Preventing Prematurity: Genomics and Preconception Care

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Preventing Prematurity Genomics and
Preconception Care

• Siobhan Dolan, MD, MPH
• Preconception SummitAtlanta, GA
• June 2005

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Preterm BirthsUnited States, 1982, 1992, 2002,
2003
Percent
Healthy People Objective
30 Percent Increase
Preliminary Data, NCHS, 11/23/04. Preterm is
less than 37 completed weeks gestation. Source
National Center for Health Statistics, final
natality data Prepared by March of Dimes
Perinatal Data Center, 2004
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What determines your risk for disease?
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Epidemiology
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EpidemiologyThe study of how disease is
distributed in populations and of the factors
that influence or determine this distribution.
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Specific Objectives of EpidemiologyFirst, to
identify the etiology or the cause of a disease
and the risk factors - that is, factors that
increase a persons risk for a disease.Epidemio
logy, Second Edition, by Leon Gordis
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Major Categories of Risk for Preterm Birth

• Extremes of maternal age
• Unintended pregnancy
• 34, 35, 36 weeks
• Maternal race
• Multiple gestation
• Cesarean section

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Clinical Approaches
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Clinical Approaches to Preterm Birth
Spontaneous Preterm Labor
Spontaneous Premature Rupture of the Membranes
Preterm Birth
Medical Intervention
While this suggests distinct pathways, many of
the risk factors for all 3 are similar.
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Risk Factors for Preterm Labor/Delivery

• The best predictor of having a preterm birth is
  multifetal gestation or history of preterm
  labor/delivery
• Other risk factors

• multifetal pregnancy
• maternal age (lt17 and gt35 years)
• black race
• low SES
• unmarried
• previous fetal or neonatal death
• 3 spontaneous losses
• uterine abnormalities
• incompetent cervix
• genetic predisposition

• low pre-pregnant weight
• obesity
• infections
• bleeding
• anemia
• major stress
• lack of social supports
• tobacco use
• illicit drug use
• alcohol abuse
• folic acid deficiency

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Risk Factors for Preterm Labor/Delivery

• The best predictor of having a preterm birth is
  multifetal gestation or history of preterm
  labor/delivery
• Other risk factors

• multifetal pregnancy
• maternal age (lt17 and gt35 years)
• black race
• low SES
• unmarried
• previous fetal or neonatal death
• 3 spontaneous losses
• uterine abnormalities
• incompetent cervix
• genetic predisposition

• low pre-pregnant weight
• obesity
• infections
• bleeding
• anemia
• major stress
• lack of social supports
• tobacco use
• illicit drug use
• alcohol abuse
• folic acid deficiency

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Genetics
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GeneticsThe study of the patterns of
inheritance of specific traits.
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Pedigree
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Genetic Conditions

• Chromosomal
• Trisomy 21 (Down Syndrome)
• Single Gene - mutation in a gene
• Sickle Cell Disease
• Teratogens
• Medications, Medical Conditions (diabetes)
• Multifactorial
• Neural Tube Defect

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Multifactorial - Neural Tube Defect
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Preterm Birth is a Common Complex Disorder
Requires paradigm shift from a conceptualization
of adverse pregnancy outcomes as acute events, to
a view of most adverse pregnancy outcomes
resulting from chronic conditions.
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Complex

• Complex genetic traits refer to those phenotypes
  not fitting patterns of Mendelian segregation
  and/or assortment but exhibiting a preferential
  familial clustering that cannot be explained by
  cultural or environmental causes.

Muenke et al. Genet Med 20046(1)1-15.
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Complex Disorders

• 1. Genetic contribution
• 2. Environmental influences
• 3. Gene-environment interactions

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Complex Disorders

• Genetic contribution
• Familial aggregation
• Recurrence of preterm birth
• Racial disparity

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The Risk of Preterm Birth Across Generations
Objective To examine the risk of preterm birth
for mothers who themselves were born before
term. 1405 preterm mothers 2781 term
mothers Conclusions An increased risk of
preterm delivery exists for women who themselves
were born before 37 weeks gestation. This risk
is inversely correlated with the maternal
gestational age at birth and is influenced by
maternal age and parity.
Porter et al. Obstetrics Gynecology.
19979063-67.
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Genetic influence on birthweight and gestational
length determined by studies in offspring of twins
Objective To determine the relative importance
of genetic effects on birthweight, gestational
length and small for gestational age. 868
monozygotic female twin pairs 1141 dizygotic
female twin pairs Conclusions Concordance rates
and intra-class correlations for birthweight,
gestational length and small for gestational age
were consistently higher in monozygotic compared
with dizygotic twins. Model fitting suggested
heritability estimates in the range from 25 to
40. PRETERM BIRTH 36 (0.03 0.51)

