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\begin{document}

\title{The incidence, maternal, fetal and neonatal consequences of single
intrauterine fetal death in monochorionic twins: a prospective
observational UKOSS study}



\author[1]{Katie Morris}%
\author[2]{Fiona Mackie}%
\author[1]{Aurelio Tobias}%
\author[3]{Marian Knight}%
\author[4]{Mark Kilby}%
\affil[1]{University of Birmingham}%
\affil[2]{Birmingham Women's and Children's NHS Foundation Trust}%
\affil[3]{National Perinatal Epidemiology Unit}%
\affil[4]{Birmingham university}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objective: report maternal, fetal and neonatal complications associated
with single intrauterine fetal death (sIUFD) in monochorionic twin
pregnancies Design: prospective observational study Setting: UK
Population: 81 monochorionic twin pregnancies with sIUFD after 14 weeks
gestation, irrespective of cause Methods: UKOSS reporters submitted data
collection forms using data from hospital records. Main outcome
measures: aetiology of sIUFD; surviving co-twin outcomes: perinatal
mortality, central nervous system (CNS) imaging, gestation and mode of
delivery, neonatal outcomes; post-mortem findings; maternal outcomes.
Results: The commonest aetiology was twin-twin transfusion syndrome
(38/81, 47\%), ``spontaneous'' sIUFD (22/81, 27\%) was second commonest.
Death of the co-twin was common (10/70, 14\%). Preterm birth
(\textless{}37 weeks gestation) was the commonest adverse outcome
(77\%): half were spontaneous and half iatrogenic. Only 46/75 (61\%)
cases had antenatal CNS imaging, of which 33 cases had known results of
which 7/33 (21\%) had radiological findings suggestive of neurological
damage. Postnatal CNS imaging revealed an additional 7 babies with CNS
abnormalities, all born at \textless{}36 weeks, including all 4 babies
exhibiting abnormal CNS signs. Major maternal morbidity was relatively
common, with 6\% requiring ITU admission, all related to infection.
Conclusions: Monochorionic twin pregnancies with single IUD are complex
and require specialist care. Further research is required regarding
optimal gestation at delivery of the surviving co-twin, preterm birth
prevention, and classifying the cause of death in twin pregnancies.
Awareness of the importance of CNS imaging, and follow-up, needs
improvement.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Monochorionic (MC) twin pregnancies constitute approximately 30\% of all
twin pregnancies and are complex due to the conjoining of the two fetal
circulations by placental vascular anastomoses, predisposing the
pregnancies to unique complications, including twin-twin transfusion
syndrome (TTTS), selective intrauterine growth restriction (sIUGR), and
single intrauterine fetal death (sIUFD)\textsuperscript{1, 2} . Data
from cohort studies and case series indicate that sIUFD complicates up
to 6\% of all twin pregnancies (although the true prevalence is
unknown)\textsuperscript{3} . sIUFD occurs more frequently in MC twins
(7.5\%) compared to dichorionic twins (3\%)\textsuperscript{4} with
morbidity affecting the surviving fetus being higher in MC
twins\textsuperscript{3} . Many sIUFDs occur before 14 weeks gestation
presenting at a dating ultrasound scan as a `vanishing' twin. However
sIUFDs after 14 weeks are potentially associated with serious perinatal
consequences for the surviving co-twin including IUFD (i.e. after death
of the first twin), preterm birth, long-term neurological comorbidity,
and neonatal death \textsuperscript{5-7}. Additionally, maternal
morbidity following sIUFD has been reported with higher rates of
pre-eclampsia, coagulopathy and sepsis\textsuperscript{8, 9}.

Clinical management is challenging as controversy exists relating to
optimal time of delivery, frequency of prenatal ultrasound surveillance
and appropriate investigations to determine central nervous system
imaging (CNS) morbidity\textsuperscript{10, 11}. In addition, the
maternal and paternal psychological effects of such a complication may
be profound. We have previously published three systematic reviews
investigating the outcomes of the surviving co-twin following
sIUFD\textsuperscript{5, 7, 12}; despite an additional 20 studies being
able to be included in the most contemporary review and reduced
heterogeneity, the same issue of small study bias persisted. Although
there appeared to be an emerging consistency within the international
literature supporting `conservative management', there was little
objective evidence as to: a) most reliable method of assessing fetal
wellbeing, b) the use of prenatal imaging to identify CNS damage (i.e.
ultrasound vs. Magnetic Resonance Imaging {[}MRI{]} or a combination),
c) optimal gestation and mode of delivery.

