Twin and Higher order Pregnancies

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 V

Foreword

This textbook, written by leading international experts, constitutes

essential reading for all healthcare professionals involved in the care of
multiple pregnancies with the ultimate goal to improve their outcomes.
The book provides a detailed account on the management of multiple
pregnancies before, during, and after birth. Also, the book incorporates
the patient’s perspective in testimonials and experience of twin advo-
cacy groups. The reader will gain a clear understanding of the biology,
the complications, and the recommended care of multiple pregnancies,
and there is special attention to parental well-being and childhood
development. The textbook offers a practical guide with a wealth of
illustrations, figures, and videos. Each chapter also contains multiple-­
choice questions to challenge the reader’s knowledge.

Kypros Nicolaides
Professor of Fetal Medicine
Harris Birthright Centre
King’s College London
London, UK
 VII

Contents

I Biology
1 The Vanishing Twin Syndrome.................................................................3
Isaac Blickstein†

2 Placentation in Multiple Pregnancy.....................................................11

Enrico Lopriore and Liesbeth Lewi

3  iology and Genetics of Dizygotic and Monozygotic

B
Twinning.................................................................................................................31
Jeffrey J. Beck, Susanne Bruins, Hamdi Mbarek, Gareth E. Davies,
and Dorret I. Boomsma

4  win-Singleton Comparisons Across Multiple

T
Domains of Life...................................................................................................51
Gonneke Willemsen, Veronika Odintsova, Eco de Geus,
and Dorret I. Boomsma

II Antenatal Care in Twins and Multiple Pregnancy

5 Dating of Twin Pregnancies.......................................................................75
Pierre Macé, Houman Mahallati, and Laurent J. Salomon

6 Determining Chorionicity and Amnionicity....................................83

Mieke Vanoppen and Liesbeth Lewi

7  win Labelling, Timing, Frequency and Content

T
of Ultrasound Assessment..........................................................................95
Laoreti Arianna, Faiola Stefano, and Lanna Mariano

8  renatal Screening for and Diagnosis of Aneuploidy

P
in Twin Pregnancies.........................................................................................109
Alexandra Matias, Beatriz Teixeira, and Miguel Macedo

9  ssessment of Fetal Growth in Twins and Multiple

A
Pregnancy..............................................................................................................123
Becky Liu and Asma Khalil

III Prenatal Complications in Multiple Pregnancy

10 Twin Pregnancies Discordant for Fetal Anomaly.........................135
Ann Langedock and Liesbeth Lewi
VIII Contents

11  etal Reduction/Selective Termination in Uncomplicated

F
Twins and Multiple Pregnancies.............................................................147
Mercede Sebghati, Becky Liu, and Asma Khalil

12  isk Assessment and Screening for Preterm Birth

R
in Twin Pregnancy............................................................................................159
Amanda Roman, Alexandra Ramirez, Guillermo Gurza,
and Vincenzo Berghella

13 Fetal Growth Restriction..............................................................................189

Becky Liu and Asma Khalil

14 Fetal Demise in Twins: Single and Double Fetal Loss................205

L. R. I. Gurney, R. K. Morris, J. L. Gibson, and M. D. Kilby

IV Complications Unique to Monochorionic Twin

Pregnancies
15 Twin-Twin Transfusion Syndrome..........................................................231
Christian Bamberg and Kurt Hecher

16 Twin Anemia Polycythemia Sequence................................................247

L. S. A. Tollenaar and Enrico Lopriore

17 Twin Reversed Arterial Perfusion Sequence...................................263

Liesbeth Lewi

18 Monochorionic Monoamniotic Twin Pregnancy..........................275

Noa Gilad, Vagisha Pruthi, Shiri Shinar, Johannes Keunen,
Greg Ryan, and Tim Van Mieghem

19 Diagnosis and Management of Conjoined Twins........................287

Clifton Brock and Anthony Johnson

V Peripartum Care
20 Timing of Birth in Uncomplicated Twin Pregnancy....................303
Becky Liu and Asma Khalil

