autoantibodies in argentine women with recurrent pregnancy loss

Autoantibodies in Argentine Women with Recurrent PregnancyLossDaniel Bustos1, Ana Moret1, Monica Tambutti2, Sebastian Gogorza3, Roberto Testa3, Amanda Ascione1,Norma Prigoshin2

1Central Laboratory, Diagnostic Department, Hospital Italiano de Buenos Aires, Gascon 450, Buenos Aires, Argentina;2Histocompatibility and Immunogenetics laboratory, Diagnostic Department, Hospital Italiano de Buenos Aires, Gascon 450, Buenos Aires, Argentina;3Reproduction Section, Gynecology Department, Hospital Italiano de Buenos Aires, Gascon 450, Buenos Aires, Argentina

Introduction

Recurrent pregnancy loss (RPL) is a health care con-

cern occurring in 2–5% of couples attempting to

become pregnant.1,2 The observed frequency of

recurrent abortion is higher than the expected by

chance (0.3%), which implies an underlying cause

contributing to the recurrent loss.3

Keywords

Autoantibodies, autoimmunity, recurrent

pregnancy loss

Correspondence

Daniel Bustos, Laboratorio Central, Hospital

Italiano de Buenos Aires, Gascon 450, (1181),

Capital Federal, Buenos Aires, Republica

Argentina.

E-mail: [email protected]

Submitted March 3, 2005;

accepted November 22, 2005.

Citation

Bustos D, Moret A, Tambutti M, Gogorza S,

Testa R, Ascione A, Prigoshin N.

Autoantibodies in Argentine women with

recurrent pregnancy loss. Am J Reprod

Immunol 2006; 55:201–207

doi:10.1111/j.1600-0897.2005.00349.x

Problem

To determine the presence or absence of subclinical autoimmunity in

Caucasian Argentine healthy women with first trimester recurrent preg-

nancy loss (RPL), the sera of 118 healthy women with a history of three

or more consecutive abortions and 125 fertile control women without

abortions and two children were analyzed for the presence of autoanti-

bodies: immunoglobulin (Ig)G and IgM anticardiolipin, antinuclear

(ANA), antismooth muscle (ASMA), antimitocondrial (AMA), antiliver-

kidney-microsomal fraction (LKM), antigastric parietal cells (GPC),

antineutrophil cytoplasmatic (ANCA) and antibodies antigliadin type IgA

and IgG and IgA antitransglutaminase related with celiac disease (CD).

Method of study

ANA, ASMA, AMA, anti-LKM, antibodies to GPC and ANCA were

determined by indirect immunofluorescence (IFI) and anticardiolipin,

antigliadina and antitransglutaminase antibodies were measured by

enzyme-linked immunosorbent assays (ELISA).

Results

There was no significant difference between controls and patients with

ANA, ASMA, AMA, LKM, ANCA and GPC. The prevalence of anticardi-

olipin antibodies in RPL was significantly higher than controls

(P < 0,01) and the prevalence of positive antibodies for antigliadina type

IgA and IgG and IgA antitransglutaminase in RPL was significantly

higher than controls (P < 0.04).

Conclusion

We show that Caucasian Argentine women with RPL showed signifi-

cantly higher incidence of anticardiolipin antibodies than normal con-

trols and finally we recommended the screening of IgA and IgG

antigliadina and IgA antitransglutaminase antibodies in pregnancy,

because of the high prevalence of subclinical CD in RPL and the chance

of reversibility through consumption of a gluten free diet.