The objectives of this study were to report on the incidence of, and
maternal, fetal and neonatal complications associated with sIUFD (after
14 weeks gestation) in MC twin pregnancies in the United Kingdom. These
data are important to: improve counselling of parents regarding the
prognosis of the surviving co-twin, and aid management decisions.

\textbf{Methods}

\textbf{Case definition}

All MC twin pregnancies with a sIUFD after 14 weeks gestation, including
spontaneous IUFD (i.e. no signs of TTTS, sIUGR or congenital/structural
anomaly), IUFD after intervention for complications such as fetoscopic
laser ablation (FLA) for TTTS, sIUGR or selective feticide (intrafetal
laser, radiofrequency ablation and cord occlusion) were included. Those
with ``major'' structural fetal anomalies (concordant and discordant)
were included, as were MC monoamniotic twins. For inclusion,
chorionicity had to have been confirmed in the first trimester based on
the presence of the 'T' sign and absence of the `lambda' sign, and a
single placental mass\textsuperscript{13-15}. The following were
excluded: higher order multiples where fetal reduction had been
performed, pregnancies with twin reversed arterial perfusion sequence.
TTTS was defined according to the Quintero
definition\textsuperscript{16}, and sIUGR as an inter-twin growth
discordance greater than 20\% in estimated fetal weights as at the time
of designing the study there were no validated twin-specific growth
charts.

\textbf{Outcomes}

There are currently no validated core outcome sets for twin pregnancy
research, thus outcomes were based on: existing literature, discussion
with representatives from the Multiple Births Foundation and the Twins
Trust, and limitations noted from systematic reviews\textsuperscript{5,
7}.

\begin{enumerate}
\tightlist
\item
  Incidence of sIUFD after 14 weeks gestation in MC twin pregnancies.
\item
  Complications associated with sIUFD: rates of sIUFD associated with
  antenatal complications (TTTS, sIUGR and congenital/structural
  anomalies), management of antenatal complications, rate of spontaneous
  sIUFDs
\item
  Surviving co-twin outcomes: perinatal mortality (miscarriage defined
  as fetal death \textless{}24 weeks, and stillbirth fetal death
  \textgreater{}24 weeks), antenatal CNS imaging, gestation at delivery
  (if preterm \textless{}37 weeks, \textless{}34 weeks, \textless{}28
  weeks, iatrogenic or spontaneous), role of induction, mode of delivery
  and reason if not normal vaginal delivery, post-mortem findings.
\item
  Neonatal outcomes: neonatal death defined as at least until discharge,
  neonatal intensive care unit admission and reason, postnatal CNS
  imaging, abnormal neurological signs in the neonatal period.
\item
  Maternal outcomes: major maternal morbidity, as reported by UKOSS
  studies\textsuperscript{17}.
\end{enumerate}

\textbf{Data collection}

Data were collected using the United Kingdom Obstetric Surveillance
System (UKOSS) which prospectively captures data on severe but rare
complications of pregnancy and childbirth from all obstetric-led
maternity units in the UK. Each unit in the UK has a designated UKOSS
clinician data collector who completes monthly returns to UKOSS. The
methodology is described elsewhere\textsuperscript{17} and is well
established having been running since 2005. Additionally, the lead of
each Fetal Medicine Centre in the UK was alerted to the study. Following
case notification to UKOSS by clinicians, a piloted, anonymised data
collection form was sent (see
www.npeu.ox.ac.uk/ukoss/current-surveillance/stwin for the form) and
completed from hospital records. Reports were cross-checked for
duplication based on the woman's year of birth and estimated delivery
date. If forms were not returned, reminders were sent.

The surveillance period was between 1st July 2016 -- 30th June 2017,
defined as the time during which the sIUFD was diagnosed. There was a
further 6 months of data collection to allow collection of delivery
data. Case ascertainment was checked by comparison with MBRRACE-UK data
from the same period. All deaths of twins were identified from
MBRRACE-UK and compared with UKOSS data based on centre, month and year
of reporting for case ascertainment. Where 1 potential additional case
was identified, centres were contacted and asked to check whether the
case met the case definition and if so to complete a UKOSS data
collection form.

\textbf{Statistics}

The incidence of sIUFD in MC twin pregnancy was planned to be calculated
using ONS data as the denominator. Maternal, fetal and neonatal outcomes
were described and reported as percentages, mean and SDs or medians and
IQRs as appropriate. Sub-group analyses were planned to determine if
TTTS or sIUGR, were associated with any characteristics, or if they were
associated with a poorer outcome for the surviving co-twin. We also
planned to explore prognostic indicators for mother and infant
associated with sIUFD in MC twin pregnancy, e.g. gestation of IUFD of
the first twin, using logistic regression. No sample size calculation
was performed, but prior to commencing the study, we had estimated,
based on ONS data from 2012 and existing literature, that of 11,228 twin
pregnancies, 30\% would be MC, and 7.5\% would result in a sIUFD, thus
there would be 253 cases per annum. No imputations of missing data were
performed, cases with missing outcomes were not included in certain
analyses as stated below. The study is funded by the \emph{British
Maternal Fetal Medicine Society} and \emph{Twins Trust} (formerly
TAMBA).

