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\begin{document}

\title{MATERNAL MIRROR SYNDROME WITH FOETAL HYDROPS DUE TO ISOIMUNIZATION BY
ANTI-KPa ANTIBODIES: A CASE REPORT AND NARRATIVE LITERATURE REVIEW}



\author[1]{Juan Pina Moreno}%
\author[2]{Ana Perez-Corral}%
\author[3]{Virginia Ortega Abad}%
\author[1]{Santiago Garcia-Tizon Larroca}%
\affil[1]{Gregorio Marañón Mother and Child Hospital}%
\affil[2]{Hospital General Universitario Gregorio Marañón}%
\affil[3]{Fetal medicine unit, Department of Obstetrics and Gynecology, Hospital General Universitario Gregorio Marañon, Madrid, Spain}%


\vspace{-1em}



  
  \date{June 16, 2024}


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\selectlanguage{english}
\begin{abstract}
We present a rare case of mirror syndrome due to anti-Kpa antibodies,
which can be difficult to identify with routine screening tests.%
\end{abstract}%



\sloppy


\textbf{MATERNAL MIRROR SYNDROME WITH FOETAL HYDROPS DUE TO
ISOIMUNIZATION BY ANTI-KPa ANTIBODIES: A CASE REPORT AND NARRATIVE
LITERATURE REVIEW}

\textbf{Authors}

Juan Pina Moreno (1), Virginia Ortega Abad (1), Ana Perez Corral (2),
Santiago Garcia-Tizon Larroca (1)

\textbf{Affiliations}

(1) Gregorio Mara\selectlanguage{ngerman}ñon Mother and Child Hospital

(2) Hospital General Universitario Gregorio Marañon, Hematology

\textbf{Corresponding author}

Santiago Garcia-Tizon Larroca

e-mail: \emph{gineteca@gmail.com}

\textbf{Data availability statement}

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

\textbf{Patient consent statement}

Written informed consent was obtained from the patient to publish this
report in accordance with the journal's patient consent policy

\textbf{Key clinical message}

The association of foetal hydrops with maternal oedema should prompt the
suspicion of mirror syndrome. In the consideration of foetal hydrops, it
is important to include immunohaematological studies that rule out the
presence of rare antibodies.

\textbf{Abstract}

We present a rare case of mirror syndrome due to anti-Kpa antibodies,
which can be difficult to identify with routine screening tests.

\textbf{Key words}

Mirror syndrome, hydrops fetalis, immune hydrops, isoimmunisation,
foetal anemia

\textbf{Introduction}

Mirror syndrome was first described in 1892 by Ballantyne. It presents a
clinical picture of maternal oedema associated with foetal hydrops and
placentomegaly, which must both be present. It is a rare entity, and in
many cases, it is underdiagnosed in routine medical practice. Its actual
incidence is unknown, and descriptions of this pathology are scarce in
the literature. Proof of this is a recent literature review with a
sample of only 113 cases reported between 1956 and
2016.\textsuperscript{1} Maternal oedema, which is the most
characteristic sign and symptom, is clinically diagnosed by the presence
of fovea after applying digital pressure for five
seconds.\textsuperscript{2} Hydrops fetalis is the pathological
accumulation of excess fluid in two or more foetal
compartments.\textsuperscript{3} Placentomegaly is defined as a
placental thickness greater than 4 cm in the second trimester or greater
than 6 cm in the third trimester, according to the published
literature.\textsuperscript{4}

Regarding the main causes of mirror syndrome, the most frequent is
foetal hydrops, which can have an immunological or nonimmunological
aetiology and can also be due to viral infections or foetal
malformations. Other symptoms that are commonly present in pregnant
women with this syndrome are arterial hypertension, mild anaemia due to
haemodilution, proteins in the urine and elevated liver enzymes. In a
high proportion of cases, perinatal death can occur as an adverse event
of pregnancy.\textsuperscript{5}

Erythrocyte alloimmunization during pregnancy is caused by the presence
of maternal antibodies against antigens present in foetal red blood
cells. The destruction of foetal erythrocytes, together with liver
damage and endothelial injury resulting from hypoxia, are sufficient
pathophysiological mechanisms for the development of hydrops in the
foetus. This immune mechanism responsible for hydrops occurs in
approximately 15\% of cases detected prenatally by ultrasound
examination.\textsuperscript{6,7}

