Pregnancy and Neonatal Outcomes in Unexplained Recurrent

Osaka City Medical Journal
Vol. 43, No. 181-87,1997
Pregnancy and Neonatal Outcomes in Unexplained
Recurrent/Habitual Aborters Treated by
Allogenic Leukocyte Immunization
TETSUJI TANAKA. NAOHIKO UMESAKI, KYOKO MAEDA.
MASATO MIYAMA and SACHIO OGITA
Department of Obstetrics & Gynecology,
Osaka City University Medical School,
1-5-7 Asahi-machi, Abeno-ku, Osaka 545, Japan
Key Words: Recurrent abortion. Habitual abortion, Leukocyte immunization
Immunotherapy. Complication
Summary
Allogenic leukocyte immunization is a common treatment of unexplained
recurrent abortions, whose immunological side effects have hardly been reported.
In this study. pregnancy and neonatal outcomes of unexplained recurrent/habitual
aborters. who were treated by their husbands' leukocyte immunization. are reviewed.
Seventy-seven patients were treated by their husbands' leukocyte immunization at the Infertility Cline of Osaka City University Hospital from 1985 to
Among the 63 pregnancies after the immunizations. 47 cases succeeded in
1995.
livebirths. Ten of the 47 cases were delivered by cesarean sections. There found
no possible relationship between their operative indications and leukocyte immunizations in the 10 cases. As for pregnancy complications, two patients showed
liver dysfunction. However we did not find any specific side effects in the
pregnancy complications. There was no specific fetal/neonatal complications to the
immunotherapy but a case of neonatal thrombocytopenia caused by maternal antiHLA IgGs.
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Mailing Address: Tetsuji Tanaka. MD. Department of Obstetrics & Gynecology, Osaka
City University Medical School. 1-5-7 Asahi-machi, Abeno-ku. Osaka
545. JAPAN. FAX 81-6-646-5800 TEL 81-6-645-2171
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TETSUJI TANAKA, et a1.
Introduction
Osaka City University Hospital opened its Infertility Clinic in 1985, and the
leukocyte immunization therapy has been performed on unexplained recurrent aborters
since 1986. Allogenic leukocyte immunization is a specific therapy for unexplained
recurrent spontaneous aborters.
There have been very few reports on cases with
side effects of leukocyte immunization. However, we have recently diagnosed a
case of neonatatal thrombocytopenia caused by maternal anti-HLA antibodies
which were found in a habitual aborter immunized with her husband's leukocyte. (1)
In this study, we have re-evaluated possible side effects of leukocyte immunization
on pregnancies or neonates.
Patients & Methods
Patients
Of the 316 patients who visited the Infertility Clinic of Osaka City University
Hospital from 1985 to 1995, 77 patients were treated by their husband's leukocyte
immunizations (Table 1). In this study, pregnancy and neonatal outcomes of the
immunized 77 patients are re-examined retrospectively.
Table 1. Classification of the 77 aborters immunized with their husband's leukocytes
in The Infertility Clinic of Osaka City University Hospital from 1985 to 1995.
Infertility
Recurrent
Habitual
Total Cases
Primary Infertility
Secondary Infertility
17 (22.1 %)
1( 1.3%)
54 (70.1 %)
5 ( 6.5%)
71 (92.2%)
6 ( 7.8%)
Total Cases
18 (23.4%)
59 (76.6%)
77 (100%)
Immunotherapy
In the outpatient clinic, the leukocyte immunizations were done in four occasions:
twice before pregnancy and twice in early pregnancy usually in 5 to 7 weeks at
gestation. Our preparation protocol of leukocyte suspension for the immunotherapy
is as follows. One hundred ml of heparinized venous blood from the husband was
placed onto lymphocyte separation solution, Separate-UM (Muso Pure Chemicals
LTD., Tokyo, Japan), and centifuged. The enriched mononuclear cells were washed
twice with 0.15M NaCI, and they were resuspended in 0.5-1.0 ml of 0.15M NaC!.
The leukocytes were r -irradiated to 20 Gy and administered to the aborter
intradermally.
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Leukocyte immunization for recurrent aborters
Results
As shown in Table 2, 14 of 16 pregnancy cases (87.5%) in recurrent aborters
who had immunization succeeded in livebirth, while 34 of 47 pregnancy cases (72.4%)
in habitual aborters who had immunization did so. Fourty-seven cases with successful livebirths (total live birth rate; 76.2%) were studied further among the
63 pregnancies after the leukocyte immunizations.
Table 2.