21 Twin Deliveries – Where Are We Now?................................................311

Amir Aviram, Jon F. R. Barrett, Elad Mei-Dan, and Nir Melamed

22  nalgesia and Anaesthetic Considerations for Twins

A
and Higher-Order Pregnancies................................................................329
M. A. Clayton, R. L. May, and D. N. Lucas

23 Maternal Complications in Multifetal Pregnancy.......................341

Paul Ian Ramler and Thomas van den Akker
 IX
Contents

VI Postnatal Care
24 Breastfeeding Twins and Multiples.......................................................355
Sophie Russell and Neal Russell

25 Perinatal Depression and Psychiatric Considerations..............363

Femke Vanwetswinkel and Titia Hompes

26 Postnatal Neonatal Assessment in Monochorionic Twins.....377

Enrico Lopriore

VII Childhood Development

27  erebral Palsy and Long-­Term Neurodevelopmental
C
Impairment in Complicated Monochorionic
Twin Pregnancy..................................................................................................391
J. M. M. van Klink, M. S. Spruijt, and Enrico Lopriore

VIII Research, Registries and Parent Views

28 Research Studies in Twins and Multiple Pregnancy...................411
Janine R. Lam, Becky Liu, Kate Murphy, and Asma Khalil

29 Twin and Higher-Order Pregnancy – Patient Voice....................425

Natasha Fenwick and Alyson Chorley

Supplementary Information
Index............................................................................................................................439
Contributors

Laoreti Arianna Fetal Therapy Unit “U. Nicolini”, Department of Obstetrics

and Gynecology, “Vittore Buzzi” Children’s Hospital, University of Milan,
Milan, Italy

Amir Aviram Sunnybrook Health Sciences Centre, Department of Obstetrics

and Gynecology, Division of Maternal-Fetal Medicine, University of Toronto,
Toronto, ON, Canada
[email protected]

Christian Bamberg Department of Obstetrics and Fetal Medicine, University

Medical Center Hamburg-Eppendorf, Hamburg, Germany
[email protected]

Jon F. R. Barrett Sunnybrook Health Sciences Centre, Department of Obstet-

rics and Gynecology, Division of Maternal-Fetal Medicine, University of
Toronto, Toronto, ON, Canada
[email protected]

Jeffrey J. Beck Avera Institute for Human Genetics, Avera McKennan Hospi-
tal and University Health Center, Sioux Falls, SD, USA
[email protected]

Vincenzo Berghella Maternal Fetal Medicine Division, Obstetrics and Gyne-

cology Department, Sidney Kimmel Medical College at Thomas Jefferson Uni-
versity, Philadelphia, PA, USA
[email protected]

Isaac Blickstein Department of Obstetrics and Gynecology, Kaplan Medical

Center, Rehovot, and the Hadassah-Hebrew University School of Medicine,
Jerusalem, Israel†
[email protected]
[email protected]

Dorret I. Boomsma Avera Institute for Human Genetics, Avera McKennan

Hospital and University Health Center, Sioux Falls, SD, USA
Netherlands Twin Register, Department of Biological Psychology, Behavioral
and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Neth-
erlands
[email protected]

Clifton Brock Department of Obstetrics, Gynecology and Reproductive Sci-

ences, University of Texas Health Science Center at Houston, Houston, TX, USA
[email protected]

Susanne Bruins Netherlands Twin Register, Department of Biological Psy-

chology, Behavioral and Movement Sciences, Vrije Universiteit Amsterdam,
Amsterdam, The Netherlands
[email protected]
 XI
Contributors

Alyson Chorley Twins Trust, Aldershot, Hampshire, UK

[email protected]

M. A. Clayton Department of Anaesthesia, Northwick Park Hospital,

London, UK

Gareth E. Davies Avera Institute for Human Genetics, Avera McKennan Hos-
pital and University Health Center, Sioux Falls, SD, USA
Netherlands Twin Register, Department of Biological Psychology, Behavioral
and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Neth-
erlands
[email protected]

Eco de Geus Department of Biological Psychology, Vrije Universiteit

Amsterdam, Amsterdam, The Netherlands
[email protected]

Natasha Fenwick Twins Trust, Aldershot, Hampshire, UK

[email protected]

J. L. Gibson Ian Donald Fetal Medicine Centre, Queen Elizabeth University

Hospital, Glasgow, UK
[email protected]