Nonimmune hydrops can have multiple causes, including viral infections,
genetic syndromes, foetal heart rhythm disorders and malformations. At
present, it is much more common than cases with immune causes due to the
establishment of programmes for the prevention of isoimmunization during
pregnancy.\textsuperscript{3,8} Specifically, the incidence of immune
hydrops has decreased since the 1970s due to the use of anti-D
immunoglobulin and the establishment of screening programmes at the
population level.\textsuperscript{9} Most clinically significant
maternal erythrocyte alloantibodies are adequately detected with routine
screening during pregnancy with an indirect Coombs test; however, there
are cases of maternal-foetal isoimmunization due to erythrocyte
antibodies against very low frequency and atypical erythrocyte antigens.
These may not be detected with routine tests and can led to severe
neonatal haemolytic disease.\textsuperscript{10}

\textbf{Case history/examination}

Our case is a 33-year-old woman who was 25 weeks pregnant and had
adequate gestational control until she came to the emergency room due to
marked oedema of the lower limbs. The patient did not report any
relevant medical history, and her pregnancy proceeded normally
throughout the follow-up. There were no complications during her
previous pregnancy with the same partner.

Upon arrival at our centre, the physical examination showed repeated
blood pressure measurements of approximately 140/90 and intense oedema
in both lower limbs with pitting reaching the knee. The patient also had
marked oedema of the face and neck.

\textbf{Investigations and treatment}

The patient underwent various studies described below.

A blood test showed mild anaemia with haemodilution (haemoglobin 11.8
g/dl and haematocrit 33.8\%), significant proteinuria (urine
protein/creatinine index of 0.47 mg/mg) and transaminasemia (ALT 54 U/L.
AST 37 U/L) as the most remarkable data. The cardiotocographic record
showed a normal preterm foetal pattern and regular uterine dynamics. The
abdominal ultrasound examination revealed foetal hydrops with ascites
and pericardial effusion, as well as suspicion of placentomegaly. The
patient was admitted to the hospital for maternal and foetal hydrops and
monitoring of uterine dynamics.

The next day, a foetal morphological ultrasound was performed that
confirmed the presence of ascites with displacement of the intestinal
loops to the pelvis and placentomegaly, with a thickness of 80 mm. In
addition, pericardial effusion marked by mild cardiomegaly and
significant generalized foetal subcutaneous oedema was visualized. No
other morphological alterations were found, and the complete Doppler
study did not demonstrate other haemodynamic alterations. The maximum
velocity of the middle cerebral artery was normal in several repeated
measurements (36 cm/s, MoM 1.1), and foetal anaemia could not be
diagnosed at the time of the examination.

The serological study was negative for the presence of maternal-foetal
infections associated with foetal hydrops (parvovirus B19, toxoplasma,
rubella, syphilis, EBV, VH6, VZV and HIV). An indirect Coombs study with
the usual panel was negative.

The most relevant ultrasound images and clinical examination results for
the patient are presented in Figures 1, 2, 3 and 4.

\textbf{Outcome and follow up}

After one day of admission, the patient began to have regular and
painful contractions with cervical dilation until she was diagnosed with
spontaneous frank delivery. An emergency caesarean section was indicated
for established labour, foetal malposition and prematurity.

The perinatal results include the birth of a female neonate weighing
1000 g with evident signs of central predominant hydrops with marked
ascites and placentomegaly. The umbilical arterial pH at birth was 7.31,
and the Apgar test results were 2/2/2. The neonate required intubation
and vasoactive drugs for stabilization. Immediately thereafter, she was
admitted to the neonatal intensive care unit (NICU) was necessary, where
a blood test was performed that revealed severe neonatal anaemia with
haemoglobin of 4.2 g/dL and haematocrit of 14.6\%. The neonate received
transfusion with packed red blood cells and ascites drainage with no
clinical improvement.

In the pretransfusion tests of the neonate, the direct Coombs test was
positive (4+), and antibody screening with a 3-cell panel was negative.
Elution to identify the antibodies could not be performed due to the
lack of a sample.

