patients refers to patients who not only have APS but are also accompanied by other spontaneous immune diseases, the most common of which is lupus erythematosus (SLE)

APS Diagnosis

Clinically, the criteria for APS disease are diagnosed according to the Sydney criteria established in 2006, which include clinical characteristics and laboratory diagnosis data:

clinical symptoms test	Laboratory testing (detection of the following three antibody concentrations to at least medium or high values, and repeated at least twice)
(1) Vascular thrombosis is required (2) Pregnancy onset: a. One or more fetal deaths of unknown causes occur in pregnant women who are more than ten weeks gestation and have normal fetal shape. b. Premature birth less than 34 weeks of gestation due to pre-epilepsy c. Three or more consecutive spontaneous miscarriages before ten weeks of gestation d. Placental insufficiency in less than 34 weeks of gestation	(1) Anticardiolipin antibody IgG/IgM (2) β2 glycoprotein 1 antibody (3) Lupus anticoagulant antibodies

clinical symptoms test

Laboratory testing (detection of the following three antibody concentrations to at least medium or high values, and repeated at least twice)

(1) Vascular thrombosis is required

(2) Pregnancy onset:

a. One or more fetal deaths of unknown causes occur in pregnant women who are more than ten weeks gestation and have normal fetal shape.

b. Premature birth less than 34 weeks of gestation due to pre-epilepsy

c. Three or more consecutive spontaneous miscarriages before ten weeks of gestation

d. Placental insufficiency in less than 34 weeks of gestation

(1) Anticardiolipin antibody IgG/IgM

(2) β2 glycoprotein 1 antibody

(3) Lupus anticoagulant antibodies

Symptoms and effects of pregnancy

APS will develop some clinical symptoms, such as neurological diseases such as stroke, cardiopulmonary diseases or blood diseases, and even necrosis of distal limbs. However, the impact of APS on women's pregnancy is collectively referred to as obstetric complications. Figure1 shows the distribution of placenta, placental blood vessels and trophoblast cells, which will cause the following mechanisms: (1) When antiphospholipid antibodies (Antiphospholipid, aPL) combines with decidual cells and extravillous trophoblast cells, which may induce inflammatory responses in the body and also promote the blood coagulation system. (2) It may cause thrombosis in placental blood vessels. If the antibody binds to trophoblast cells, it will inhibit the differentiation of trophoblast cells and even cause their apoptosis. Therefore, the results of the above reactions are many pregnancy complications, including infertility, preeclampsia, fetal restriction, miscarriage, and the more serious one is the protagonist of this article, "recurrent miscarriage." (recurrent pregnancy loss, RPL)".

The culprit causing APS - Antiphospholipid antibodies (aPL)

“Research has pointed out that there are major antibodies in APS, and these three antibodies are generally tested to diagnose APS, including lupus anticoagulant antibodies, β2 glycoprotein 1 antibodies (IgG/IgM) and anticardiolipin antibodies (IgG /IgM )”

This article mainly focuses on two autoimmune antibodies: β2 glycoprotein 1 antibody (IgG/IgM) and anticardiolipin antibody (IgG/IgM) (Figure 2).

β2 glycoprotein 1 antibody: Also known as Apolipoprotein H, it is a serum cofactor that generally inhibits coagulation. It usually exists in a ring-like form in the blood circulation, but when there is systemic inflammation A J-shaped oxidized β2 glycoprotein 1 will be formed, and then the β2 glycoprotein 1 antibody will bind and trigger a series of effects.
Cardiolipin: It is a type of phospholipid that is abundantly present in living cell membranes and mitochondria. When cardiolipin antibodies are present, they will bind to cardiolipin in cell membranes and mitochondrial cell membranes, thereby causing inflammation and promoting blood coagulation. In severe cases, it can cause embolism.

In previous studies, it has been found that the presence of anticardiolipin (aCL) IgG in amniotic fluid has a certain impact on antiphospholipid syndrome. However, there is no in-depth discussion of amniotic fluid about another protagonist, β2 glycoprotein 1 antibody. the role it plays, or whether it is related to APS. In addition, there are potential antiphospholipid antigens at the implantation sites of trophoblast cells and placental endothelial cells, and whether these antigens can also bind specific antibodies in amniotic fluid has not yet been clarified.