\textbf{Results}

\textbf{Incidence}

82 cases were reported to UKOSS in the one year study period (Figure1).
One local reporter included a trichorionic triamniotic triplet pregnancy
which was excluded; 81 MC (diamniotic) twin pregnancies were included in
analysis. Data were collected from 47 centres. Case ascertainment via
comparison with MBRRACE-UK data identified a potential additional 94
cases which centres were asked to investigate. Twenty-eight centres
replied, with most potentially eligible cases not meeting the case
definition (fetal demise was outside the study period, both twins died
at the same time or the twins were not MC). Only three additional cases
were identified which were included in the 81 cases analysed.

The characteristics of the study population are shown in Table 1. 22/81
(27\%) sIUFDs were classified as spontaneous (i.e. no signs of TTTS,
sIUGR or congenital/structural anomaly), 38/81 (47\%) pregnancies with a
sIUFD were complicated by TTTS, 5/81 (6\%) with sIUGR, and 12/81 (15\%)
with a congenital/structural anomaly. In 4/81 (5\%) cases it was not
clear whether there was a preceding diagnosis of a complication of MC
twin pregnancy, therefore they were classified as `unclear'. The median
gestation at diagnosis of first sIUFD was 157 days, equating to 22+3
weeks (IQR 25\textsuperscript{th}-75th: 134-186 days).

\textbf{sIUFD in pregnancies that underwent antenatal interventions}

Most pregnancies affected by complications related to monochorionicity
had undergone prenatal therapeutic intervention to treat a complication
(43/55 {[}78\%{]} pregnancies): TTTS 31/38, and sIUGR 4/5, and selective
termination in 8/12 pregnancies with congenital/structural anomalies.

\textbf{Spontaneous sIUFDs}

For spontaneous sIUFDs (n=22), the median gestation at first sIUFD was
24 weeks (IQR: 11 weeks) with the latest gestation a sIUFD was diagnosed
at 36 weeks (Table 2).

\textbf{Surviving co-twin outcomes}

Figure 1 summarises the outcomes.The outcome data for the surviving
co-twin was missing in 11/81 cases (14\%). 8 of the 11 cases were
reported by a Fetal Medicine Centre who had treated complications, but
the referring hospital where they received their ongoing maternity care
did not provide outcome data, thus the data presented are the outcomes
of 70 surviving co-twins. The perinatal death rate of the co-twin was
14\% (10/70): there were 8 prenatal deaths and 2 neonatal deaths,
equating to 62/70 livebirths (88.6\%). The surviving co-twin miscarried
in 3 pregnancies. There were 2 stillbirths both following FLA for TTTS
in the second trimester. There were no intrapartum stillbirths. Three
pregnancies with TTTS had further complications of the condition
resulting in a decision for selective termination of pregnancy (e.g.
abnormal CNS imaging, severe IUGR). There were 2 neonatal deaths due to
extreme prematurity following fetal therapy.

\textbf{Antenatal CNS imaging}

Of the 81 included pregnancies, the local reporter was unable to confirm
whether antenatal CNS imaging had occurred in 6 cases. In the remaining
75 cases, antenatal CNS imaging was performed in 46/75 (61\%) surviving
co-twins. Of the 46 cases that underwent imaging, 36 had ultrasound
assessment alone, 52 had fetal MRI in addition to USS. The results of at
least one imaging modality was known by the UKOSS reporter in 33/46
cases. Abnormal CNS imaging was reported antenatally in 7/33 (21\%)
surviving co-twins, in 3 cases the abnormality was confirmed on fetal
MRI, in all 7 cases the imaging abnormalities were of a severity known
to be associated with neurological sequelae.

\textbf{Delivery outcomes of those resulting in a livebirth}

For the 70 cases with known outcomes, there were 62 livebirths (outcomes
summarised in Table 2). The majority (48/62, 77\%) were born before 37
weeks gestation: 23/48 due to spontaneous preterm birth, and 24/48
iatrogenic, this information was missing for 1 case. 28/62 (45\%) babies
were born at \textless{}34 weeks (17 spontaneous, 11 iatrogenic), and
5/62 (8\%) at \textless{}28 weeks (all spontaneous). Of those who
underwent induction of labour, 3/11 were induced at \textless{}37 weeks.
24/62 (39\%) were born vaginally, and 38/62 (61\%) by caesarean section.
Seven were planned caesarean sections, 31/38 were emergency caesarean
sections, the commonest indication for emergency caesarean section was
fetal distress (13/31).