Given the suspicion of undiagnosed isoimmunization, an expanded panel
study of irregular antibodies in the maternal blood was requested,
Isoimmunization with anti-Kpa was identified, with a titre of 1/16.
Subsequently, the erythrocyte phenotype Kpa (+) was confirmed in the
neonate, with maternal Kpa (-), Kpb (+) and paternal Kpa (+),Kbp (+).

Due to haemodynamic instability associated with prematurity and severe
anaemia, the new-born died at 19 hours of age.

The patient continued to present mild hypertension during the immediate
puerperium, which required control with descending doses of enalapril
until it ceased. During the 7 days after delivery, the patient achieved
a negative fluid balance, with an evident decrease in oedema and
normalization of laboratory values and proteinuria.

\textbf{Discussion}

In this article, the authors present the case of a pregnant woman who
met all of the diagnostic criteria for mirror syndrome or Ballantyne
syndrome. This syndrome is associated with intrauterine foetal death in
35.7\% of cases; therefore, it is especially important to identify its
cause to reduce possible adverse gestational events. The usual reasons
for consultation in affected patients are maternal oedema (up to
89.3\%), increased blood pressure (60.7\%) and headache and visual
disturbances (14.3\%). In analytical studies, mild anaemia with
haemodilution is a characteristic sign, in contrast with anaemia and
haemoconcentration, which can be present in other entities, such as
preeclampsia. Proteinuria, elevated liver enzymes and uric acid are also
frequent.\textsuperscript{5,11} Our patient presented the vast majority
of the signs and symptoms previously described in the literature and
associated findings in laboratory tests.

Regarding the precipitating causes of this condition, a systematic
review conducted by Braun et al.\textsuperscript{5} in 2010 analysed 56
cases compatible with this syndrome . A total of 28.6\% of the cases
were associated with foetal-maternal isoimmunization, 17.9\% with
multiple pregnancies, 6.1\% with viral infections and the remaining
37.5\% with foetal malformations, arrhythmias and foetal or placental
tumours. In the cases described in the literature, the symptoms
disappeared an average of 8.9 days after the pregnancy
ended.\textsuperscript{5} In the particular case of our patient, the
cause of the syndrome was isoimmunization resulting in foetal hydrops
due to severe foetal anaemia, and the patient's symptoms reversed 7 days
after the end of pregnancy.

At present, less than 10\% of cases of hydrops fetalis have an immune
cause. The origin of its pathophysiology is the presence of maternal
antibodies against foetal erythrocyte surface antigens. This
isoimmunization usually originates during pregnancy or in cases of
previous transfusions.\textsuperscript{10,12} Our patient did not report
previous transfusions but had a previous pregnancy that progressed
normally.

In our environment, gestational screening for irregular antibodies is
usually performed using an indirect Coombs test. The panels used in
maternal screening studies are capable of detecting the majority of
clinically significant isoimmunizations\textsuperscript{13}; however,
they rarely include very low frequency erythrocyte antigens, such as
Kpa, which are present in less than 2\% of the Caucasian population and
are even less common in other ethnic groups. This is the why our patient
was not identified with a high-risk pregnancy by the gestational
screening tests for isoimmunization.

Regarding isoimmunization with causes other than RhD, those involving
other Rh group antigens (C, c, E, e) stand out for their frequency and
clinical importance. Isoimmunization against Kell group antigens,
including the Kpa antigen, is also clinically significant in pregnancy.
The anti-K antibody is particularly important because it can lead to
neonatal haemolytic disease with enormous clinical severity. The
anti-Kpa antibody can be difficult to identify with routine screening
tests, as occurred in our patient.\textsuperscript{12}

In a high proportion of cases, foetal anaemia can be diagnosed by
measuring the maximum systolic peak of the middle cerebral artery (MCA).
According to a systematic review published in 2019 that included 12
studies and 696 foetuses, MCA measurement presented a diagnostic
sensitivity of 86\%, with a specificity of 71\% for predicting
moderate-severe foetal anaemia.\textsuperscript{14} The anaemia that
develops in foetuses affected by antibodies to erythrocyte antigens is
mainly caused by the suppression of erythropoiesis and, to a lesser
extent, the haemolysis of foetal erythrocytes. For this reason, some
articles suggest that foetal assessment by ultrasound measurement of the
MCA may not be a good predictor of foetal anaemia. This decreased
diagnostic sensitivity in cases of isoimmunization could explain the
presence of moderate and severe foetal anaemia with normal MCA values,
as occurred in our case.\textsuperscript{15}

Within the Kell system, there are also antibodies that rarely cause
erythroblastosis fetalis. Among them is anti-Kpa. In the literature,
there are only seven previous cases of perinatal involvement and three
cases of foetal hydrops (Table 1). We therefore present the first case
of mirror syndrome with foetal hydrops caused by anti-Kpa to be
described in the literature.

