New Technologies and Perinatal Medicine-Prediction and Prevention of Pregnancy Complications

265 Pages·2019·7.628 MB·\265

by  Moshe Hod (Editor), Vincenzo Berghella (Editor), Mary D`Alton (Editor), Gian Carlo Di Renzo (Editor), Eduard Gratacos (Editor), Vassilios Fanos (Editor)

New Technologies and
Perinatal Medicine
Prediction and Prevention of
Pregnancy Complications
Series in Maternal-Fetal Medicine
About the Series
Published in association with the Journal of Maternal Fetal and Neonatal Medicine, the series in Maternal Fetal Medicine
keeps readers up to date with the latest clinical therapies to improve the health of pregnant patients and ensure a successful
birth. Each volume in the series is prepared separately and typically focuses on a topical theme. Volumes are published on
an occasional basis, depending on the emergence of new developments.
Textbook of Diabetes and Pregnancy, Third Edition
Moshe Hod, Lois G. Jovanovic, Gian Carlo Di Renzo, Alberto De Leiva, Oded Langer
Cesarean Delivery: A Comprehensive Illustrated Practical Guide
Gian Carlo Di Renzo, Antonio Malvasi
Obstetric Evidence Based Guidelines, Third Edition
Vincenzo Berghella
Maternal-Fetal Evidence Based Guidelines, Third Edition
Vincenzo Berghella
Maternal-Fetal and Obstetric Evidence Based Guidelines, Two Volume Set, Third Edition
Vincenzo Berghella
The Long-Term Impact of Medical Complications in Pregnancy: A Window into Maternal and Fetal Future Health
Eyal Sheiner
Operative Obstetrics, 4E
Joseph J. Apuzzio, Anthony M. Vintzileos, Vincenzo Berghella, Jesus R. Alvarez-Perez
Placenta Accreta Syndrome
Robert M. Silver
Neurology and Pregnancy: Clinical Management
Michael S. Marsh, Lina Nashef, Peter Brex
Fetal Cardiology: Embryology, Genetics, Physiology, Echocardiographic Evaluation, Diagnosis, and Perinatal
Management of Cardiac Diseases, Third Edition
Simcha Yagel, Norman H. Silverman, Ulrich Gembruch
New Technologies and Perinatal Medicine: Prediction and Prevention of Pregnancy Complications
Moshe Hod, Vincenzo Berghella, Mary E. D’Alton, Gian Carlo Di Renzo, Eduard Gratacós, Vassilios Fanos
For more information about this series please visit: https://www.crcpress.com/Series-in-Maternal-Fetal-Medicine/
book-series/CRCSERMATFET
New Technologies and
Perinatal Medicine
Prediction and Prevention of
Pregnancy Complications
Edited by
Moshe Hod
md
Director, Mor Comprehensive Women’s Health Care Center
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Vincenzo Berghella
md facog
Director, Division of Maternal-Fetal Medicine
Professor, Department of Obstetrics and Gynecology
Sidney Kimmel Medical College of Thomas Jefferson University
Philadelphia, Pennsylvania, USA
Mary E. D’Alton
md mb bs
Chair, Department of Obstetrics & Gynecology
Willard C. Rappleye Professor of Obstetrics & Gynecology
Columbia University Irving Medical Center
Director of Services, Sloane Hospital for Women
New York-Presbyterian, New York City, New York, USA
Gian Carlo Di Renzo
md phd
Professor and Chairman, Department of Obstetrics and Gynecology
Director, Perinatal and Reproductive Medicine Center and
Midwifery School, University Hospital, Perugia, Italy
Director, Permanent International and European School of Perinatal
and Reproductive Medicine (PREIS), Florence, Italy
Eduard Gratacós
md
Director and Professor, BCNatal,
Hospital Clínic and Hospital Sant Joan de Deu,
University of Barcelona, Barcelona, Spain
Vassilios Fanos
md
Professor of Pediatrics
Director, Neonatal Intensive Care Unit
University of Cagliari, Cagliari, Italy
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Contents
Introduction: Why do we need omics and systems biology? vii
Contributors xi
Section i PReGnAncY coMPLicAtionS: SettinG tHe Scene
1 The mother: Adaptation to pregnancy and normal metabolism 2