ORIGINAL ARTICLE

American Journal of Reproductive Immunology 55 (2006) 201–207 ª 2006 The Authors

Journal compilation ª 2006 Blackwell Munksgaard 201

The underlying causes of recurrent spontaneous

abortion are not entirely clear but suggest that some

couples have a systematic cause for repeated preg-

nancy loss. Recurrent miscarriage is a heterogeneous

condition4,5 and even when potential explanations

for recurrent miscarriage are considered, 20–40% of

cases remain unexplained.6,7

Immunologic mechanisms have been suggested as

a cause of otherwise unexplained recurrent abor-

tion.8 The association between human reproductive

failure and autoimmune diseases has long been

recognized. Antibodies and lymphoid cells from

affected individuals have been shown to react with

specific structures such as nuclei of cells and recep-

tors or tissues.9 Autoantibody levels can result in

clinical, subclinical, or preclinical autoimmune con-

ditions. This concept was also supported in clinically

healthy women by the recognition of autoantibodies

and the presence of different forms of reproductive

failure.10,11 In this regard CD has been suggested

that affects the outcome of pregnancy12 and has

been reported that untreated CD women have more

abortions than CD women on gluten-free diets.13

The aim of this study was to estimate the preval-

ence of autoimmune markers: anticardiolipin anti-

bodies, antinuclear antibodies (ANA), antismooth

muscle antibodies (ASMA), antimitocondrial anti-

bodies (AMA), antiliver-kidney-microsomal fraction

antibodies (LKM), antibodies against gastric parietal

cells (GPC), antineutrophil cytoplasmatic antibodies

(ANCA) and also antigliadin IgA and IgG antibodies

and anti transglutaminase IgA antibodies in women

with recurrent spontaneous abortions.

Materials and methods

Patients and controls

The patients who participate in this study were

admitted to the Reproduction Section, Gynecology

Department, Hospital Italiano of Buenos Aires City,

Argentina. The studied group included 118 Argen-

tine Caucasian women (mean 32 years, range: 20–

43 years) with RPL, consecutively referred. All of

them had a history of at least three consecutively

spontaneous miscarriages and no previous successful

pregnancy. The following tests were performed to

exclude known causes of abortion: hysteroscopy,

hysterosalpingography, serial ultrasound, parental

karyotypes, investigation of lethal phase insuffi-

ciency (repeated for three times serum progesterone

concentration measurements and endometrial

biopsy), prolactin dosage, glycemic curve, determin-

ation of thyroid hormones levels, investigation of

toxoplasmosis, cytomegalovirus, rubeolla, AIDS,

streptococci of B group, Chlamydia trachomatis, hepatitis

B and C and bacterial vaginosis.

The inclusion criteria to the study were as follows:

Argentine Caucasian women who had RPL and who

had undergone all the above mentioned tests with

negative results.

The control group was obtained from the blood

bank and consisted of 125 Argentine Caucasian

women (mean 34 years, range 19–53 years) who had

at least two children and without known pregnancy

losses. The protocol of this investigation was approved

by the Bioethic Committee of our Institution.

Blood samples collection and methods

Blood samples were taken from each patient and

every women from the control group by venipun-

ture in sterile conditions. Each blood specimen was

encoded, so that the identity of the participants

could not be determined by the laboratory.

ANA, ASMA, AMA, anti-LKM and antibodies to

GPC were determined by indirect immunofluores-

cence (IFI) using slides of rat liver/kidney/stomach

as antigen.

Detection of ANCA was done according to the

standard procedure by IFI. Briefly, neutrophil was

isolated, heparinized blood of normal individuals was

centrifuged by polymorphprep solution (dextran 500

and sodium metrizoate). After centrifugation, the

polymorphonuclear fraction was transferred to a tube

and washed with PBS. Neutrophils at a concentration

of 2.10 exp 6 cells/mL were placed on glass slides

and air-dried, then the slides were fixed on cold 99%

ethanol at 4�C for 5 min and stored at )70�C.

Immunoglobulin G and M anticardiolipin antibod-

ies were measured by enzyme-linked immunosorb-

ent assays (ELISA). Polystyrene plates were coated

with 4.8 mg/dL cardiolipin (Sigma C-1649, Sigma, St.

Louis, MO, USA) in ethanol, and incubated over-

night at 4�C. Wells were then blocked with 10%

bovine fetal serum (BFS) and incubated overnight at

4�C. PBS was used to wash each step of the ELISA.

