\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[english]{babel}



\usepackage{float}








\begin{document}

\title{Severe fetal anaemia resulting from a widely metastatic antenatal
choriocarcinoma}



\author[1]{Mohamed Khalil}%
\author[1]{Shamma Al-Inizi}%
\author[2]{Angharad James}%
\affil[1]{South Tyneside and Sunderland NHS Foundation Trust}%
\affil[2]{Newcastle University}%


\vspace{-1em}



  
  \date{May 14, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup








\sloppy


\textbf{Severe fetal anaemia resulting from a widely metastatic
antenatal choriocarcinoma}

\textbf{Authors:}

\textbf{Corresponding Author:}

\textbf{Name:} Dr Mohamed Ali Mustafa Khalil (MAMK)

\textbf{Post:} Specialist Registrar, South Tyneside and Sunderland NHS
Foundation Trust

\textbf{E-mail Address:}Mohamed.khalil@nhs.net

\textbf{Address:} Sunderland Royal Hospital, Kayl Road, Sunderand, UK,
SR4 7TP.

\textbf{Contribution to Authorship:} Dr Khalil, was the Operating
Surgeon, contributed to the care provided antenatally, postnatally and
followed up the patient in line with the trophoblastic center at
Sheffield, UK. Dr Khalil wrote the introduction and discussion of the
case reported.

\textbf{Other Authors:}

\textbf{Name:} Mrs Shamma Al-Inizi

\textbf{Post:} Consultant Obstetric and Gynaecology, South Tyneside and
Sunderland NHS Foundation Trust\textbf{Contribution to Authorship:} Mrs
Al-Inizi was the consultant on duty upon delivery of the patient,
followed the patient during her course of stay in hospital postnatally.
She reviewed the written case report.

\textbf{Name:} Angharad Mai James (AMJ)

\textbf{Post:} Medical Student, Newcastle University

\textbf{Contribution to Authorship:} Angharad shared in writing the body
of the case reported.

\textbf{Introduction:}

Molar pregnancies belong to a group of diseases classified as
gestational trophoblastic diseases, which result from an altered
fertilization (1, 2). Partial molar pregnancy with a live fetus is a
very rare condition, occurring in 0.005 to 0.01\% of all pregnancies
(1). it presents a challenging diagnosis, especially when clinical signs
are nearly absent (5,~13).

\textbf{Case presentation:}

This is a rare case of molar pregnancy complicated by metastatic
choriocarcinoma during pregnancy, in which a normal-appearing male fetus
with diploid karyotype was delivered at 35 weeks gestation by emergency
caesarean in a 42-year-old Chinese woman. This was a spontaneous first
pregnancy with a background history of subfertility. The dating
ultrasound scan (US) raised concerns of the associated molar changes at
the placental site, however; a review with fetal medicine consultant
assured that it is likely due to vanished second twin or degenerated
subchorionic hematoma. This lady was booked in the high-risk maternal
medicine clinic following blood investigations indicating elevated
thyroid function tests and was started on Carbimazole 20 mg once daily.
The pregnancy progressed smoothly with regular antenatal visits and
follow up by the maternal medicine consultant with normal growth
ultrasound scan finings. At 33 weeks gestation, she was admitted to the
respiratory ward with un-explained cough \& shortness of breath (SOB),
and a CT chest indicated some pulmonary infiltrates and was treated as
pneumonia with antibiotics, fetal monitoring was normal. She was
readmitted 2 weeks later to the respiratory ward with increasing cough
and SOB, with a low O2 saturation. A repeat CT scan of the chest
indicated some lung changes suggesting the possibility of vasculitis and
pulmonary embolism was ruled out. Next day she complained of increasing
shortness of breath, she continued to be hypoxic with reduced fetal
movement. Cardiotocography (CTG) indicated a pathological trace. She was
delivered by an emergency caesarean section (LSCS), delivering a 2.235
kg male baby severely pale handed to the neonatologists. Severe fetal
anaemia (Hb 35 mg/dl) was immediately confirmed, and the baby was
transfer to the neonatal unit (NNU) where he made a full recovery
following blood transfusion. Bilateral enlarged haemorrhagic cystic
ovaries were noticed during the CS with the right around 12 cm size,
which was biopsied. Histology confirmed theca lutein cysts. Pathological
analysis of the removed placenta confirmed choriocarcinoma. She made a
good post operative recovery but remained hypoxic with PO2 ranging
between 90-92\%. Choriocarcinoma was confirmed following receiving the
result of a very high B-HCG of 2622500 IU/L which was followed by full
maternal body imaging indicating widespread metastasis to the lungs,
liver, kidneys and brain. The patient was transferred to the regional
Trophoblastic centre where she started her systemic and intrathecal
chemotherapy after scoring which indicated high score. She is making
good response and the trophoblastic team is hoping for full cure.