Francesca Parisi, Alice Zavatta, Roberta Milazzo, and Irene Cetin
2 Maternal and fetal normal and abnormal nutrition 7
Sarah Louise Killeen, Eilleen C. O’Brien, and Fionnuala M. McAuliffe
3 Great obstetrical syndromes: It’s all in the placenta 12
Martin Gauster and Gernot Desoye
4 Normal and abnormal fetal growth 18
Javier Caradeux, Eduard Gratacós, and Francesc Figueras
5 Preterm labor and birth 23
Vincenzo Berghella and Eduardo da Fonseca
6 Gestational diabetes mellitus 28
Silvia Vannuccini and Federico Mecacci
7 Preeclampsia 34
Jon Hyett and Liona C. Poon
8 Maternal obesity 40
Tahir A. Mahmood and Rohan Chodankar
9 Maternal health: Immediate, short-, and long-term complications following pregnancy 46
Gil Gutvirtz, Omri Zamstein, and Eyal Sheiner
10 The fetus and the neonate: Immediate, short-, and long-term impact 56
Umberto Simeoni and Elie Saliba
11 Cost of pregnancy complications related to noncommunicable diseases and cost effectiveness of
interventions to address them 60
Anil Kapur, Jon Hyett, and H. David McIntyre
Section ii toWARDS PReDiction AnD PReVention
12 Integrated system biology approaches to fetal medicine problems 74
Jezid Miranda, Fátima Crispi, and Eduard Gratacós
13 Omics and female reproduction 81
Galia Oron
14 Maternal genome and pregnancy outcomes 85
Nagendra K. Monangi, Ge Zhang, Mikko Hallman, Kari Teramo, Bo Jacobsson, and Louis J. Muglia
15 Placental development and omics 90
Sylvie Hauguel-de Mouzon, Gernot Desoye, and Silvija Cvitic
16 Placental metabolomics in obese pregnancies 95
Irene Cetin, Chiara Novielli, and Chiara Mandò
17 Methylome and epigenetic markers 98
Skevi Kyriakou, Marios Ioannides, George Koumbaris, and Philippos Patsalis
18 Microbiome and pregnancy complications 102
Maria Carmen Collado and Omry Koren
19 Small noncoding RNAs as biomarkers for pregnancy complications 107
Liron Yoffe, Meitar Grad, Avital Luba Polsky, Moshe Hod, and Noam Shomron
20 Urine metabolomics and proteomics in prenatal health 112
Daniela Duarte, Maria do Céu Almeida, Pedro Domingues, and Ana M. Gil
21 Metabolomics and perinatal complications 125
Flaminia Bardanzellu, Moshe Hod, and Vassilios Fanos
22 Metabolomics in normal and pathologic pregnancies 133
Antonio Ragusa, Alessandro Svelato, and Sara D’Avino
v
vi Contents
23 Metabolomics in amniotic fluid 139
Alexandra-Maria Michaelidou, Foteini Tsakoumaki, Maria Fotiou, Charikleia Kyrkou, and Apostolos P. Athanasiadis
24 Omics and coagulation disorders in pregnancy 149
Sara Ornaghi and Michael J. Paidas
25 Omics and perinatal medicine: Preeclampsia 156
Piya Chaemsaithong and Liona C. Poon
26 Single nucleotide polymorphisms and pregnancy complications 172
Federica Tarquini, Giuliana Coata, Elena Picchiassi, and Gian Carlo Di Renzo
27 Metabolomics and perinatal cardiology 174
Roberta Pintus, Angelica Dessì, and Vassilios Fanos
28 Metabolomics and human breast milk: A unique and inimitable food for infants 177
Flamina Cesare Marincola, Sara Corbu, Roberta Pintus, Angelica Dessì, and Vassilios Fanos
29 Neurodevelopment and placental omics 181
Despina D. Briana and Ariadne Malamitsi-Puchner
30 Early life complications, placental genomics, and risk for neurodevelopmental disorders in offspring 185
Pasquale Di Carlo, Giovanna Punzi, and Gianluca Ursini
31 Metabolomics and perinatal asphyxia 192
Ernesto d’Aloja, Emanuela Locci, Antonio Noto, Matteo Nioi, Giovanni Bazzano, and Vassilios Fanos
32 Environment, pregnancy complications, and omics 204
Chen Ben David and Ido Solt
33 Sleep and pregnancy complications 209
Orna Sever and Riva Tauman
34 Maternal plasma cell-free DNA screening: Basic science and applications 214
Peter Benn and Howard Cuckle
35 Maternal plasma cell-free DNA screening: Integration into clinical practice 218
Howard Cuckle and Peter Benn
36 Microarrays 223