Outcomes of the leukocyte immunization therapy
Outcome
Case
Recurrent Aborters
18
No pregnancy
1
Spontaneous abortion
2
Premature delivery
1
Term delivery
13
Unknown (failed to be followed-up after 1
Immunotherapy)
Habitual Aborters
Success Rate
Pregnancy rate 16/17 (94.1 %)
Live birth rate 14/16 ( 87..5 %)
S9
No pregnancy
S
Spontaneous abortion
13
Premature delivery
3
Term delivery
30
Now being pregnant
1
Unknown (failed to be followed-up after 7
immunotherapy)
Pregnancy rate 47/S2 (90.4 %)
Live birth rate 34/47 ( 72.4 %)
Pregnancy rate 63/69 ( 91/3 %)
Total
Live birth rate 48/63 ( 76.2 %)
Ten out of the 47 cases (21.3%) were delivered by cesarean sections (Table 3).
There could not be found any possible relationship between their operative indications and leukocyte immunizations in the 10 cases with cesarean deliveries (Table 4).
As to complications during pregnancy (Table 5), we managed two patients
with liver dysfunction. One case was of a suspected HELLP syndrome complicated
with severe pre-eclampsia, elevated liver enzymes, and low platelet counts, but not
with hemolysis. Another case with liver dysfunction was thought to be due to a
possible side effect of long-term administration of ,82-blocker to relax premature
uterine contractions. To date, the latter patient had already finished two vaginal
deliveries.
Her liver function in her second delivery was normal.
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TETSUJI TANAKA, et al.
Table 3. Delivery modes of 47 aborters who had successful livebirths after
immunotherapy
Recurrent
Aborter
Delivery modes
Vaginal
Abdominal
Unknown
Total
Table 4.
Habitual
Aborter
Case(%)
6
6
2
26
4
3
32 (60.1 %)
10 (21.3%)
5 (10.6%)
14
33
47 (100%)
Main indication for cesarean section
Indication
Case
Fetal distress
Cephalopelvic disproportion
Intrauterine infection
Breech presentation
suspected HELLP syndrome
3
2
2
2
1
Total
10
Table 5. Maternal and fetal/neonatal complications of 47 successful livebirths
after immunotherapy.
Maternal complications during pregnancy
Severe preeclampsia
Hepatic dysfunction
FetaIINeonatal complications
SFD (Small for date infant)
Neonatal thrombocytopenia caused by
maternal anti-HLA antibodies
(Death of cardiomyositis on the 82th day)
1/47
2/47
4147
1/47
1/47
As for fetal/neonatal complications (Table 5), we had a very rare case with
transient neonatal thrombocytopenia (41,000 platelets/,uI) caused by maternal antiHLA antibodies. Lymphocyte cytotoxity tests revealed that the aborter (mother) had
lymphocytotoxic anti-HLA antibodies against paternal and neonatal lymphocytes.
And maternal anti-HLA IgGs have been shown to react against paternal and neonatal
platelets. Other than that, there was no specific fetal/neonatal complications to
the leukocyte imm unization.
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Leukocyte immunization for recurrent aborters
In our clinic, patients who once had a successful livebirth after leukocyte
immunizations are not immunized in the next pregnancy. Table 6 shows second pregnancy outcomes of the 5 cases who had a successful livebirth after immunotherapy.
Four ou t of the 5 cases succeeded in second li vebirth wi thou t any additional
immunization, and one case resulted in a spontaneous abortion.
Table 6. Second pregnancy outcomes of the aborters who had a successful livebirth
after husband's leukocytes immunization.
First Pregnancy
Second Pregnancy
Case Name
Type of
Abortion
Gestational Week Delivery
(Birth Weight)
Gestational Week
(BIrth Weight)
Delivery
HIO-RI
Habitual
Recurrent
Recurrent
Habitual
Recurrent
36 (2454g)
37 (2870g)
40 (319Og)
40 (3435g)
40 (335Og)
38 (2720g)
38 (2870g)
40 (3100g)
40 (362Og)
7GW Spontaneous abortion
Abdominal
Abdominal
Transvaginal
Transvaginal
Abortion
H19-YM
H92-MM
H223-MM
H82-KU
Abdominal
Abdominal
Transvaginal
lhmsvaginal
Transvaginal
Discussion
Unexplained recurrent abortions are thought to be caused by immunological
disorders, and various immunotherapies such as intravenous administration of immunoglobulin, (2,3) blood transfusion, (4) allogenic leukocyte immunization, (5,6)
and trophoblast membrane infusion, (7) have been reported to be effective in
preventing abortions.
Nowadays, the allogenic leukocyte immunization therapy is
the most common treatment for unexplained recurrent abortions. Since 1986 we too
have been performing leukocyte immunization on unexplained recurrent aborters
twice before pregnancy and twice during the first trimester of pregnancy.
But it
is still unclear in what way leukocyte immunization therapy has an effect on recurrent
abortions. Allogenic leukocyte immunization to unexplained recurrent aborters has
been reported to be a safe therapy because specific side effects have been hardly
ever reported. (8, 9)
In our study, we too found no specific side effects to the leukocyte immunization but found neonatal thrombocytopenia in mothers and neonates. Considering
the rare case with neonatal thrombocytopenia caused by maternal anti-HLA
antibodies, however, clinicians need to pay attentions to hematological findings in
newborn infants who were delivered from the aborters immunized with their
husbands' leukocytes.