Noa Gilad Fetal Medicine Unit, Department of Obstetrics and Gynaecology,

Mount Sinai Hospital and University of Toronto, Toronto, ON, Canada
Ontario Fetal Centre, Toronto, ON, Canada

L. R. I. Gurney West Midlands Fetal Medicine Centre, Birmingham Women’s

and Children’s NHS Foundation Trust, Birmingham, UK
[email protected]

Guillermo Gurza Maternal Fetal Medicine Division, Obstetrics and Gynecol-

ogy Department, Sidney Kimmel Medical College at Thomas Jefferson Univer-
sity, Philadelphia, PA, USA

Kurt Hecher Department of Obstetrics and Fetal Medicine, University Medi-

cal Center Hamburg-Eppendorf, Hamburg, Germany
[email protected]

Titia Hompes Department of Neuroscience, Department of Adult Psychiatry,

KU Leuven – University Psychiatric Center KU Leuven, Leuven, Belgium
[email protected]

Anthony Johnson The Fetal Center at Children’s Memorial Hermann Hospi-

tal, Houston, TX, USA
[email protected]
XII Contributors

Johannes Keunen Fetal Medicine Unit, Department of Obstetrics and Gynae-

cology, Mount Sinai Hospital and University of Toronto, Toronto, ON, Canada
Ontario Fetal Centre, Toronto, ON, Canada
[email protected]

Asma Khalil Fetal Medicine Unit, St George’s University Hospitals NHS

Foundation Trust, London, UK
Vascular Biology Research Centre, Molecular and Clinical Sciences Research
Institute, St George’s University of London, London, UK
[email protected]

M. D. Kilby West Midlands Fetal Medicine Centre, Birmingham Women’s and

Children’s NHS Foundation Trust, Birmingham, UK
Centre for Women’s and Children Health, Institute of Metabolism and Systems
Research, University of Birmingham, Birmingham, UK
[email protected]

Janine R. Lam Twins Research Australia, The University of Melbourne,

­Melbourne, Australia

Ann Langedock Department of Obstetrics & Gynaecology, University Hospi-

tals Leuven, Leuven, Belgium
[email protected]
[email protected]

Liesbeth Lewi Department of Obstetrics & Gynaecology, University Hospi-

tals Leuven, Leuven, Belgium
Department of Development and Regeneration, Biomedical Sciences, KU Leu-
ven, Leuven, Belgium
[email protected]

Becky Liu Fetal Maternal Medicine Unit, St George’s University Hospitals,

London, UK
[email protected]

Enrico Lopriore Division of Neonatology, Department of Pediatrics, Leiden

University Medical Center, Leiden, The Netherlands
Head of the Neonatal Intensive Care Unit, Leiden University Medical Centre,
Leiden, The Netherlands
[email protected]

D. N. Lucas Department of Anaesthesia, Northwick Park Hospital, London,

UK
[email protected]
[email protected]

Pierre Macé Service de Gynécologie-Obstétrique, Hôpital Necker-Enfants

Malades, Assistance Publique – Hôpitaux de Paris (AP-HP), Université Paris
Descartes, Paris, France
 XIII
Contributors

Miguel Macedo University Hospital of S. João, Porto, Portugal

Houman Mahallati Department of Radiology, University of Calgary, Cal-

gary, AB, Canada

Lanna Mariano Fetal Therapy Unit “U. Nicolini”, Department of Obstetrics

and Gynecology, “Vittore Buzzi” Children’s Hospital, University of Milan,
Milan, Italy
[email protected]

Alexandra Matias Department of Obstetrics and Gynecology, Faculty of

Medicine, University Hospital of S. João, Porto, Portugal

R. L. May Department of Anaesthesia, Northwick Park Hospital, London,

UK
[email protected]

Hamdi Mbarek Netherlands Twin Register, Department of Biological Psy-

chology, Behavioral and Movement Sciences, Vrije Universiteit Amsterdam,
Amsterdam, The Netherlands
[email protected]