Melissa Stosic, Jessica L. Giordano, Brynn Levy, and Ronald Wapner
37 Whole exome and whole genome sequencing 230
Mary E. Norton
Index 239
Introduction
Why do we need omics and systems biology?
Omics implies many different approaches are concurrently In obstetrics, the prevalence of preeclampsia is
applied to a seemingly singular problem. The presumption 5%–7%. We know its epidemiology (primigravid
is that the plethora of concurrent data will lead to causal women; multiparous women with new partners). We
elucidations and treatment of pregnant woman and fetuses diagnosed on the basis of elevated blood pressure,
not otherwise possible. Those of us who have practiced and hyperreflexia, edema, and proteinuria. We knew that
conducted investigations for decades could be forgiven a woman whose pre-pregnancy blood pressure was
for wondering just why this unfamiliar and vastly more 100/70 need not reach 140/90 to be considered to have
complex assignment has suddenly become necessary. After preeclampsia. Diagnosis, prevention, and treatment
all, we have long been conducting randomized clinical trials have not fundamentally changed for many years—
(RCTs), often happy with results, regardless of whether nor has progress. The current elixir—aspirin—might
resolution had been reached on an arguable issue. RCTs benefit 20% of women. This means that 80% would
funded by the National Institutes of Health (NIH), Medical not be “cured.” Despite this noninfectious condition
Research Council (MRC), and other agencies seemed well affecting 5% of the population, we persisted in thinking
constructed, took into account potential confounding there was usually only one etiology. Yet, heterogeneity
variables that could be adjusted (multivariate analysis), exists; thus, something else is necessary for progress.
and delivered crisp conclusions on the primary outcomes. Omics and systems biology become candidates.
Why, then, must we current investigators embark on II. All common disorders are etiologically heterogeneous:
a much more complex strategy? The simple answer is If almost all noninfectious medical disorders of
that the disorders we once believed to be a homogenous incidence 2%–5% are heterogeneous in etiology, what
condition are rarely so. These disorders are heterogeneous. is their underlying basis? Illustrative is that medical
This volume illustrates well the approaches that are thus geneticists had the advantage of knowing that heritable
needed. In turn, we are in need of hypotheses derived in inborn errors of metabolism were heterogeneous.
agnostic (“out of the box”) fashion, not just derivative of Mutations in different enzymes in a common pathway
our preconceived beliefs. could have the same end result, for example, elevated
Let us, then, briefly consider why omics and systems cholesterol or decreased cortisol. This was the result
biology will open doors that one could say are locked at of defects in one of the sequential enzymes in a
present. single biosynthetic pathway. That each disorder was
due to a different gene (etiologic heterogeneity) was
I. Common disorders were once considered homogenous evident, even if at least one component of a pleiotropic
in etiology: Perusing textbooks written perhaps 30–40 phenotype was similar. Differentiation was also
years ago leaves one with the conclusion that most possible as a result of different profiles of metabolites.
common perinatal diseases were of a single etiology. A familiar example is phenylketonuria (PKU). PKU
Phenotypes of affected patients might differ in degree is an autosomal recessive disorder due to deficiency of
of expression, as for example shown by chronological the enzyme phenylalanine hydroxylase (PAH), which
age of onset or gestational week of manifestation. is necessary to convert phenylalanine to tyrosine.