Serum samples diluted 1/50 in BFS 10% were incu-

bated for 4 hr at 4�C. After washing, 50 lL of a 1/

1000 dilution of peroxidase conjugated antihuman

IgM and IgG in SFB 10% were added. Following 1 hr

incubation at 4�C the plates were washed and the

BUSTOS ET AL.


202 Journal compilation ª 2006 Blackwell Munksgaard

color was developed by adding 50 lL of o-pheny-

lendiamine-peroxidasa solution. After another incu-

bation period of 30 min in dark, OD was measured at

492 nm with an optical reader. International stand-

ards (Louisville APL Diagnostics, Louisville, KY, USA)

and own control sera were used for the preparation

of a standard calibration curve. Results were

expressed as standard units for either IgG (GPL) or

IgM (MPL). Results were considered as positive over

more than 15 Units.

Antigliadin antibodies were measured by ELISA.

Polystyrene plates were coated with gliadin 0.2%

(Sigma G-3375) in carbonate buffer. Patient serum

was diluted 1/200 for IgA and 1/600 for IgG. Patient

IgA was detected using peroxidase conjugated anti-

human IgA and patient IgG using peroxidase conju-

gated antihuman IgG and the cromogenic substrate.

Antitransglutaminase antibodies were measured by

ELISA. Polystyrene plates were coated with 1 mg of

transglutaminase (Sigma T-5398) in 100 mL of 0.05 m

tris buffered saline with 5 mm CaCI2, pH 7.5. The

plates were washed three times with 0.1% Tween 20.

Serum samples diluted 1:200 in PBS were incubated

for 30 min at 37�C. The plates were washed and incu-

bated for 30 min at 37�C with 1:500 peroxidase con-

jugated antihuman IgA (Sigma A-3062). The immune

reaction was developed by adding substrate solution

and the absorbance was read in microplates at

405 nm. The reference values for IgA antitransgluta-

minase antibodies is <14 U (units), for IgA antigliadin

<24 U and IgG antigliadin is <40 U. In the patients

that presented IgG antigliadin antibodies over the

reference values we studied the serum concentration

of IgA inmunoglobulin with the aim to search an IgA

deficiency. IgA serum inmunoglobulin was deter-

mined by nefelometry (Beckman Instruments Inc.,

Brea, USA). Reference values: 70–400 mg/dL.

Statistical analysis

The Mann–Whitney test was used to assess differ-

ences in cardiolipin antibodies titers between

patients and controls. Chi-square analysis was used

to compare dichotomous variables.

Results

There were no significant differences between

patients and controls when they were categorized

according to the frequency of positive results per-

centage for ANA, AMA, ASMA, GPC and ANCA

(Table I).

The titers of ANA were similar between patients

and controls. The patterns of immunofluorescent

staining were also similar among patients (80%

homogeneous, 15% speckled and 5% others) and

controls (70% homogeneous, 12% speckled and

18% others). One patient and one control were pos-

itive for ANCA and the pattern was cytoplasmic for

both samples. We found no positive samples for

AMA and LKM in both studied groups.

Anticardiolipin antibodies type IgG and IgM in

patients and controls were expressed as median and

ranges; the prevalence of positive results were statis-

tically higher for anticardiolipin antibodies type IgG

in patients versus controls (15.3% versus 3.3%)

(P < 0.05) but for anticardiolipin antibodies type

IgM, the prevalence of the positive samples did not

show significant differences between RPL and con-

trols (21.2% versus 12.9%); for IgM antibodies the

range of MPL were statistically higher for RPL (range

1–250) compared with controls (range 1–38,

P < 0.05; Table II).