Finally, regarding the perinatal management of mirror syndrome,
termination of pregnancy if the maternal condition worsens, since 21.4\%
of cases develop serious maternal complications, such as acute lung
oedema. In some reported cases of immune hydrops associated with this
condition, intrauterine red blood cell transfusion has been performed,
and maternal symptoms have disappeared after the correction of foetal
anaemia.\textsuperscript{11,16}

\textbf{Acknowledgments}

Nothing to declare

Table 1: Literature review\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
Author & Time of Alloimmunization diagnosis & Foetal symptoms & Maternal
symptoms & Intrauterine treatment & Neonatal symptoms & Neonatal
Treatment & Neonatal outcome\tabularnewline
\midrule
\endhead
Smoleniec et al. 1994 (17) & 25 weeks & Hydrops foetalis & None &
Intrauterine exchange transfusion & Neonatal anemia & RBC transfusion &
Healthy\tabularnewline
Koshy et al. 2013 (18) & 25 weeks & Hydrops foetalis & None &
Intrauterine exchange transfusion & Neonatal anemia & RBC transfusion &
Healthy\tabularnewline
Le Vaillant et al. 2015 (19) & 27 weeks & Hydrops foetalis & None &
Intrauterine exchange transfusion & Neonatal anemia & RBC transfusion &
Healthy\tabularnewline
Braumbaugh et al. 2011 (20) & Postnatal & Hydrops foetalis &
Hypertension & None & Neonatal anemia, purpura thrombocytopenia,
coagulopathy and hypoglycemia & Neonatal intensive care (RBC, platelet,
plasma and cryoprecipitate transfusion) & Healthy\tabularnewline
Geczy et al. 1964 (21) & Postnatal & Unknown & None & None & Neonatal
anemia & RBC transfusion & Healthy\tabularnewline
Costamagna et al. 1997 (22) & Postnatal & None & None & None & Neonatal
anemia & RBC transfusion and phototherapy & Healthy\tabularnewline
Tuson et al. 2011 (23) & Postnatal & None & None & None & Neonatal
anemia & RBC transfusion & Healthy\tabularnewline
\bottomrule
\end{longtable}

*RBC; Red Blood Cells

\textbf{Author contributions}

JPM wrote the final manuscript, RAR reviewed the final manuscript, APC
reviewed the final manuscript, VOA reviewed the final manuscript, SGTL
wrote the final manuscript

\textbf{Ethical statement}

This manuscript is the author\selectlanguage{ngerman}´s own original work, which has not been
previously published elsewhere.

\textbf{Acknowledgments}

Nothing to declare

\textbf{References}

1. Allarakia S, Khayat HA, Karami MM, et al. Characteristics and
management of mirror syndrome: a systematic review (1956-2016). \emph{J
Perinat Med} . 2017;45(9):1013-1021.

2. Lawenda BD, Mondry TE, Johnstone PA. Lymphedema: a primer on the
identification and management of a chronic condition in oncologic
treatment. \emph{Ca-Cancer J Clin} . 2009;59(1):8-24.

3. Czernik C, Proquitté H, Metze B, Bührer C. Hydrops fetalis--has there
been a change in diagnostic spectrum and mortality? \emph{J Matern-Fetal
Neonat Med} . 2011;24(2):258-263.

4. Porat S, Fitzgerald B, Wright E, Keating S, Kingdom JC. Placental
hyperinflation and the risk of adverse perinatal
outcome.\emph{Ultrasound Obstet Gynecol} . 2013;42(3):315-321.

5. Braun T, Brauer M, Fuchs I, et al. Mirror syndrome: a systematic
review of fetal associated conditions, maternal presentation and
perinatal outcome. \emph{Fetal Diagn Ther} . 2010;27(4):191-203.