Clausson et al. BJOG. 107375-381. 2000.
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Rate of and Factors Associated With Recurrence of
Preterm Delivery
Objective To identify the rate of recurrence of
preterm delivery in second pregnancies, factors
associated with recurrence, and the percentage of
preterm deliveries in women with a history of
preterm delivery. Design Population-based
cohort study of data from birth and fetal death
certificates from the state of Georgia between
1980 and 1995. First and second singleton
deliveries at 20-44 weeks gestation 122,722
white women 56,174 black women
Adams et al. JAMA. 283(12)1591-1596. 2000.
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Rate of and Factors Associated With Recurrence of
Preterm Delivery

• Conclusions
• Of 1023 white women whose first delivery was at
  20-31 wks
• 8.2 (6.6-10.1) delivered their 2nd at 20-31
  weeks
• 20.1 (17.7-22.8) delivered their 2nd at 32-36
  weeks
• Of 1084 black women whose first delivery was at
  20-31 wks
• 13.4 (11.4-15.6) delivered their 2nd at 20-31
  weeks
• 23.4 (20.9-26.1) delivered their 2nd at 32-36
  weeks

Adams et al. JAMA. 283(12)1591-1596. 2000.
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Complex Disorders

• Genetic contribution
• Environmental influences
• Gene-environment interactions

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Complex Disorders

• Environmental influences
• Smoking
• Infection
• Stress

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Complex Disorders

• Genetic contribution
• Environmental influences
• Gene-environment interactions

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Maternal Cigarette Smoking, Metabolic Gene
Polymorphism, and Infant Birth Weight

• Objective To investigate whether the
  association between maternal cigarette smoking
  and infant birth weight differs by polymorphisms
  of 2 maternal metabolic genes CYP1A1 and GSTT1.
  
• 741 mothers with singleton livebirths
• 174 ever smokers
• 567 never smokers
• 207 cases low-birth-weight or preterm
• 534 controls

Wang et al. JAMA. 2002287195-202.
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Maternal Cigarette Smoking, Metabolic Gene
Polymorphism, and Infant Birth Weight
Conclusions Maternal CYP1A1 and GSTT1 genotypes
modified the association between maternal
cigarette smoking and infant birth weight,
suggesting an interaction between metabolic genes
and cigarette smoking.
Wang et al. JAMA. 2002287195-202.
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A polymorphism in the promoter region of TNF and
bacterial vaginosis Preliminary evidence of
gene-environment interaction in the etiology of
spontaneous preterm birth
Objective To assess if the presence of
symptomatic bacterial vaginosis amplifies the
risk of spontaneous preterm birth in those with a
susceptible TNF genotype (TNF-2). 125 cases
delivered before 37 weeks as a result of
ruptured membranes or preterm labor 250
controls delivered after 37 weeks
Macones et al. AJOG. 20041901504-8.
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A polymorphism in the promoter region of TNF and
bacterial vaginosis Preliminary evidence of
gene-environment interaction in the etiology of
spontaneous preterm birth
Group TNF-2 carriers TNF-2 carriers OR (95
CI) in cases in controls Overall 45 23
2.1 (1.7-4.5) BV Positive 69 27
6.1 (1.9-21.0) BV Negative 34 22 1.7
(1.0-3.1)
Conclusion This study provides preliminary
evidence that an interaction between genetic
susceptibilities (TNF-2 carriers) and
environmental factors (BV) is associated with an
increased risk of spontaneous preterm birth.
Macones et al. AJOG. 20041901504-8.
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Genomics
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GenomicsAll of the structure and function of
an entire genome (e.g., the human genome),
including its sequences, structures, regulation,
interactions, and products.
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GenomeAll of the genetic material (DNA)
belonging to a particular organism.
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HuGEHuman Genome Epidemiology
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Framework for a Genomic Approach to Preterm Birth

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Pathways to Preterm Birth

• Inflammation / Infection (ascending), 40
• Stress (maternal/fetal), 25
• Bleeding / Clotting Abnormality (thrombophilia,
  decidual hemorrhage, abruption), 25
• Abnormal Uterine Distension (stretching), 10