\textbf{Neonatal outcomes and postnatal CNS imaging}

Most neonates (45/62 babies; 73\%) were admitted to the neonatal/special
care baby unit, the commonest reason for admission was prematurity
(29/45 babies; 64\%). The median length of stay in the neonatal/special
care baby unit was 11.5 days (IQR: 5 - 34 days). Only 9/62 (15\%) babies
underwent postnatal CNS imaging: imaging in 8/9 babies was abnormal, and
normal in 1 baby. It was not known if postnatal CNS imaging occurred
later in 22/62 babies (35\%), the remaining 31/62 (50\%) did not have
postnatal CNS imaging. Of the 8 babies with abnormal postnatal CNS
imaging, 1 baby's ultrasound was repeated and was subsequently was
reported as ``normal''; the remaining 7 were all were delivered at
\textless{}36 weeks (median: 33+0 weeks, IQR: 30+3 -- 34+2 weeks) with a
median birthweight of 1980g (IQR:1610-2085g). Of these, 3/7 had
undergone antenatal CNS imaging although the results were unknown by the
reporter, the other 4 had not undergone antenatal CNS imaging. There was
no association with aetiology of the initial sIUFD: 3 spontaneous at
32-34 weeks, 3 TTTS treated, 1 congenital/structural anomaly. 4/62
liveborn babies had evidence of abnormal CNS signs, all of which had
abnormal postnatal CNS imaging. Only 12/60 (20\%) babies discharged home
were reported to have follow-up planned, 45/60 (75\%) were reported to
have no follow-up, these data were unknown in 3/60.

\textbf{Post} -\textbf{mortem examination}

Post-mortem examination was performed on 17/70 (24\%) pregnancies for
whom there were known outcomes. 4 cases were double IUFD (both twins
died). The post-mortem was able to provide a cause of death in only 3/17
(18\%) cases: `acute twin to twin transfusion', chronic TTTS, and
extreme prematurity. Post-mortem examination was inconclusive in 4
cases, the fetus was unable to be examined in 2 cases due to severe
maceration, and data were missing in the 8 remaining cases. The 2
neonatal deaths did not undergo post-mortem.

\textbf{Maternal outcomes}

4/70 women (6\%) with known outcomes were admitted to intensive care
{[}ITU{]} (critical care level 3). Of these women, 3 women were admitted
with sepsis (with a background of chorioamnionitis). Two of these had
previously undergone invasive, prenatal intervention for MC twin
complications earlier in pregnancy. There was more than 6 weeks between
the procedure and ITU admission. One woman was admitted for suspected
``mirror syndrome'' (severe pre-eclampsia in association with a hydropic
fetus). The maximum length of stay in ITU was 2 days (range 1-2 days).
No maternal deaths or other major maternal morbidities were reported.

\textbf{Discussion}

\textbf{Main findings}

The commonest associated aetiology with sIUFD in MC twin pregnancies was
TTTS and the majority had undergone prenatal therapy prior to sIUFD (as
opposed to being conservatively managed). The second most common
aetiology was ``spontaneous'' with no obvious underlying aetiology (i.e.
no signs of TTTS, sIUGR or congenital/structural anomaly), followed by
congenital/structural anomaly, and sIUGR being the least common. Death
of the co-twin following sIUFD was common, complicating 1 in 7
pregnancies. Less than two thirds of cases had investigation by
antenatal CNS imaging to identify ischaemic brain injury. Of the cases
whose imaging results were known to the UKOSS reporter, 1 in 5 had
radiological findings suggestive of neurological morbidity. Postnatal
CNS imaging revealed a further 7 babies with brain abnormalities (mainly
on cranial USS), all of which were born at \textless{}36 weeks, and 4 of
whom also had abnormal CNS signs. Preterm birth was the commonest
adverse outcome, with three quarters of twins born at less than 37 weeks
gestation, and an equal split between spontaneous preterm birth, and
those delivered iatrogenically. Major maternal morbidity was not
uncommon, with 6\% requiring ITU admission, compared to 0.22\% of the
general obstetric population reported in the 2015/2016 National
Maternity and Perinatal Audit\textsuperscript{18}. Interestingly, all
maternal admissions were related to sepsis, although not all women had
undergone prenatal `invasive' interventions for therapy.