Therefore, the purpose of this article is to explore:

Independently of APS disease, anticardiolipin antibodies and anti-β2-glycoprotein 1 antibodies may play a potential role in physiological and pathological abnormal pregnancy implantation. The subjects were divided into a control group and an experimental group, and basic tests as well as anti-phospholipid antibody and anti-β2 glycoprotein 1 tests were performed as experimental methods.

Experimental methods and strategies

Subject grouping

First, the authors selected 167 Caucasian women of reproductive age and divided them into four groups:

Control group: included 47 non-smoking women who were pregnant, had at least two full-term pregnancies, and were not affected by human or miscarriage or autoimmune diseases.
Recurrent miscarriage group (RPL): included 36 women who suffered from recurrent miscarriage but did not have autoimmune diseases
Smoking group: includes 40 smokers, who are pregnant, have at least two full-term pregnancies, and are not affected by human and miscarriage or autoimmune diseases.
Thyroid immune problem group: included 44 non-smoking women who were pregnant, had at least two full-term pregnancies, were not affected by pregnancy or miscarriage, but were affected by autoimmune hypothyroidism.

Subject basic testing

The subjects selected above all underwent some basic tests before becoming pregnant, including obstetric and gynecological medical history examination, basic gynecological examination, vaginal ultrasound, hysteroscopy, and endometrial examination when necessary. Biopsies, hormonal tests such as LH, FSH, progesterone, and thyroxine, karyotype analysis of both spouses, and immune tests including LA, β2 glycoprotein 1 and other related immune diseases are tested, as well. Blood-related tests include coagulation and special mutations. The purpose of these projects is mainly to select healthy and non-APS subjects.

Antiphospholipid antibody and anti-β2 glycoprotein 1 detection

All subjects were tested for amniocentesis. The amniotic fluid remaining during puncture was taken out and then subjected to enzyme-linked immunosorbent assay (ELISA) to analyze the concentration of two antibodies in the amniotic fluid, which can identify anti-cardiac antibodies. The contents of phospholipid antibodies IgM and IgG, as well as anti-β2 glycoprotein 1 antibodies IgM and IgG.

"After comparing the control group and the experimental group pairwise, the only thing found was that the anti-β2 glycoprotein 1 antibody IgM was significantly different in all experimental groups compared with the control group."

Test result

First, the authors evaluated the clinical characteristics of all the women tested (Table 1). Among the four groups, there was not much difference in age between 36 and 39 years old, and there was not much difference in BMI between 23 and 39 years old. Between 26 and 26 years old, all the women tested were negative in the blood test for antiphospholipid syndrome, which confirmed that they were not affected by antiphospholipid syndrome, and all other basic tests mentioned above were negative and normal. Therefore, the authors defined the recurrent miscarriage group as recurrent miscarriage for which the cause has not yet been clarified.

The author then compared the antiphospholipid antibody concentrations in the amniotic fluid of the two groups:

1. Comparison between the control group and the recurrent miscarriage group (RPL) (Figure 3): There is no statistical difference between the anti-cardiolipin antibodies IgM and IgG, and the anti-β2 glycoprotein 1 antibody IgG, and the only visible difference is There was a significant difference in the anti-β2 glycoprotein 1 antibody IgM between the two groups.

2. Comparison between the control group and the smoking group (Figure 4): The results are similar to the previous group. There is no statistical difference between the anti-cardiolipin antibodies IgM and IgG, and the anti-β2 glycoprotein 1 antibody IgG. Anti-β2 glycoprotein 1 antibody IgM was significantly different between the two groups.

3. Comparison between the control group and the thyroid immune group (Figure 5): anti-cardiolipin antibodies IgM and IgG, as well as anti-β2 glycoprotein 1 antibody IgG, there is no statistical difference between the two, while anti-β2 glycoprotein 1 antibody IgM There is a significant difference between the two groups.