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Pathological Uterine Distention
Inflammation
Activation of Maternal/Fetal HPA Axis
Decidual Hemorrhage Abruption
Infection - Chorion-Decidual - Systemic
Multifetal Pregnancy Polyhydramnios Uterine
abnormalities
Maternal-Fetal Stress Premature Onset of
Physiologic Initiators
Prothrombin G20210A Factor V Leiden Protein C,
Protein S Type 1 Plasminogen MTHFR
Interleukins TNF-a Fas L
Gap jct IL-8
PGE2 Oxytocin recep
CRH E1-E3
Mechanical stretch
Chorion Decidua

CRH
CYP1A1 GSTT1
Susceptibility to environmental toxins
MMPs

proteases
uterotonins
PROM
Cervical change
Uterine Contractions
PTD
Adapted from C. J. Lockwood, E. Kuczynski,
Paediatr Perinat Epidemiol 15, 78 (2001) X.
Wang et al. Paediatr Perinat Epidemiol 15, 63
(2001)
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Common Complex Disorders

• From a public health perspective, genes with
  mutations that are less highly penetrant but much
  more prevalent have a greater effect on the
  population than genes that are highly penetrant
  but uncommon.

Guttmacher AE, Collins FS. Genomic Medicine A
Primer. N Engl J Med 2002347(19)1512-1520.
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in Preconception Care
Genomics ...

• Allows us to consider genetic variation as the
  background for environmental influences
• Encourages research to examine gene-environment
  interactions

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in Preconception Care
Genomics ...

• May enhance our understanding of the mechanisms
  of disease and allow us to target or expand
  clinical interventions and public health
  strategies

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Prevalence of spina bifida and anencephaly among
all 24 surveillance programs
Pre-fortification
Optional Fortification
Mandatory Fortification
1995
1996
1997
198
1999
2000
2001
Teratology 2002 6633-39. Updated 6/2004.
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Source Cummings AM, Kavlock RJ. Crit Rev Toxicol
200434461-85.
Folate Metabolism
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Botto, LD, Yang Q. 2000. Am J Epidemiol.
151862.
MTHFR Gene - 1p36.3

• Polymorphism (variant) at position 677
• Thymine is substituted for cytosine
• Association with NTDs
• OR 95 CI
• homozygotes 1.8 1.4-2.2
• heterozygotes 1.2 0.99-1.3

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in Preconception Care
Genomics ...

• Highlights the role of family history

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What determines your risk for disease?
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The Use of Family History in Genomics

• Most common diseases result from the
  interactions of multiple genes with multiple
  environmental factors in complex patterns that,
  despite progress in sequencing the human genome,
  are unlikely to be understood fully in the near
  future.
• Family medical history represents a genomic
  tool that can capture the interactions of
  genetic susceptibility, shared environment, and
  common behaviors in relation to disease risk.

CDCs Office of Genomics and Disease Prevention
cdc.gov/genomics
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Family history is a risk factor for diseases
throughout all stages of life
diabetes depression
Alzheimers disease osteoporosis
birth defects blood disorders
infants
adolescents
older adults
children
adults
cancer heart disease
asthma autism
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Guttmacher AE, Collins FS, Carmona RH. N Engl J
Med. 2004 Nov 25351(22)2333-6.
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If we could predict preterm delivery ..

• We could strengthen and target public health
  messages
• We could personalize strategies for health
  promotion and disease prevention
• We could identify high risk women earlier (prior
  to their first preterm birth) and develop
  research protocols for promising interventions
• We might be able to broaden applications of
  promising clinical treatments such as
  progesterone

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Hypothetical Protocol
Routine components of preconception prenatal
care
Extremely High Risk

Targeted smoking cessation and weight reduction

Consider progesterone
Assess Family History
HighRisk
Routine components of preconception prenatal
care

Targeted smoking cessation and weight reduction
Average Risk
Routine components of preconception prenatal
care
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Genetic and Genomic approaches do not replace but
can add to

• Community based interventions
• Patient / Consumer education
• Provider education
• Equity in health outcomes and health care

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Common Complex Disorders

• The study of genomics will most likely make its
  greatest contribution to health by revealing
  mechanisms of common, complex diseases, such as
  hypertension, diabetes, and asthma.

Guttmacher AE, Collins FS. Genomic Medicine A
Primer. N Engl J Med 2002347(19)1512-1520.
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Common Complex Disorders

• The study of genomics will most likely make its
  greatest contribution to health by revealing
  mechanisms of common, complex diseases, such as
  hypertension, diabetes, and asthma. and
  preterm birth.

Guttmacher AE, Collins FS. Genomic Medicine A
Primer. N Engl J Med 2002347(19)1512-1520.
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Challenges in MCH
Thank you