\textbf{Conclusion:} Molar pregnancy with an alive fetus is a very rare
condition that presents a challenging diagnosis especially when BhCG is
within normal. High index of suspicion is paramount when the US in early
pregnancy suspects this possibility and follow up with repeated BhCG in
pregnancy together with checking the placental history at birth are
vital. Severe fetal anaemia secondary to metastatic Choriocarcinoma was
never reported before which could follow the same mechanism of severe
fetal anaemia secondary to an associated partial hydatidiform mole.

\textbf{Introduction:}

Hydatidiform mole belongs to a group of diseases classified as
gestational trophoblastic disease which results from an impaired
fertilization (1, 2). Hydatidiform moles have been divided into complete
or partial moles on the basis of distinctive histopathological features
and genetic abnormalities (3). Partial molar pregnancy with coexisting
fetus is a rare complication with an incidence of 0.005-- 0.01\% of all
the pregnancies (1). It usually develops from dispermic fertilization of
a haploid normal oocyte and produces a triploid set of chromosomes (69
XXX, 69 XXY, or 69 XYY) and is most commonly associated with the
presence of a malformed fetus (1, 2). The most relevant symptom of a
molar pregnancy is heavy vaginal bleeding in early pregnancy. Other
symptoms can be severe nausea, hyperemesis, hyperthyroidism,
hypertension, and proteinuria, and the occurrence of fetal anaemia.
Human chorionic gonadotropin (hCG) levels are generally lower than in
complete molar pregnancy (3, 4). A diagnosis can be achieved with US and
sensitive measurement of serum BhCG. However, partial moles are often
misdiagnosed as an incomplete or missed miscarriage during the first
trimester. In less than 25\% of cases, pregnancy with a partial mole and
a single normal fetus evolves to a viable fetus: in such cases the
diagnosis can be suspected but the management can be challenging due to
the potential maternal and fetal complications (5). We report a rare
case of a misdiagnosed partial molar pregnancy in which a severely
anaemic but normal-appearing male fetus with a diploid karyotype was
delivered at 35 weeks gestation.

Fetal anaemia caused by fetomaternal transfusion in a case of partial
mole has been previously reported before (20). Although the neonatal
anaemia was effectively treated by exchange transfusion, the infant died
from respiratory distress syndrome 67 days after birth.

A 42-year-old Chinese woman was booked at 7 weeks gestation. Her
pregnancy was deemed high risk due to maternal age of 42 and
thyrotoxicosis. Dating scan at 11 weeks gestation raised a concern of an
echo free area measuring 25mm x 11mm posterior to the gestation sac
which could represent a small amount of fluid or possibly a second early
gestation sac (Figure 1). Combined maternal serum screening indicated a
low risk for triploidy. A repeat scan at 13 weeks revealed a mixed echo
structure with cystic spaces measuring 66.4 X 27.8 X 56.6 mm between the
gestational sac and the cervix raising a differential diagnosis of
co-eisting partial mole versus atypical fibroid or an atypical hematoma
(patient mentioned that she had a scan while being in china with
suspicion of fibroid uterus). (Figure 2)

She developed gestational diabetes (GDM) confirmed by oral glucose
tolerance test. The GDM was managed by diet control and Modified release
Metformin. Although she had been feeling well in herself, blood tests
revealed a high T4 of 31.1 with low TSH \textless{} 0.2 with no signs or
symptoms of Grave's disease. She was started on carbimazole 20mg OD by
the maternal medicine and endocrinology teams.

She was admitted through the emergency department at 33 weeks gestation
following a one-week history of intermittent pleuritic chest pain and
haemoptysis with SOB. With pregnancy being a risk factor for pulmonary
embolism, a CTPA (computerised tomography perfusion scan) was done.
Although it showed no pulmonary embolism, a widespread peripheral tree
in bud appearance with multifocal peripheral consolidation was seen
suspicious of an atypical pneumonia. Screening for tuberculosis (TB)
confirmed negative results. She was started on amoxicillin for a week
and was discharge home aiming for bronchoscopy in 4 weeks.