However, guidelines were fundamentally predicated Diagnosis of PKU was initially made not on the basis
on the assumption that a given disorder was singular. of directly measuring excess phenylalanine, but by
Systemic hypertension in adults was diagnosed detecting an increase in the by-product metabolite
(then and now) if blood pressure was greater than phenylpyruvic acid. Phenylpyruvic acid accumulated
140/90 mm Hg. Simply put, below that value was secondarily to elevated levels of phenylalanine. But
normal. True, professional societies frequently even the uncommon disorder PKU is heterogeneous.
explored different thresholds. Yes, we knew rare Classical, variant, and benign phenotypes exist, all
causes existed, such as Cushing syndrome or adrenal due to different perturbations in the PAH enzyme.
biosynthetic disorders. However, these “zebras” Perturbations exist in still other genes—PCR and
were considered exceptional, merely to be excluded PHPR. All contribute to clinical PKU.
initially for completeness of our differential diagnosis. We in obstetrics-gynecology (OB-GYN) have lacked
Most cases would eventually prove to be of the same analogous examples like inborn errors of metabolism.
etiology and, hence, treated similarly. Aggressiveness Global conferences are convened to codify diagnostic
of therapy (e.g., dosage) might differ, but qualitatively criteria (e.g., Rotterdam criteria), but classifications
the strategy would not. tend to be quantitative variants on the theme of
vii
viii Introduction
follicles, hirsutism, and anovulation. Yet over a dozen individuals. Let us assume that any of a set of genes (A,
different genes are associated with polycystic ovarian B, C, D, or E) could if perturbed produce a histologically
syndrome (PCOS) and characterized by robust identical cancer. Assume further that three different
statistical significance (1,2). chemotherapeutic agents confer benefit in patients
Fortunately, increased appreciation of genetic and having a tumor of common histologic type. Yet no drug
etiological heterogeneity is occurring in many common alone is universally efficacious. Chemotherapeutic
obstetrical conditions. Progress in differentiating agents 1 and 3 might be efficacious in certain patients,
hyperglycemias is an example. Once, only binary whereas only agent 2 might provide benefit in other
stratification into childhood (insulin-dependent) and patients. Higher doses of agent 2 could be delivered if 1
adult-onset (insulin resistant) diabetes mellitus (DM) and 3 are not concurrently administered. The converse
existed. This categorization later became disrupted also is applicable. We can predict that analogous
with the recognition of maturity onset diabetes of strategies will evolve for detecting and treating
youth (MODY). Its age of onset (late teens; early third preeclampsia and preterm birth.
decade) was different. Heritability was different (often IV. Precision medicine integrates omics, clinical data,
a single gene). Later, MODY began to be stratified environmental exposures, and social determinants:
into different types on the basis of genes and mode of Marketing teams often tout an institution for its
inheritance. “precision medicine.” Applicability to obstetrics
III. Phenotypically similar but etiologically distinct disorders is not a new idea (3). However, do we in 2019 offer
require different diagnostic criteria and different “precision medicine in obstetrics”? Not really. To date,
treatments: Adrenal hyperplasia is the result of one only limited diagnostic options exist for women with
of a series of enzyme defects in the biosynthetic path obstetrical disorders. We can measure the presence
that results in cortisol. Negative feedback inhibition or absence of an associated protein (recall that
based on cortisol levels modulates rate of synthesis. enzymes are gene products) or metabolites indicative
If an enzyme block exists in the pathway, precursors of an altered pathway. But usually this information
accumulate prior to the block, leading secondarily to overlaps with those characteristics of other conditions
excesses of other steroids. A dozen distinct defects thus not being qualitatively unique. By contrast, a
exist. Many differ considerably from one another in novel footprint might exist if we interrogated DNA
phenotype, but others show only nuanced differences. sequences in a targeted region from among the 21,000
The adrenal biosynthetic pathway includes the protein-coding genes. We can compare a promising
enzymes 21-hydroxylase and 11-β-hydroxylase. sequence in a patient-derived sample to the normal
21-Hydroxylase is required to convert 17α-OH reference genome. Sequencing is no longer difficult,
progesterone to 11-deoxycortisol, a penultimate step in expensive, or time-consuming. Benign variants can be
the synthesis of cortisol. Genital ambiguity occurs in distinguished readily from pathogenic variants.