Elad Mei-Dan Department of Obstetrics and Gynecology, North York Gen-

eral Hospital, University of Toronto, Toronto, ON, Canada

Nir Melamed Sunnybrook Health Sciences Centre, Department of Obstetrics

and Gynecology, Division of Maternal-Fetal Medicine, University of Toronto,
Toronto, ON, Canada
[email protected]

R. K. Morris West Midlands Fetal Medicine Centre, Birmingham Women’s and

Children’s NHS Foundation Trust, Birmingham, UK
Centre for Women’s and Children Health, Institute of Metabolism and Systems
Research, University of Birmingham, Birmingham, UK
[email protected]

Kate Murphy Twins Research Australia, The University of Melbourne, Mel-

bourne, Australia
[email protected]

Veronika Odintsova Department of Biological Psychology, Vrije Universiteit

Amsterdam, Amsterdam, The Netherlands
Kulakov National Medical Research Center for Obstetrics, Gynecology and
Perinatology, Moscow, Russia
[email protected]

Vagisha Pruthi Fetal Medicine Unit, Department of Obstetrics and Gynaeco-

logy, Mount Sinai Hospital and University of Toronto, Toronto, ON, ­Canada
Ontario Fetal Centre, Toronto, ON, Canada
[email protected]
XIV Contributors

Alexandra Ramirez Maternal Fetal Medicine Division, Obstetrics and Gyne-

cology Department, Sidney Kimmel Medical College at Thomas Jefferson Uni-
versity, Philadelphia, PA, USA

Paul Ian Ramler Department of Obstetrics, Leiden University Medical Cen-

ter, Leiden, The Netherlands
[email protected]

Amanda Roman Maternal Fetal Medicine Division, Obstetrics and Gynecol-

ogy Department, Sidney Kimmel Medical College at Thomas Jefferson Univer-
sity, Philadelphia, PA, USA
[email protected]

Neal Russell Paediatric Infectious Disease Research Group, St Georges Uni-

versity, London, UK
[email protected]

Sophie Russell Women’s Health, Lewisham and Greenwich NHS Trust,

London, UK
[email protected]

Greg Ryan Fetal Medicine Unit, Department of Obstetrics and Gynaecology,

Mount Sinai Hospital and University of Toronto, Toronto, ON, Canada
Ontario Fetal Centre, Toronto, ON, Canada
[email protected]

Laurent J. Salomon Service de Gynécologie-Obstétrique, Hôpital Necker-­

Enfants Malades, Assistance Publique – Hôpitaux de Paris (AP-HP), Université
Paris Descartes, Paris, France

Mercede Sebghati Fetal Medicine Unit, St George’s University, London, UK

[email protected]

Shiri Shinar Fetal Medicine Unit, Department of Obstetrics and Gynaecol-

ogy, Mount Sinai Hospital and University of Toronto, Toronto, ON, Canada
Ontario Fetal Centre, Toronto, ON, Canada
[email protected]

M. S. Spruijt Division of Neonatology, Department of Pediatrics, Leiden Uni-

versity Medical Center, Leiden, The Netherlands
[email protected]

Faiola Stefano Fetal Therapy Unit “U. Nicolini”, Department of Obstetrics

and Gynecology, “Vittore Buzzi” Children’s Hospital, University of Milan,
Milan, Italy
[email protected]

Beatriz Teixeira Department of Obstetrics and Gynecology, Faculty of Medi-

cine, University Hospital of S. João, Porto, Portugal
 XV
Contributors

L. S. A. Tollenaar Department of Obstetrics, Division of Fetal Therapy, Leiden

University Medical Center, Leiden, The Netherlands
[email protected]

Thomas van den Akker Department of Obstetrics, Leiden University Medical

Center, Leiden, The Netherlands
Athena Institute, Faculty of Science, VU University, Amsterdam, The Nether-
lands
[email protected]

J. M. M. van Klink Division of Pediatric Psychology, Department of Pediatrics,

Leiden University Medical Center, Leiden, The Netherlands
[email protected]

Tim Van Mieghem Fetal Medicine Unit, Department of Obstetrics and Gynae-
cology, Mount Sinai Hospital and University of Toronto, Toronto, ON, Canada
Ontario Fetal Centre, Toronto, ON, Canada
[email protected]