She was readmitted two weeks later with persistent cough and pain
radiating to her kidneys with increasing SOB and hypoxia (PO2 90-92\%).
A repeat CXR showed multifocal opacities which were more extensive than
previously. A rare carbamazepine induced vasculitis was suggested due to
negative cultures, so carbimazole was stopped.

Two days later, the patient complained of diminished fetal movement \&
had a CTG which confirmed a pathological antenatal pattern necessitating
delivery. She was delivered by an emergency CS delivering a male fetus
weighing 2.235 kg who looked very pale at birth. Severe fetal anaemia
confirmed Hb 35 mg/dl. The baby was transferred to the NNU and recovered
well following blood transfusion. Bilateral enlarged haemorrhagic cystic
ovaries were noticed, largest on right ovary around 10-12 cm. A wedge
biopsy of the right ovary was taken. Thea placenta looked normal with
some difficulty to remove it, was sent for histology. Tumour Markers
were collected.

Alfa fetoprotein (AFP) was high (7126 ng/mL) and dropped to 1982 ng/mL
next day and B-HCG was 2622500 IU/L. Placental histology confirmed
choriocarcinoma and the ovarian wedge biopsy confirmed theca leutin
cysts (thecoma).

The patient continued to be hypoxic and breathless with haemoptysis. A
repeat CT Angiography on day 7 postpartum, ruled out pulmonary embolism
but showed multiple scattered lesions throughout both lungs which were
concerning of malignancy. There was a few ill-defined low-density
lesions located within the liver (Figure 3 and 4). Once the BhCG was
received, the diagnosis of antenatal metastatic choriocarcinoma was
made.

The regional Trophoblastic Centre was informed, and the patient was
transferred there following imaging for staging. This has confirmed
widespread metastasis of choriocarcinoma to both lungs, liver, kidneys,
and brain.

Scoring system indicated high risk gestational trophoblastic disease and
multiple potent systemic chemotherapeutic agents were commenced low dose
Etoposide and cisplatin along with intrathecal Methottrexate for 2
weeks. Thereafter she received EP/EMA which consists of the drugs
Etoposide, Cisplatin, Methotrexate and Dactomycin. This regimen is
administered weekly alternating with EP and EMA along with intrathecal
Methotrexate on the week given EP. The chemotherapy was given till the
B-HCG reached normal levels and continued for 8 weeks after.

\textbf{Discussion}

Partial molar pregnancy with coexisting fetus is an extremely rare
variation of gestational trophoblastic disease. It accounts for 0.005 to
0.01\% of all pregnancies and usually derives from dispermic
fertilization of a haploid normal oocyte and produces a triploid set of
chromosomes (1,~6). An increased incidence could be explained by the
greater use of assisted reproductive techniques (7).

There are three types of molar pregnancy with coexisting normal live
fetus: the most frequent case is a twin pregnancy with one normal fetus
having a normal placenta and another complete mole; the second type is a
twin pregnancy with regular fetus and placenta coexisting with a partial
mole (8); the third and most uncommon occurrence reported only 19 times
in the literature is a singleton normal fetus with partial molar
placenta, which has some similarity to our case (5).

The diagnosis of molar pregnancy with coexisting fetus is difficult. In
fact, the diagnosis can be achieved with ultrasonography and sensitive
measurement of serum B-HCG usually during the first trimester (9).
Moreover, in molar pregnancy, symptoms are hyperemesis, heavy vaginal
bleeding, increased blood pressure with possible proteinuria that can
lead to preeclampsia (6,~9,~10). Women with hydatidiform mole may
experience symptoms typical of hyperthyroidism because of extremely high
levels of B-HCG which can mimic the action of TSH (11,~12). High
concentrations of B-HCG and suppressed levels of TSH can help to confirm
the diagnosis.

Many of these pregnancies don't continue due to triploidy of the fetuses
and severe intrauterine growth restriction and limited normal functional
placental circulation. If the pregnancy continues, management of molar
pregnancies with an apparently normal fetus remains challenging (5,~13).

In our patient, severe fetal anaemia was probably due to Malfunction
cancerous placenta. There is no fetal bleeding into the abnormal
hydatidiform molar placenta evidenced by a negative Kleihauer-Betke
test.