affected females because when 17α-OH progesterone Imagine the power of expanding and applying our
accumulates, conversion to androgens occurs. Salt nascent genomic knowledge to obstetrical conditions.
wasting also occurs because 11-deoxycortisol, which Of the protein-coding genes, function is known in
facilitates salt retention, is not synthesized in normal only one-third. A portion of the remaining two-thirds
amounts. The situation differs in part with the can be expected to play pivotal roles in embryonic/
next enzyme in the adrenal biosynthetic pathway: fetal differentiations or placentation. The sentinel
11-β-hydroxylase, whose deficiency results in excess genomewide association study (GWAS) by Zhang,
11-deoxycortisol that again leads to deficiencies in Muglia, and colleagues is a shining example (4). A
cortisol. Like 21-hydroxylase, genital ambiguity total of 43,568 women of European ancestry had
occurs as a result of accumulation of excess androgens. self-reported their experience with preterm birth.
However, no longer does salt retention occur. Instead, This discovery group was compared to replicates of
the salt-retaining steroid 11-deoxycortisol accumulates, three Nordic data sets comprising 8,643 women. Six
resulting in hypertension due to hypervolemia. Thus, significant sequences were found. Their contiguous
salt wasting occurs in 21-hydroxylase deficiency, genes were thus associated with preterm birth,
whereas salt retention occurs in 11β-hydroxylase gestational length, or both. Several genes had not been
deficiency. Treatment with cortisol abrogates genital appreciated or received attention previously. Hallman,
ambiguity in both. Were genital ambiguity the only Zhang, Muglia, and colleagues further describe how
feature, phenotypic differences would not be so well GWAS is only the start (5).
appreciated. Protein-coding genes (exome) constitute only 1.5%
Differentially treating phenotypically similar but of DNA; 98.5% of the human genome is not protein-
actually nonidentical conditions is a major principle coding genes, carrying out regulatory functions.
underlying improvement in oncology treatment. Regulatory regions govern the degree of gene
Genetic testing often reveals a series of different expression. Expression of a given gene is not necessarily
mutations in histologically similar tumors in different on or off, but quantifiable in degree. Imagine a
Introduction ix
temperature thermostat, in which a single setting is might be traditional, or a novel idea hypothesized
not expected and does not need to be constant. Gene by an investigator. Despite immense software and
expression can be increased, decreased, or turned off computer prowess needed, recall that this approach
without altering the DNA sequence. The mechanism fundamentally requires a human. Computers are very
is presumed to involve DNA methylation. One efficient at processing massive data sets to recognize
can thus track gene expression by RNA expression patterns; however, someone must program the endpoint
(transcription) or by DNA suppression (methylome). If or threshold that justifies an algorithmic response. To
a gene ordinarily not expressed (imprinted) suddenly illustrate, let us fancifully try to identify members of a
becomes expressed, its regulatory sequence might terrorist cell. As the investigator, one might enumerate
have become demethylated and, hence, transcribed a plethora of nefarious characteristics hypothesized
(transcriptome). to distinguish terrorist from nonterrorist. This list
From study of the genome, transcriptome, and would doubtless be based on our prior assumption
methylome, one can concurrently study proteins of behavior expected by a terrorist. For example, one
(proteome) and metabolites (metabolome). This might predict gun purchase, proclivity for fast cars,
approach is well illustrated by the integrated system and social isolation. A machine learning approach
biology approach of Than et al. (6) on preeclampsia. An could thus sort through massive data in hopes of
integrated approach was applied by Tsang et al. (7) to identifying recurring patterns indicative of suspect
determine DNA or RNA in individual placental cells, individuals. Law enforcement could then focus on
correlating with histology, metabolic information, individuals identified. In medicine, we can apply
and single cell function and morphology via cell machine learning to fine-tune disease predictions or
separation. There was shown to be 18 different types stratify given a known set of associated characteristics.