Until now, to our knowledge, while a case with neonatal
neutropenia after leukocyte immunization was reported, (0) there has been no
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TETSUJI TANAKA, et al.
report on neonatal thrombocytopenia after the immunotherapy.
Our case with
throm bocytopenia showed a mild leukocytopenia (7,200 cells/ pI) in her umbilical
cord blood and cytotoxic anti-HLA antibodies against both paternal and neonatal
lymphocytes were found in the maternal serum. (1)
In this study, an incidence of cesarean section in immunized aborters was
high. Operative indications for the cesarean sections were common diseases except
a suspected HELLP syndrome. It is speculated, therefore, that operative indications
for the aborters were widened because they had a valuable baby.
It is not confirmed whether additional immunizations are necessary to the
aborters who already had a successful live birth after the previous immunotherapy.
Kilpatrick and Liston reported that any benefit from leukocyte immunotherapy does
not appear to be long lasting. (11) On the other hand, Takakuwa et al. reported
that additional immunotherapy is not necessary for patients who have obtained
successful results after the initial immunotherapy. (12)
In our clinic, infertile
patients who once had a successful livebirth after immunization, have not been
immunized in the next pregnancy.
Although we need more cases to make a firm
conclusion, our experiences show that unexplained recurrent aborters who once had
a livebirth does not need any additional leukocyte immunizations for their second
pregnancy.
References
1)
2)
Tanaka, T., Umesaki, N., Maeda, K., Nishio, J., Kawamura, T., Araki, N. and
Ogita, S.: Neonatal thrombocytopenia induced by maternal anti-HLA antibodies: A
potential side effect of allogenic leukocyte immunization for unexplained recurrent
aborters, Submitted.
Coulam, C.B.: Immunotherapy with intravenous immunoglobulin for treatment
of recurrent pregnancy loss: American experience. Am. J. Reprod. lmmunol. 32:
286-289 (1994)
3)
Mueller, E.G.: Immunotherapy with intravenous immunoglobulin for treatment
of recurrent pregnancy loss: European experience. Am. J. Reprod. lmmunol. 32:
281-285 (1994)
4)
Christiansen, O.B., Grunnet, N., Andersen, E.S. and Lauritsen, J.G.: Blood transfusions in habitual abortion. Fertil. Steril. 49: 186-187 (1988)
5) Gatenby, P.A., Cameron, K., Simes, R.J., Adelstein, S., Bennett, M.J., Jansen,
R.P., Shearman, R.P., Stewart, G.J., Whittle, M. and Doran, T.J.: Treatment of
recurrent spontaneous abortion by immunization with paternal lymphocytes:
results of a controlled trial. Am. J. Reprod. Immunol. 29: 88-94 (1993)
6) Aoki, K., Kajiura, S., Matsumoto, Y., Yagami, Y.: Clinical evaluation of immunotherapy in early pregnancy with x-irradiated paternal mononucler cells for
primary recurrent aborters. Am. J. Obstet. Gynecol. 169: 649-653 (1993)
7) Johnson, P.M., Chia, K.V., Hart, C.A., Griffith, H.B. and Francis, W.J.:
Trophoblast membrane infusion for unexplained recurrent miscarriage. Brit. J.
Obstet. Gynecol. 95: 342-347 (1988)
8) Takakuwa, K., Goto, S., Hasegawa, 1., Veda, H., Maruhashi, T., Kajino, T.,
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Leukocyte immunization for recurrent aborters
9)
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11)
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Yoshizawa, H., Kanazawa, K. and Takeuchi, S.: Is immunotherapy for habitual
aborters an immunologicaIIy hazardous procedure for infants? Am. J. Reprod.
Immuno!. 19: 53-56 (l989)
Aoki, K., Matsumoto, Y., Tsuji, A., Ozaki, Y., Kajiura, S., Kimbara, T. and
Yagami, Y.: The evidence of safety of immunotherapy for unexplained habitual
aborters. Acta Obstet. Gyneco!. Jpn. 44: 405-411 (l992)
Bux, J., Westphal, E., de Sousa, F., Mueller, E.G. and Mueller, E.C.: Alloimmune
neonatal neutropenia is a potential side effect of immunization with leukocytes
in women with recurrent spontaneous abortion. J. Reprod. Immuno!. 22: 299-302
(1992)
Kilpatrick, D.C. and Liston, W.A.: Remote pregnancy outcome after leukocyte
immunotherapy. FertiI. Steri!. 62: 409-411 (l992)
Takakuwa, K., Higashino, M., Yasuda, M., Ishi, S., Veda, H., Asano, K., Kazama,
Y. and Tanaka, K.: Is an additional vaccination necessary for a successful second
pregnancy in unexplained recurrent aborters who were successfuIIy immunized
with their husband's lymphocytes before the first pregnancy? Am. J. Reprod.
Immuno!. 19: 39-44 (1993)
Received December 25, 1996
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