\textbf{Strengths and limitations}

To the authors' knowledge, this is the first UK-wide study of sIUFD in
MC twin pregnancies. A major strength of this study is that data were
collected from UK centres, thus the results represent current UK-wide
practice. UKOSS is a validated mechanism of collecting data on
relatively rare conditions that is UK wide. Data collection relies on a
system of designated clinician data collectors. In this study there were
8 cases for whom outcome data was missing following fetal therapy at a
tertiary centre. This is in contrast to the only other UKOSS study
relating to a fetal condition, gastroschisis, where there were no
missing outcome data. This difference might reflect the complexity of
complicated MC twins requiring management at multiple care providers
(supraregional, regional and local), and that within the gastroschisis
study outcome data was also collected via paediatric surgeons and via
cross-checking with congenital anomaly registers. One of the
difficulties of data collection in complex conditions is a lack of
standard pathways of care and definitions of outcomes (e.g. ultrasound
findings). This is especially true for the complex conditions
complicating MC pregnancies, where each fetus maybe affected
differently. Since data collection for this study there have been
initiatives to guide the management of these complex pregnancies, and
define outcomes \textsuperscript{19, 20}and within the UK specialist
fetal medicine commissioning will improve pathways of care.

The number of cases notified was considerably lower than our pre-study
estimate. However, MBRRACE-UK data (national surveillance of perinatal
deaths) in 2016, noted perinatal mortality rates amongst twins as the
lowest ever reported\textsuperscript{21, 22} and thus we employed
triangulation of data with MBRACCE-UK to check case ascertainment. Using
ONS data\textsuperscript{23} and MBRACCE data\textsuperscript{21}, and
newer evidence to suggest that 20\% of twins are
monochorionic\textsuperscript{24, 25} (as opposed to the 30\% of our
original estimate), we calculated incidence of single twin demise across
the 2 years of our study. This gives very similar figures of an
estimated 75 cases in 2016 and 84 in 2017 with incidence of 37.6-38.7
per 1000 monochorionic maternities. A further strength of this study was
the collection of data relating to interventions, management and
outcomes for both mother and neonate. It is not possible to collect data
for the baby via the UKOSS system past the point of discharge from
hospital after birth. Further studies and research in this area should
include data related to longer term outcomes for the
baby\textsuperscript{7}.

\textbf{Interpretation}

The lower than expected number of cases reflects the decrease seen in
twin pregnancy perinatal mortality reported by MBRRACE-UK in
2013-2016\textsuperscript{2}. It is thought this decrease may be a
consequence of improved care for MC twin pregnancies, particularly in
recognising and treating complications unique to MC twins, and
development of new treatment techniques including the Solomon Technique
for FLA\textsuperscript{26}. This is also linked to updated national and
international guidance\textsuperscript{13, 15, 19} , which if
implemented has been demonstrated, by Twins Trust, to lower adverse
outcome rates\textsuperscript{27}. However the latest MBRRACE-UK report
published in October 2019 reported an increase in the stillbirth and
neonatal death rates in twin pregnancies in 2017\textsuperscript{22}. It
is important to consider data over a longer period alongside the use of
three year rolling averages to better reflect trends in perinatal
mortality\textsuperscript{2}.

MC twin pregnancies complicated by sIUFD have a high risk of subsequent
co-twin neurologic morbidity. From these data it appears that prenatal
and indeed postnatal screening for abnormalities of the central nervous
system in survivors is not routine in the UK. There is a need to
strengthen professional guidance and practice amongst both obstetricians
and neonatal paediatricians\textsuperscript{19}.

This study strengthens the argument made in our 2019 systematic review
and meta-analysis for the need for a purposely designed prospective
study, ideally with antenatal and postnatal imaging and long-term
follow-up \textsuperscript{7}.

There is no specific guidance regarding when and how co-twins after
sIUFD should be delivered. Of note in this study there was a high rate
of preterm birth (both spontaneous and iatrogenic) and a high rate of
emergency caesarean sections. The majority of co-twin survivors were
admitted to the neonatal unit with prematurity the commonest indication.
Despite the high risk nature of the pregnancy and requirement for
admission to NNU, very few babies had planned follow-up despite an
association with adverse long-term outcomes\textsuperscript{10}.