The woman must be counselled regarding the maternal and fetal
complications of this condition which include late miscarriage, vaginal
bleeding, malpresentations, preterm labour, persistent gestational
trophoblastic disease, severe fetal anaemia, hyperthyroidism,
hypertensive disorders of pregnancy, pulmonary oedema, and
thromboembolic phenomena (14,~15).

Hence following such pregnancy with regular ultrasound assessment of
fetal anatomy and growth is important. A chorionic villous biopsy could
be done if a live fetus is present, to confirm the diagnosis and to
differentiate between a partial mole and complete mole: it has been
reported that the latter has approximately 20\% tendency to become an
invasive mole or even a choriocarcinoma, while the risk was lower for
partial moles (14,~16). Follow-up BhCG during and following pregnancy in
order to early identify cases of persistent trophoblastic disease,
invasive mole and choriocarcinoma is necessary (17-19).

\textbf{Conclusion}

High index of suspicion of coexistent molar pregnancy with a normal
fetus is paramount considering BhCG follow up in pregnancy and
postnatally. Severe fetal anaemia secondary to widely metastatic
antenatal choriocarcinoma was never reported. However, the aetiology of
fetal anaemia can be similar to coexistent partial molar pregnancy where
the trophoblastic changes result in dysfunctional placental unit.
Confirming the diagnosis by post-natal B-HCG and placental histology are
important.

\textbf{Disclosure of interest}

There is no financial, personal, political, intellectual, or religious
interests associated with the case reported.

\textbf{Patient's consent}

Patient was consented and permission from her personally was granted for
publication of the case reported.

\textbf{Funding}

There is no funding provided during the care provided for this patient
and no funding for publication of this case report.