Mieke Vanoppen Department of Obstetrics & Gynaecology, University Hos-

pitals Leuven, Leuven, Belgium
[email protected]
[email protected]

Femke Vanwetswinkel Department of Adult Psychiatry, University Psychiat-

ric Center KU Leuven, Leuven, Belgium
[email protected]

Gonneke Willemsen Department of Biological Psychology, Vrije Universiteit

Amsterdam, Amsterdam, The Netherlands
[email protected]
 1 I

Biology
Contents

Chapter 1 The Vanishing Twin Syndrome – 3

Isaac Blickstein†

Chapter 2 Placentation in Multiple Pregnancy – 11

Enrico Lopriore and Liesbeth Lewi

Chapter 3 Biology and Genetics of Dizygotic

and Monozygotic Twinning – 31
Jeffrey J. Beck, Susanne Bruins,
Hamdi Mbarek, Gareth E. Davies,
and Dorret I. Boomsma

Chapter 4 Twin-Singleton Comparisons Across

Multiple Domains of Life – 51
Gonneke Willemsen, Veronika Odintsova,
Eco de Geus, and Dorret I. Boomsma
 3 1

The Vanishing Twin

Syndrome
Isaac Blickstein†

Contents

1.1 Introduction – 4

1.2 Embryonic Loss After ART – 4

1.3 Types of VTS – 5

1.4 V TS and Cerebral Palsy – 5

1.5 V TS and Prenatal Diagnosis – 6

1.6 V TS and Perinatal Outcomes – 7

1.7 Epilogue – 7
1.7.1  eview Questions – 8
R
1.7.2 Multiple-Choice Questions – 8

References – 8

Electronic Supplementary Material The online version of this chapter (https://doi.

org/10.1007/978-­3-­030-­47652-­6_1) contains supplementary material, which is available to
authorized users. The videos can be accessed by scanning the related images with the SN
More Media App.