Four patients had positive autoantibodies for

subclinical CD, one was positive for antigliadin

Table I Frequency of Results Percentage and Titer (Median and Range) for ANA, ASMA, AMA, LKM, GPC and ANCA in RPL and Controls

RPL (n ¼ 118) Controls (n ¼ 125)

P-value

Positive

[n (%)]

Titer

[median (range)]

Positive

[n (%)]

Titer

[median (range)]

ANA 16 (13.5) 1/40 (1/20–1/160) 14 (11.2) 1/40 (1/40–1/80) NS

ASMA 12 (10.1) 1/40 (1/20–1/160) 7 (5.6) 1/160 (1/20–1/320) NS

GPC 9 (7.6) 1/160 (1/20–1/640) 3 (2.4) 1/160 (1/40–1/320) NS

ANCA 1 (0.84) 1/80 1 (0.8) 1/40 NS

NS, not significant.

AUTOANTIBODIES IN ARGENTINE WOMEN WITH RECURRENT PREGNANCY LOSS



antibodies type IgG and IgA, two were positive for

IgA antigliadine and antitransglutaminase and finally

one was positive for all the tests (Table III). The con-

trol group was negative. The prevalence of positive

antibodies for CD in RPL was statistically higher than

controls (3.51% versus 0%, P < 0.04; Table IV). All

the patients that presented IgG antigliadin antibodies

over the reference values the serum concentration of

IgA Inmunoglobulin were between the reference

values.

Discussion

Autoimmune disease occurs in women in an over-

whelming preponderance. The diagnosis of an auto-

immune disease is usually based on a combination

of clinical and laboratory findings. However, the

concept of subclinical autoimmune disease is now

well established.14,15 Such subclinical diseases may

present with some of the classical clinical features

but they are not enough to meet the American

Rheumatism Association criteria;16 they are mainly

characterized by the presence of autoantibodies in

apparently healthy individuals.17 It has been sugges-

ted that women not only experience a significantly

increased incidence of autoimmune diseases, but also

a higher incidence of subclinical autoimmunity than

men.18 In this work, we found that 22% of patients

showed presence of the antibodies that were mainly

associated with autoimune diseases.

We did not find significant differences for ANA,

ASMA, AMA, GPC and ANCA antibodies between

RPL and control group. Our paper disagrees with

Petri’s one,10 who found that ANCA are present

more frequently in patients with RPL than controls.

Nevertheless they studied ANCA by an immunoassay

(antimyeloperoxidase and antiproteinase-3) and we

studied ANCA by IFI.

The antiphospholipid antibodies and pregnancy

wastage have gained widespread recognition among

obstetricians and gynecologists. An analysis of differ-

ent reports yielded an average prevalence of 8.9%

(range 3.3–28%).14,18,19,20,21,22,23 In this report we

found a higher positive result of IgG anticardiolipin

antibodies in patients with RPL compared with the

control group (15.3% versus 3.3%, P < 0.05), how-

ever the results in MPL were significantly higher in

the range of IgM anticardiolipin antibodies in patients

versus controls (range 1–250 versus 1–35, P < 0.05).

The prevalence of anticardiolipin antibody both in

the non-pregnant and the pregnant women with

history of RPL was significantly higher than controls,

which suggest that these antibodies are deleted for

RPL. It has been reported that anticardiolipin anti-

bodies interfere with implanted embryos by reacting

directly with the pre-implantation24 and produce

abnormalities in hormonal secretion of the placenta.

In animal studies anticardiolipin antibodies have a

direct effect on fecundity and on the outcome of

pregnancy in the pregnant mice.25,26 Highly purified

anticardiolipin antibodies bound to b2-glycoprotein I

(b2GPI), which is a heavily glycosylated 50-kDa

Table II The Prevalence of Anticardiolipin IgG and IgM in RPL

and Normal Controls

RPL (n ¼ 118) Controls (n ¼ 125)

Positive

[n (%)]

Median and

range

Positive

[n (%)]

Median and

range

GPL Units 18 (15.3)* 8 (1–250) 4 (3.2) 5 (1–18)

MPL Units 25 (21.2) 7 (1–250)* 16 (12.8) 5 (1–38)

*P < 0.01.

GPL units: standard units for IgG; MPL units: standard units for

IgM.