6. Takci S, Gharibzadeh M, Yurdakok M, et al. Etiology and outcome of
hydrops fetalis: report of 62 cases. \emph{Pediatr Neonatol} .
2014;55(2):108-113.

7. McEwan A. Fetal anaemia. \emph{Obstet Gynaecol Reprod Med} .
2019;29(8):233-239.

8. Gaetani M, Damiani gr, Pellegrino A, et al. Diagnosis and management
of a rare case of fetal mediastinal teratoma without non-immunological
hydrops. \emph{J Obstet Gynaecol} . 2015;36:1-3.

9. Moise KJ, Jr. Management of rhesus alloimmunization in
pregnancy.\emph{Obstet Gynecol} . 2008;112(1):164-176.

10. Sohan K, Carroll SG, De La Fuente S, Soothill P, Kyle P. Analysis of
outcome in hydrops fetalis in relation to gestational age at diagnosis,
cause and treatment. \emph{Acta Obstet Gynecol Scand} .
2001;80(8):726-730.

11. Hobson SR, Wallace EM, Chan YF, Edwards AG, Teoh MWT, Khaw AP.
Mirroring preeclampsia: the molecular basis of Ballantyne
syndrome.\emph{J Matern-Fetal Neonat Med} . 2020;33(5):768-773.

12. ACOG practice bulletin no. 192: management of alloimmunization
during pregnancy. \emph{Obstet Gynecol} . 2018;131(3):e82-e90.

13. Krishnan V, Shenoy V, Sunny S, et al. Defining critical antibody
titre in column agglutination method to guide fetal
surveillance.\emph{Transfus Apher Sci} . 2020;59(3):102732.

14. Martinez-Portilla RJ, Lopez-Felix J, Hawkins-Villareal A, et al.
Performance of fetal middle cerebral artery peak systolic velocity for
prediction of anemia in untransfused and transfused fetuses: systematic
review and meta-analysis.
https://doi.org/10.1002/uog.20273.\emph{Ultrasound Obstet Gynecol} .
2019;54(6):722-731.

15. Deleers M, Guizani M, Jani J, Hulot M, El Kenz H. A case of severe
foetal anaemia due to anti-Kell that could not be detected by the weekly
assessment of middle cerebral artery peak systolic
velocity.\emph{Transfus Apher Sci} . 2018;57(1):111-113.

16. Arslan E, Demir SC, Ozsurmeli M, Akcabay C. Perinatal outcomes and
survival predictors of severe red-cell alloimmunization treated by
intrauterine transfusion. \emph{J Obstet Gynaecol} .
2021;47(8):2632-2640.

Smoleniec J, Anderson N, Poole G. Hydrops fetalis caused by a blood
group antibody usually undetected in routine screening. Archives of
disease in childhood Fetal and neonatal edition. 1994;71(3):F216-217.

18. Koshy R, Patel B, Harrison JS. Anti-Kpa-induced severe delayed
hemolytic transfusion reaction. Immunohematology. 2009;25(2):44-47

19. Le Vaillant C, Jacopin-Bruneau L, Nowak C, Riteau AS. Two cases of
unusual allo-immunization caused by atypical antibodies. Presse medicale
(Paris, France : 1983).2015;44(10):1078-1082.Allo-immunisation
materno-f\selectlanguage{polish}œ\selectlanguage{english}tale par anticorps atypiques \selectlanguage{ngerman}à propos de deux cas cliniques.

20. Brumbaugh JE, Morgan S, Beck JC, et al. Blueberry muffin rash,
hyperbilirubinemia, and hypoglycemia: a case of hemolytic disease of the
fetus and newborn due to anti-Kp(a). Journal of perinatology : official
journal of the California Perinatal Association. 2011;31(5):373-376.

21. Geczy A, Ennis J, Golian PR. A further example of anti-kpa.
Transfusion. 1965;5:89-91.

22. Costamagna L, Barbarini M, Viarengo GL, Pagani A, Isernia D,
Salvaneschi L. A case of hemolytic disease of the newborn due to
anti-Kpa. Immunohematology. 1997;13(2):61-62.

23. Tuson M, Hue-Roye K, Koval K, et al. Possible suppression of fetal
erythropoiesis by the Kell blood group antibody anti-Kp(a).
Immunohematology. 2011;27(2):58-60.\selectlanguage{english}
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