\textbf{Details of ethics approval}

There is no need for ethical approval for publication of this case
report.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Smith HO, Kohorn E, Cole LA. Choriocarcinoma and gestational
  trophoblastic disease.~\emph{Obstet Gynecol Clin North Am.~}
  2005;\textbf{32} (4):661--684. doi:~10.1016/j.ogc.2005.08.001.
\item
  Soper JT. Gestational trophoblastic disease.~\emph{Obstet Gynecol.~}
  2006;\textbf{108} (1):176--187.
  doi:~10.1097/01.AOG.0000224697.31138.a1.
\item
  Stevens FT, Katzorke N, Tempfer C, Kreimer U, Bizjak GI, Fleisch MC,
  Fehm TN. Gestational Trophoblastic Disorders: An Update in
  2015.~\emph{Geburtshilfe Frauenheilkd.~} 2015;\textbf{75}
  (10):1043--1050. doi:~10.1055/s-0035-1558054.
\item
  Campitiello MR, De Franciscis P, Mele D, Izzo G, Sinisi A, Delrio G,
  Colacurci N. Endometrial LGR7 expression during menstrual
  cycle.~\emph{Fertil Steril.~} 2011;\textbf{95} (8):2511--2514.
  doi:~10.1016/j.fertnstert.2011.01.124.
\item
  Kawasaki K, Kondoh E, Minamiguchi S, Matsuda F, Higasa K, Fujita K,
  Mogami H, Chigusa Y, Konishi I. Live-born diploid foetus complicated
  with partial molar pregnancy presenting with pre-eclampsia, maternal
  anemia, and seemingly huge placenta: A rare case of confined placental
  mosaicism and literature review.~\emph{J Obstet Gynaecol Res.~}
  2016;\textbf{42} (8):911--917. doi:~10.1111/jog.13025.
\item
  Hancock BW, Tidy JA. Current management of molar pregnancy.~\emph{J
  Reprod Med.~} 2002;\textbf{47} (5):347--354.
\item
  Malhotra N, Deka D, Takkar D, Kochar S, Goel S, Sharma MC.
  Hydatidiform mole with coexisting live foetus in dichorionic twin
  gestation.~\emph{Eur J Obstet Gynecol Reprod Biol.~} 2001;\textbf{94}
  :301--303. doi:~10.1016/S0301-2115(00)00338-9.
\item
  Hsieh CC, Hsieh TT, Hsueh C, Kuo DM, Lo LM, Hung TM. Delivery of a
  severely anaemic foetus after partial molar pregnancy; clinical and
  ultrasonographic finding.~\emph{Hum Reported.~} 1999;\textbf{14}
  :1122--1126. doi:~10.1093/humrep/14.4.1122.
\item
  Ross JA, Unipan A, Clarke J, Magee C, Johns J. Ultrasound diagnosis of
  molar pregnancy.~\emph{Ultrasound.~} 2018;\textbf{26} (3):153--159.
  doi:~10.1177/1742271X17748514.
\item
  Santos A, Trocado V, Gama AP, Pinheiro P, Nogueira R. Partial Molar
  Pregnancy with Live Foetus Diagnosed on Second Trimester: A Case
  Report.~\emph{J Gynecol Neonatal Biol.~} 2017;\textbf{3} (2):1--4.
  doi:~10.15436/2380-5595.17.1475.
\item
  Wang Y, Qian H, Wang J. Medical termination of a partial hydatidiform
  mole and coexisting foetus during the second trimester: A case
  report.~\emph{Oncol Lett.~} 2015;\textbf{10} (6):3625--3628.
  doi:~10.3892/ol.2015.3743.
\item
  Walkington L, Webster J, Hancock BW, Everard J, Coleman RE.
  Hyperthyroidism and human chorionic gonadotrophin production in
  gestational trophoblastic disease.~\emph{Br J Cancer.~}
  2011;\textbf{104} (11):1665--1669. doi:~10.1038/bjc.2011.139.
\item
  Siciliano RA, Mazzeo MF, Spada V, Facchiano A, d'Acierno A, Stocchero
  M, De Franciscis P, Colacurci N, Sannolo N, Miraglia N. Rapid
  peptidomic profiling of peritoneal fluid by MALDI-TOF mass
  spectrometry for the identification of biomarkers of
  endometriosis.~\emph{Gynecol Endocrinol.~} 2014;\textbf{30}
  (12):872--876. doi:~10.3109/09513590.2014.943718.
\item
  Rathod S, Samal SK, Ghose S. Twin pregnancy with hydatidiform mole and
  co-existing foetus: a case report and review of literature.~\emph{Int
  J Health Sci Res.~} 2014;\textbf{4} (7):275--279.
\item
  Simonelli A, Guadagni R, De Franciscis P, Colacurci N, Pieri M,
  Basilicata P, Pedata P, Lamberti M, Sannolo N, Miraglia N.
  Environmental and occupational exposure to bisphenol A and
  endometriosis: urinary and peritoneal fluid concentration
  levels.~\emph{Int Arch Occup Environ Health.~} 2017;\textbf{90}
  (1):49--61. doi:~10.1007/s00420-016-1171-1.
\item
  Callen PW. Ultrasound evaluation of gestational trophoblastic disease.
  In: Callen PW, editor.~\emph{Ultrasonography in Obstetrics and
  Gynecology.} ~2. Philadelphia: W.B. Saunders; 1988. p. 416.
\item
  Worley MJ, Jr, Joseph NT, Berkowitz RS, Goldstein DP. Women with a
  partial mole during their first pregnancy and diagnosed earlier in
  gestation are at increased risk of developing gestational
  trophoblastic neoplasia.~\emph{Int J Gynecol Cancer.~}
  2014;\textbf{24} :941--945. doi:~10.1097/IGC.0000000000000130.
\item
  Berkowitz RS, Goldstein DP. Current advances in the management of
  gestational trophoblastic disease.~\emph{Gynecol Oncol.~}
  2013;\textbf{128} (1):3--5. doi:~10.1016/j.ygyno.2012.07.116.
\item
  Khanom R, Khatun K, Akter S. Pregnancy with a normal live foetus and a
  partial molar placenta - an extremely rare condition.~\emph{J Dhaka
  Med Coll.~} 2009;\textbf{18} (1):82--84. doi:~10.3329/jdmc.v18i1.6313.
\item
  Crooij, M.J., Harten, V.D., Puyenbroek, partial hydatidiform mole,
  dispersed throughout the placenta, coexisting with a normal living
  fetus. J.I.~\emph{et al.} ~1985 \emph{Br. J. Obstet. Gynaecol.,}
  ~92\textbf{,} 104--106.
\end{enumerate}

\textbf{Figures}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure - booking US scan 11 weeks\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure - US scan 13 weeks\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Figure CT scan findings day 7\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

Figure - CT scan finding Day 7

\selectlanguage{english}
\FloatBarrier
\end{document}