The author mentioned that the concentration difference of anti-β2 glycoprotein 1 antibody IgM found in this article does not necessarily have pathological significance. Future research will definitely need to explore more deeply and understand the related mechanisms; in addition, the author also believes that The results obtained this time are due to the lower number of subjects. In the next step, the authors must use a larger number of specimens and random testing to increase reliability.

Conclusion

Among antiphospholipid antibodies, especially the anti-β2 glycoprotein 1 antibody IgM, plays a specific role in physiologic pregnancy and specific obstetric complications independent of APS, and the anti-β2 glycoprotein 1 antibody IgM It may be used as a potential indicator of abnormal implantation process in the future.

"Whether controlling APS antibodies in amniotic fluid has an impact on pregnancy, although the exact mechanism is not yet clear, it is definitely one of the directions of research significance in the future."

Reference

1.Nature Reviews Disease Primers volume 4, Article number: 17103 (2018)
2.Nature Review Rheumatology 2018;7:433-440
3. J Intern Med 2020 Apr;287(4):349-372.
4.Blood Rev. 2017 Nov;31(6):406-417

*This article only reflects the treatment status at the time of writing, and the actual situation should be discussed with the doctor.

Comment

Dr. I-Ting Liang, MD

The role of immune issues in recurrent miscarriage has been controversial, including its diagnosis, prevalence, clinical management, etc. Miscarriage caused by immune problems can be divided into two types: one is autoimmune, which refers to the miscarriage caused by the embryo being attacked by the mother's own autoimmune antibodies (autoantibody); the other is alloimmune , refers to the mother's rejection of allogeneic antigens in the fetus, in other words, the process of immune adaptation to the fetus is poorly regulated. The antiphospholipid antibody that is the subject this time belongs to the former, and its prevalence ranges from 6 to 45% depending on the diagnostic conditions. However, in addition to the three antibodies mentioned in the article, there are also other antiphospholipid antibodies whose clinical position is currently unclear, with dozens of types; in addition, alloimmunization is difficult to confirm clinically. , these groups are often classified as having unexplained recurrent miscarriages. Therefore, whether immunotherapy needs to be considered clinically, in addition to test results, maternal and childbirth history is also an important reference factor.
The current mechanism by which antiphospholipid antibodies cause obstetric complications is simply inflammation and thrombosis, which in turn leads to placental dysplasia. Therefore, clinical treatment is to control inflammation and prevent thrombosis. However, the clinical manifestations of antiphospholipid syndrome vary with the forms of antibodies present. Even for the same antibody, the degree of activation varies from pregnancy to pregnancy, and the final results are not necessarily the same. Therefore, drug control during pregnancy There is still no clinical consensus on the method, how many weeks treatment needs to be involved, and how to monitor it. At present, aspirin and heparin/low molecular weight heparin have been studied more clinically. Other clinical studies also believe that they may be effective include quinine, steroids, immunoglobulins, monoclonal antibodies, etc. The clinical dilemma is that late-line treatment is often expensive, but when severe obstetric complications occur, it is often difficult to recover. Therefore, whether late-line treatment is needed requires pregnant women and clinicians to discuss the severity, pros and cons of the condition. Go and decide. In addition to drug treatment, control of predisposing factors (such as infection) and co-aggravating factors (such as smoking cessation, metabolic syndrome and other factors that aggravate the risk of thrombosis) should also be considered.
What is noteworthy about this article is that even if the mother does not have autoimmune antibodies, the amniotic fluid itself may contain autoimmune antibodies, and the most likely source is the placenta (the placenta is also one of the hematopoietic organs during the fetal period, and the placenta produces The autoimmune antibodies can be regarded as autoimmune antibodies produced by the fetus itself to some extent), although whether the presence of these antibodies has pathological significance is still unclear. In current research on obstetric complications (recurrent miscarriage, preeclampsia, fetal growth retardation), the mechanism of immunity is generally considered to be the immune attack of the pregnant mother against the fetus. Can the results of this article be regarded as in addition to maternal autoimmunity? and alloimmunization, there is a third path - the fetus's own autoimmunity, which deserves further research and discussion.