The uptake of post-mortem examination was low (25.4\%) for the initial
sIUFD but increased to 40\% if the co-twin died as well. This is below
the 75\% recommended uptake by the RCOG\textsuperscript{28}, and may
reflect that parents accept that MC twin pregnancies are higher risk,
and even if a cause was not apparent antenatally, the findings of the
post-mortem are unlikely to affect a subsequent pregnancy as it may be
linked to monochorionicity. Despite post-mortem being considered the
most useful investigation for parents to find out why their baby
died\textsuperscript{29}, in 6/9 post-mortems in which the UKOSS
reporter knew the findings, the post-mortem was inconclusive. This
highlights another area of future research, as there is not currently a
specific classification system for cause of death in MC twins, which is
often different to the cause of death in singletons, and is the
classification system which pathologists have to currently use. Since
performing this study, we have proposed a new classification system of
causes of death in twin pregnancies (CoDiT) which requires further
validation\textsuperscript{30}. These findings also raise the
consideration of whether specialist perinatal pathologists are needed
for MC twin pregnancy post-mortems, and whether injection studies should
be performed in all MC twin pregnancies to aid determining cause of
death.

\textbf{Conclusion}

MC twin pregnancies with sIUFD remain complex and high-risk. They should
not be treated as low-risk singleton pregnancies. Women at risk of
developing sepsis (prenatal therapy) should be closely monitored. It is
not clear what gestation to deliver the surviving co-twin; this should
be investigated with a randomised controlled trial but given the
relative rarity of sIUFD this is unlikely to occur. Preterm birth was
the commonest adverse outcome, and more research is required in this
area. Awareness of the importance of CNS imaging, and follow-up, needs
to be increased, and may be aided by better communication between
specialities and hospitals.

\textbf{Acknowledgements}

We thank all the clinicians who contributed to the UKOSS data
collection, the study would not have been possible without them.

\textbf{Disclosure of interests}

Professor Mark Kilby, Dr R Katie Morris and Dr Fiona Mackie have
received funding from the Richard and Jack Wiseman Trust (charity number
1036690) to conduct research into twin-twin transfusion syndrome. The
remaining authors have no disclosures.

\textbf{Contribution to authorship}

RKM, FLM and MDK performed the previous systematic reviews and designed
the study, with MKn. All authors were involved in analysing and
interpreting the data led by AT. FLM drafted the first manuscript, and
all authors amended and approved the manuscript.

\textbf{Details of ethical approval:} This study has ethical approval
from the North London REC1 (REC Ref. Number: 10/H0717/20) awarded
13\textsuperscript{th} April 2016.

\textbf{Funding} : The study is funded by the British Maternal Fetal
Medicine Society (BMFMS) and Twins Trust.



\textbf{Table/figure caption list}

Table 1 Maternal characteristics of sIUFD in monochorionic twin
pregnancies

Table 2 Outcomes of those ending with a livebirth following sIUFD in
monochorionic twin pregnancies, grouped according to aetiology of sIUFD

Figure 1 Outcomes of co-twins following sIUFD in monochorionic twin
pregnancies

\textbf{References}

1. Sebire NJ, Snijders RJ, Hughes K, Sepulveda W, Nicolaides KH. The
hidden mortality of monochorionic twin pregnancies. BJOG. 1997
Oct;104(10):1203-7.

2. Kilby MD, Gibson JL, Ville Y. Falling perinatal mortality in twins in
the UK: organisational success or chance? BJOG. 2019 Feb;126(3):341-7.

3. Pharoah POD, Adi Y. Consequences of in-utero death in a twin
pregnancy. Lancet. 2000 2000;355(9215):1597-602.

4. Lewi L, Gucciardo L, Van Mieghem T, de Koninck P, Beck V, Medek H, et
al. Monochorionic diamniotic twin pregnancies: natural history and risk
stratification. Fetal Diagn Ther. 2010;27(3):121-33.

5. Hillman SC, Morris RK, Kilby MD. Co-twin prognosis after single fetal
death: a systematic review and meta-analysis. Obstet Gynecol. 2011
Oct;118(4):928-40.

6. Mackie FL, Morris RK, Kilby MD. Fetal Brain Injury in Survivors of
Twin Pregnancies Complicated by Demise of One Twin: A Review. Twin Res
Hum Genet. 2016 Jun;19(3):262-7.

7. Mackie FL, Rigby A, Morris RK, Kilby MD. Prognosis of the co-twin
following spontaneous single intrauterine fetal death in twin
pregnancies: a systematic review and meta-analysis. BJOG. 2019
Apr;126(5):569-78.

8. Santema JG, Swaak AM, Wallenburg HC. Expectant management of twin
pregnancy with single fetal deathBJOG. 1995 1/1995;102(1):26-30.

9. Kilby MD, Govind A, O'Brien PM. Outcome of twin pregnancies
complicated by a single intrauterine death: a comparison with viable
twin pregnancies. Obstetrics \& Gynecology. 1994 7/1994;84(1):107-9.