© Springer Nature Switzerland AG 2021

A. Khalil et al. (eds.), Twin and Higher-order Pregnancies,
https://doi.org/10.1007/978-3-030-47652-6_1
 4 I. Blickstein

Trailer nancies is largely unknown because the vast

1 The vanishing twin syndrome (VTS) is used to majority of women are not scanned in early
describe the spontaneous loss of one develop- pregnancy, and many cases of VTS are thus
ing embryo early in a multiple pregnancy. The unnoticed. The best estimate comes from
incidence of the VTS in spontaneous pregnan- pregnancies following assisted reproduction
cies is largely unknown, whereas the incidence technologies (ART). Pinborg and her co-
in pregnancies following assisted reproduction workers observed that 1 in 10 ART singletons
is estimated to be 3–10%. Regardless of chori- originated from a twin gestation in early preg-
onicity, the VTS has been associated with nancy [2]. A more recent approximation lacks
adverse outcomes, especially related to cerebral data about VTS in as many as 1:8 pregnancies,
palsy and premature births. The retained prod- and therefore, the quoted 3% appears to be an
ucts of the vanished twin may lead to errors in underestimate [3].
risk estimation using biochemical markers as Birth certificates are also to no avail.
well as with more advanced techniques such as Despite a constantly increasing clinical inter-
cell-free DNA in maternal blood. While the est, VTS is rarely, if ever, recorded in birth
VTS is mainly diagnosed during the late first certificates. Pharoah [4] opined that whereas
trimester, the advent of early sonography, espe- it is a legal requirement of parents to reg-
cially following ART, will soon allow an earlier ister a fetal death (a dead fetus born after
diagnosis. 24 weeks’ gestation), there is worldwide con-
fusion regarding fetal death before 24 weeks.
Definitions Hence, a legal definition for the registration
Vanishing twin syndrome: Loss of one of embryonic/fetal death, including the VTS,
developing embryo early in a multiple requires international agreement and appli-
pregnancy. cation [4].
The VTS can be considered as a natural
equivalent of multifetal pregnancy reduction
(MFPR) performed to reduce the number
nnLearning Objectives of fetuses in a high-order multiple gestation.
55 To understand the biology of the VTS However, the main difference between MFPR
55 To acknowledge the adverse outcomes and VTS is that in the former, the final num-
attributed to the VTS ber of remaining embryos is usually (but not
55 To identify errors in risk estimation of exclusively) two, whereas the VTS is usually
prenatal diagnosis resulting from the (but not exclusively) referring to a singleton
VTS survivor after a twin pregnancy. Hence, it is
basically incorrect to compare outcomes of
MFPR and VTS.
1.1 Introduction With these caveats in mind, this chapter
will discuss several clinical issues related to
The vanishing twin syndrome (VTS) is used the VTS.
to describe the spontaneous loss of one devel-
oping embryo early in a multiple pregnancy.
Although suspected for many years, it is a 1.2 Embryonic Loss After ART
relatively new diagnosis that emerged only
after the implementation of ultrasonography Every conception has its own risk of loss.
in early gestation. In the beginning, this find- Thus, it is conceivable that each twin has,
ing was met with skepticism; however, careful potentially, an equal chance for survival or
examination of the placenta revealed in 1986 loss. It has been repeatedly shown that fol-
the histological evidence that confirmed the lowing ART, the chance of early loss of the
validity of VTS, consisting of a chorion-lined entire singleton pregnancy is significantly (2
sac containing amorphous material [1]. The to 5 times) higher than the entire early loss of
incidence of the VTS in spontaneous preg- a twin pregnancy [5]. This observation sug-
The Vanishing Twin Syndrome
5 1
gests that the intuitive view about the gloomy
outcome of early twin gestations should be
reappraised [6]. Although most data point to
better implantation rates as a feasible expla-
nation of better twin survival, it is unknown
why in some early pregnancies this presum-
able advantage of twins is partially lost and
results in VTS [6]. Put differently, if indeed
ART represents an advantage for early twin
gestations, than the VTS or entire early loss
of the twin set might represent an effect of an
unspecified hostile uterine environment. More
importantly, it is unknown if the situation
following ART is equivalent to spontaneous
pregnancies. Some idea comes from Márton
et al. [7] that the incidence of VTS was sig-
nificantly higher after natural than after ART
conceptions. However, a clear explanation for ..      Fig. 1.1 Empty sac along a gestational sac contain-
this observation remains elusive. ing an 8+ weeks’ embryo in dichorionic pregnancy.
Pereira and co-workers [8] looked at the (Image courtesy Dr. Y. Chazan)
VTS by day of embryo transfer and showed
that cleavage- and blastocyst-stage embryo
transfers were associated with early VTS in
11.6 and 6.32% patients, respectively, which
represented 0.5 times lower odds, albeit not
significant, of early VTS in the blastocyst-­stage
group compared to the cleavage-stage group.

1.3 Types of VTS

In principle, four types of VTS may exist. The

first is the unknown case of the VTS, namely
a singleton is seen by sonography, and there ..      Fig. 1.2 Vanishing twin with crown-rump length of
8+ weeks in a dichorionic twin pregnancy at 12 weeks)
is no clue that a co-twin existed. These may
(https://doi.org/10.1007/000-2sw)
present with a hint of an ill-defined gesta-
tional sac or with a hematoma formation
adjacent to the other sac that contains an 1.4 V TS and Cerebral Palsy
embryo. The second is the VTS with an empty
sac (“blighted ovum”), namely a singleton Regardless of the etiology, most studies on the
is seen by sonography along with a blighted VTS show an increased incidence of perina-
ovum (. Fig. 1.1). The third is the clear-cut tal complications [2, 7]. For the death of one
VTS with two embryos—one alive and the twin to cause damage to the survivor, one may
other dead—which is easily diagnosed during assume a vascular connection between the
the first trimester (. Fig. 1.2). It is unknown two twins. This is the case in monochorionic
if there is a difference in the VTS between the (MC) twins where the inter-twin anastomoses
presence of an empty sac and the presence of are invariably present. Following single fetal
a “missed” twin in terms of outcome. Finally, death, blood is shunted to the low resistance
all the above may occur in high-order multiple circulation of the demised twin, and depend-
gestations affecting one or more of the mul- ing on the magnitude of this shunt, the survi-
tiples. vor twin may die, may become handicapped,