Table III Type of Antibodies of Four Patients Positives for

Subclinical CD

Patient

Type of antibodies

IgA antigliadina

antibodies

RV: <24 U

IgG antigliadina

antibodies

RV: <40 U

Antibodies

antitransglutaminasa

RV: <14 U

1 45 (+) 102 (+) 1.3 ())

2 28 (+) 18 ()) 32 (+)

3 102 (+) 98 (+) 198 (+)

4 29 (+) 32 ()) 24 (+)

+, positive; ), negative.

Table IV Prevalence of Antigliadina Antibodies Type IgG e IgA

and IgA Antitransglutaminase Antibodies in RPL and Controls

RPL

(n ¼ 118) [N (%)]

Controls

(n ¼ 125) [N (%)] P-value

Positives 4 (3.51) 0 (0) <0.04

BUSTOS ET AL.



anionic phospholipid binding protein.27 The physio-

logical functions of this glycoprotein are not totally

known. It has been suggested that glycoprotein binds

to exposed anionic phospholipids and functions as

an anticoagulant by inhibiting the intrinsic coagula-

tion pathway,28 neutralizing negatively charged

macromolecules that might enter the blood stream

activating blood coagulation,26 inhibiting prothromb-

inase activity,29 and inhibiting ADP-mediated plate-

let aggregation.30 All these findings suggest the

possibility that anticardiolipin antibodies may inter-

fere with b2GPI in vivo, and therefore predispose to

thrombotic events.31

Furthermore, it has been shown that other anti-

phospholipid antibodies are associated with RPL like

phosphatidylserine and phosphadylinositol antibod-

ies that were significantly higher in the primary

aborters than the control group (P < 0.05). With

regard to autoantibodies to phospholipids, 41.2% of

the primary aborters had antibodies to at least one

phospholipid and this was statistically significant

(P < 0.001).32

The prevalence of positive antibodies for subclini-

cal CD in RPL versus controls (taking patients with

at least two positive tests) was 3.51% versus 0.0%

(P < 0.04). The condition of all these patients is

silent from the gastrointestinal viewpoint, however

this condition can be the cause of an unfavorable

outcome of pregnancy.33

The CD is an autoimmune disorder associated with

the production of an autoantibody against transglut-

aminase which is present in human tissue.34 Early

expression of anti-endomysium is observed in the

cultured small intestinal mucosa of patients with

celiac disease exposed to gliadin.35

An increased prevalence of autoimmune disorders

in CD has been reported and this is related to the

duration of exposure to gluten. When these patients

were further subdivided into five subgroups accord-

ing to age: in children <2 years the prevalence of

autoimmune disorders in CD was 5.1%, in children

2–4 years was 10.5%, in children 4–12 years was

16.7%, in 12–20 years was 27% and in adults of

>20 years 34% (P < 0.000001).36 Women with undi-

agnosed celiac disease seem to have an 8.9-fold rel-

ative risk of multiple abortions and low birth weight

babies compared with treated patients.37

A gluten free diet resulted in a 9.18-fold reduction

in the abortion rate and a reduction in the preval-

ence of low birth weight babies from 29.4% to

zero.37 In another study, 15% of 68 women with

untreated CD had miscarriages compared with 6% of

controls, but after a gluten free diet, the miscarriage

rate was similar in patients and controls.38

The frequent association of autoimmune disorders

and CD has usually been explained by a common

genetic factor that may be some human leukocyte

antigen (HLA) antigens (DQ2 or DQ8 haplotype).39

The interaction between tissue transglutaminase and

gliadin produces a neoepitope that is recognized by

the HLA moiety specific for celiac disease.40 This

finding provides a new approach to exploring why

and how the autoantibody and the T cell mediated

reaction provoke a series of conditions, including

unfavorable outcome of pregnancy.

Conclusion

We show that Caucasian Argentine women with

RPL showed significantly higher incidence anticardi-

olipin antibodies than normal controls and finally

we recommended the screening for celiac disease in

pregnancy, because of the high prevalence and

avoidable outcomes and the chance of reversibility

through consumption of a gluten free diet.

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autoantibodies in argentine women with recurrent pregnancy loss

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