10. van Klink JM, van Steenis A, Steggerda SJ, Genova L, Sueters M,
Oepkes D, et al. Single fetal demise in monochorionic pregnancies:
incidence and patterns of cerebral injury. Ultrasound Obstet Gynecol.
2015 Mar;45(3):294-300.

11. Griffiths PD, Sharrack S, Chan KL, Bamfo J, Williams F, Kilby MD.
Fetal brain injury in survivors of twin pregnancies complicated by
demise of one twin as assessed by in utero MR imaging. Prenat Diagn.
2015 Jun;35(6):583-91.

12. Ong SS, Zamora J, Khan KS, Kilby MD. Prognosis for the co-twin
following single-twin death: a systematic review. {[}Review{]} {[}36
refs{]}. BJOG: An International Journal of Obstetrics \& Gynaecology.
2006 9/2006;113(9):992-8.

13. National Institute for Health and Care Excellence. The Management of
Twin and Triplet Pregnancies in the Antenatal Period. In: NICE, editor.
129 ed. Manchester: National Institute for Health and Clinical
Excellence; 2011.

14. National Institute for Health and Care Excellence. Twin and Triplet
Pregnancy. In: NICE, editor. 137 ed. Manchester: National Institute for
Health and Clinical Excellence; 2019.

15. Khalil A, Rodgers M, Baschat A, Bhide A, Gratacos E, Hecher K, et
al. ISUOG Practice Guidelines: role of ultrasound in twin pregnancy.
Ultrasound Obstet Gynecol. 2016 Feb;47(2):247-63.

16. Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M.
Staging of twin-twin transfusion syndrome. J Perinatol. 1999 Dec;19(8 Pt
1):550-5.

17. Knight M, Kurinczuk JJ, Tuffnell D, Brocklehurst P. The UK Obstetric
Surveillance System for rare disorders of pregnancy. BJOG. 2005
Mar;112(3):263-5.

18. Jardine J, NMPA Project Team. Maternity Admissions to Intensive Care
in England, Wales and Scotland in 2015/16: A Report from the National
Maternity and Perinatal Audit. 2019 {[}cited; Available from:
https://maternityaudit.org.uk/FilesUploaded/NMPA\%20Intensive\%20Care\%20sprint\%20report.pdf

19. Kilby M, Bricker L, Gynaecologosts RCoOa. Management of
Monochorionic Twin Pregnancy. BJOG. 2016;124:e1-e45.

20. Perry H, Duffy JMN, Reed K, Baschat A, Deprest J, Hecher K, et al.
Core outcome set for research studies evaluating treatments for
twin-twin transfusion syndrome. Ultrasound Obstet Gynecol. 2019
Aug;54(2):255-61.

21. Draper ES GI, Kurinczuk JJ, Smith PW, Boby T, Smith LK, Manktelow
BN, on behalf of the, Collaboration M-U. MBRRACE-UK Perinatal Mortality
Surveillance Report, UK Perinatal Deaths for Births from January to
December 2016. : Department of Health Sciences, University of Leicester;
2018.

22. Draper ES GI, Smith LK, Kurinczuk JJ, Smith PW, Boby T, Fenton AC,
Manktelow BN, on behalf of the MBRRACE-UK Collaboration. MBRRACE-UK
Perinatal Mortality Surveillance Report, UK Perinatal Deaths for Births
from January to December 2017. Leicester: MBRACCE-UK; 2019.

23. National Office of Statistics. Birth Characteristics in England and
Wales: 2016 and 2017. 2017 {[}cited 2020 21st February 2020{]};
Available from:
https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/livebirths/datasets/birthcharacteristicsinenglandandwales

24. Litwinska E, Syngelaki A, Cimpoca B, Frei L, Nicolaides KH. Outcome
of twin pregnancy with two live fetuses at 11-13 weeks' gestation.
Ultrasound Obstet Gynecol. 2020 Jan;55(1):32-8.

25. Glinianaia SV, Obeysekera MA, Sturgiss S, Bell R. Stillbirth and
neonatal mortality in monochorionic and dichorionic twins: a
population-based study. Hum Reprod. 2011 Sep;26(9):2549-57.

26. Slaghekke F, Lopriore E, Lewi L, Middeldorp JM, van Zwet EW,
Weingertner AS, et al. Fetoscopic laser coagulation of the vascular
equator versus selective coagulation for twin-to-twin transfusion
syndrome: an open-label randomised controlled trial. Lancet. 2014 Jun
21;383(9935):2144-51.