of placental cells. In addition, one can incorporate AI is agnostic. There is no a priori hypothesis. The
information on environment and interaction with principle involves interrogating all relationships, not just
genome (epigenome), measures of social determination those logically deduced by humans but those seemingly
(e.g., nutrition), and clinical status. Examples of the illogical. AI would thus explore all hypotheses. In fact,
latter are clinical risk factors and sociodemographic we already use agnostic approaches to locate gene-
findings gathered from individual patient data on 4.1 associated sequences. Zhang et al. (4) had no restrictions
million women in four countries and California (8). on genes likely to be associated with gestational length
These data were used to generate population-based or preterm birth, but found six associated protein-
odds ratios (ORs) for risk factors. These differ from coding genes. Not all were anticipated. A human-
ORs for an individual’s risk factor. A high OR (e.g., 6.0) derived hypothesis might have been restrictive and
for a woman having had a prior preterm birth (PTB) perhaps counterproductive; humans can imagine only
would be good counsel, but because PTB occurs only so much, and in doing so subliminally filter out the
in 8%–10% of deliveries the population-attributable implausible. Unimaginable relationships would never
risks would not be great. By contrast, a lower OR (OR be explored. Let us return to our search for terrorists. AI
1.3) would confer a greater attributable risk for the can proceed agnostically without prior hypotheses and
general population if the frequency of a risk factor without unwitting restriction of a hypothesis. Perhaps
were more than 8%–10%. Thus, nulliparity and male attending a certain movie theater on the Saturday before
sex actually confer a greater overall (population) effect a planned terrorist action will unwittingly pinpoint
than preeclampsia or PTB. In aggregate, both nature terrorist members. Perhaps the members also frequent a
and nurture can be concurrently assessed. particular ice cream parlor and eat pistachio ice cream.
V. Data interrogation and clinical conclusion: Perhaps members unexpectedly enjoy a television show
Accumulating an enormous amount of data is of unexpected motif—not an action movie but a fashion
attractive but presents a problem. Data accumulation show. AI can interrogate and correlate all this, without
and ongoing monitoring are necessary. The bias. A set of characteristics could evolve that would not
integrated repository being created for the March of be imaginable by us.
Dimes Prematurity Research Centers is exemplary Machine learning and AI are being utilized for
(9). How, then, can one utilize these data to system biology, and “multiomic” approaches have
determine causative significance and therapy? How resulted in novel observations, especially relating
can one extract truly novel information? There are to adaptations during pregnancies using patterns of
two conceptual approaches for data exploration fetal gene expression. Predictions can be made on
and mining: (1) machine learning and (2) artificial gestational length—not by ultrasound but by analysis
intelligence (AI). Tools are similar and overlap, but of maternal blood. Maternal (and fetal) cell free DNA
expectations differ. correlated with gestational age predicts gestational
Machine learning implies brute-force iterative age within 2 weeks (10). A Stanford team is pursuing
queries, using computers and bioinformatics to the concept of gestational clocks: immunologic (11),
accomplish such searches. The underlying hypothesis proteomic (12), and a truly agnostic “multiomic” (13).