27. Twins Trust. NICE works the final report. {[}cited 2020 10th
February{]}; Available from:
https://twinstrust.org/uploads/assets/afcc44b3-776e-4341-8a16e9bd990c3425/NICE-works-final-report.pdf

28. Royal College of Obstetricians and Gynaecologists and Royal College
of Pathologists. Fetal and Perinatal Pathology: Report of a Joint
Working Party. London: RCOG; 2001.

29. Lewis C, Hill M, Arthurs OJ, Hutchinson C, Chitty LS, Sebire NJ.
Factors affecting uptake of postmortem examination in the prenatal,
perinatal and paediatric setting. BJOG. 2018 Jan;125(2):172-81.

30. Gulati N MF, Cox P, Kilby MD. Classifying causes of in utero and
neonatal death in twin pregnancies from post-mortem examinations
undertaken in a tertiary hospital over a 4 year period.BJOG.
2019;126(S1):121-2.

\textbf{Table 1 Maternal characteristics of sIUFD in monochorionic twin
pregnancies}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
Characteristic\strut
\end{minipage} & \begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
All (n=81)\strut
\end{minipage} & \begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
Missing data n (\%)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Age (years)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
29.5 (9)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
3 (3.7)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Ethnicity n (\%) White Asian Black Other\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
68 (88.3) 6 (7.9) 2 (2.6) 1 (1.3)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
4 (4.9)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
BMI (kg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
26.3 (7.0)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
8 (9.9)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Paid employment n (\%) Yes No\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
47 (69.1) 21 (30.9)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
13 (16.0)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Smoking status n (\%) Never Stopped pre- pregnancy Stopped during
pregnancy Current\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
53 (74.6) 6 (8.4) 6 (8.4) 6 (8.4)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
2 (2.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Nulliparity n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
43 (53.1)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1 (1.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Assisted conception n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
6 (7.4)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
2 (2.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Gestation at first sIUFD (days)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
157 (52)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Presumed aetiology of sIUFD n (\%) Spontaneous TTTS sIUGR
Congenital/structural anomaly Unclear\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
22 (27.1) 38 (46.9) 5 (6.1) 12 (14.8) 4 (5)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Median and IQR reported unless otherwise stated

\textbf{Table 2 Outcomes of those ending with a livebirth following
sIUFD in monochorionic twin pregnancies, grouped according to aetiology
of sIUFD}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Outcome\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
All (n=62)\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Spontaneous (n=22)\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Complicated (n=39)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Fetal sex Male Female\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
26 (41.9) 36 (58.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
11 (50.0) 11(50.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
14 (35.9) 25 (64.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Birthweight surviving co-twin (g) median (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2049 (819)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2215 (588)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1832 (1159)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Gestation at delivery (days) median (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
240.5 (39)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
249 (26.8)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
225.5 (52)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Delivery \textless{}37 weeks* Iatrogenic\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
48 (77.4) 24 (50.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
16 (77.7) 12 (75.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
31 (79.5) 11 (35.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Delivery \textless{}32 weeks+ Iatrogenic\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
19 (30.6) 4 (21.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4 (18.2) 2 (50.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
15 (38.5) 11 (73.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Induction of labour\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
11 (17.7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3 (13.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8 (20.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Mode of delivery of surviving co-twin NVD/Instrumental Breech Pre-labour
caesarean section Caesarean section after onset of labour\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
22 (35.5) 2 (3.2) 26 (41.9) 12 (19.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4 (18.2) -14 (63.6) 4 (18.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
18 (46.1) - 11 (28.2) 8 (20.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NICU admission\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
45 (72.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
19 (86.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
26 (66.6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CNS abnormality on postnatal imaging\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8 (12.9)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3 (13.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5 (12.8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abnormal neonatal neurological signs\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4 (6.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2 (9.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2 (5.1)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

N (\%) are reported unless otherwise stated. Excluding: the 3
pregnancies which underwent feticide of the surviving co-twin, 3 that
were miscarried, 2 that were a co-twin stillbirth, and the 11 cases for
which the outcome data were missing were not included. 1 pregnancy with
`unclear' aetiology was included in the `All' column only. Data were
missing for one TTTS pregnancy which delivered at 36 weeks and it was
not known if delivery was spontaneous or iatrogenic. *28/48 were
\textless{}34 weeks. +5/19 were \textless{}28 weeks. `-` data not
provided to reduce patient identifiability. `Complicated' included
pregnancies with TTTS, sIUGR and/or congenital/structural anomalies

\textbf{Hosted file}

\verb`Figure 1.docx`  available at \url{https://authorea.com/users/308045/articles/439029-the-incidence-maternal-fetal-and-neonatal-consequences-of-single-intrauterine-fetal-death-in-monochorionic-twins-a-prospective-observational-ukoss-study}

\selectlanguage{english}
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\end{document}

