Preconceptional Health: Who Cares

1
Preconceptional HealthWho Cares?

• Karla Damus, RN MSPH PhD
• Ob/Gyn and Womens Health, AECOM, Bronx, NY
• Office of the Medical Director
• March of Dimes Birth Defects Foundation, White
  Plains, NY
• kdamus_at_marchofdimes.com 914 997 4463

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Objectives

• State the goals of preconcpetion care
• Identify the major elements of preconcpeiton care
• Understand the limitations of the research and
  science
• Describe the benefits and challenges of
  preconception care
• Learn about the most current national efforts and
  guidelines

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Healthy PeopleThe Road Map to the Nations Health

• HP2000- Increase the proportion of women
  receiving appropriate preconceptional care to 60

• HP2010- Removed- unable to measure and track
  objective

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Major March of Dimes Funded Research

• Polio vaccine
• PKU
• Neonatal Intensive Care Unit (NICU)
• Fetal Alcohol Syndrome
• Surfactant therapy for RDS
• Nitric oxide therapy for PPHN
• PERI Grants
• PRI Grants

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March of Dimes Birth Defects Foundation

• Mission
• To improve infant health by preventing infant
  mortality, birth defects, LBW and PTB
• The Continuum of Reproductive Health
• Improving health of infants requires focusing on
  the entire spectrum of reproductive health from
  prior to conception through the first year of an
  infants life and throughout the womans
  childbearing years
• Preconceptional health is the cornerstone of
  healthy infants, children, families and
  communities

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Definition of Preconception Care

• Preconception care is comprised of biomedical and
  behavioral interventions that aim to identify and
  address reversible risks to a womans health or
  pregnancy outcome, emphasizing those factors
  which must be acted on before conception or early
  in pregnancy to have maximal impact.
• Thus, it is neither a single visit nor all
  well-woman care.
• 8/29 DRAFT SUMMARY OF RECOMMENDATIONS TO IMPROVE
  PRECONCEPTION HEALTH

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Definition of Preconception Care

• Preconceptional care is an anticipatory process,
  often facilitated by a care provider, that
  encourages individuals and couples to seriously
  consider their decision to become parents.
  Through this process they become aware that
  preconception, conception, pregnancy, birth, and
  childbearing are a continuum in which earlier
  events affect the present and the future.
• This process helps people examine their desire
  and readiness for parenthood.
• Individuals consider their health, age, emotions,
  support network, finances and career goals as
  they decide to become parents, to delay
  parenthood or not to become parents.
• Wisconsin Association for Perinatal Care
• Position Statement on Preconceptional Care

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Goal of Preconception Care

• To reduce the risk of adverse health effects for
  the woman, fetus, or neonate by optimizing the
  womans health and knowledge before planning and
  conceiving a pregnancy.
• Because reproductive capacity expands almost four
  decades for most women, optimizing womens health
  before and between pregnancies is an ongoing
  process that requires access to and the full
  participation of all segment of the health care
  system.
• The Importance of Preconception Care in the
  Continuum
• of Women's Health Care
• ACOG Committee Opinion Number 313, September
  2005

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What is Preconception Care

• Counseling about folic acid and prevention of
  neural tube defects
• Education about risks for diabetes, glycemic
  control and pregnancy outcome
• Education to increase awareness of the importance
  of diet, weight and fitness
• Education about the importance of compliance with
  treatment in women with chronic conditions and
  when appropriate, obtaining preconceptional
  genetic counseling
• Identification of and help for victims of
  domestic violence/abuse
• Appropriate screening, prevention and treatment
  of infectious diseases
• Education to increase awareness that during the
  earliest weeks of pregnancy, no level of alcohol
  and tobacco ingestion is proven safe
• California Preconception Care Initiative Every
  Woman, Every Time

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Pre/Interconception/Internatal Care

• Readiness for pregnancy (FP)
• Optimal management of any medical conditions
  (diabetes, HBP, asthma, infections, heart
  disease, depression, addiction )
• Infections and STIs
• Immunizations
• Family history, genetic counseling, carrier
  testing
• Substance abuse (smoking, alcohol, other drugs)
• Domestic violence (DV/IPV)
• Stress reduction
• Optimal weight and activity
• Good nutrition-- folic acid for men and women
• Avoid teratogens (work site, environment)
• Review all meds and home remedies with hcp

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Critical Periods of Development
Weeks gestation

4 5 6 7 8 9
10 11 12
from LMP
Most susceptible

Central Nervous System
Central Nervous System
time for major

malformation
Heart
Heart
Arms
Arms
Eyes
Eyes
Legs
Legs
Teeth
Teeth
Palate
Palate
External genitalia
External genitalia
Ear
Ear
Mean Entry into Prenatal Care
Missed Period
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Why Preterm Birth?

• 1 obstetric challenge in the U.S.
• Leading problem in pediatrics
• Common, serious, and costly

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Preterm Birth/Prematurity

• Single most important cause of perinatal
  mortality in U.S. (about 75 of these losses)
• Leading cause of neonatal mortality (0-27 days)
  in U.S. since 1999
• Second leading cause of infant mortality in U.S.
• Leading cause of black infant mortality in U.S.

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Preterm Birth/Prematurity

• Major determinant of neonatal and infant illness
• Neurodevelopmental handicaps (CP, mental
  retardation)
• Chronic respiratory problems
• Intraventricular hemorrhage
• Periventricular leukomalacia
• Infection
• Retinopathy of prematurity
• Necrotizing enterocolitis
• Neurosensory deficits (hearing, visual)

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Birth Weight and Coronary Heart Disease Barker
Hypothesis
Age Adjusted Relative Risk
Birthweight (lbs)
Rich-Edwards 1997
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Birth Weight and Insulin Resistance Syndrome
Barker Hypothesis
Odds ratio adjusted for BMI
Barker 1993
Birthweight (lbs)
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Current Definitions

• Gestation Length
• Premature (preterm delivery, PTD)- lt 37 weeks
• Early preterm delivery - lt 32 weeks
• Birth Weight
• Low Birth weight (LBW) - lt 2500 grams or 5.5 lbs
• Very low birth weight - (VLBW) lt 1500 grams or
  3.3 lbs
• Growth Restriction
• lt 10th percentile for gestational age
• IUGR - intrauterine growth restricted applies to
  fetuses
• SGA - small for gestational age applies to
  neonates

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www.marchofdimes.com/peristats
21
Preterm Birth RatesUnited States, 1983, 1993,
2003
Percent
Percent
HP 2010 Objective
28 Increase
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
22
Distribution of Live Births by Gestational
Age United States, 1990 and 2001
2001 Live Births n 3,986,102
1990 Live Births n 4,111,396
Not Preterm (88.4)
Not Preterm (89.4)
Very Preterm (1.9)
Moderately Preterm (8.7)
Moderately Preterm (10.0)
Very Preterm (1.9)
Total Preterm 10.6
Total Preterm 11.9
Note Live births with missing gestational age
data were excluded from the analysis.
Source National Center for Health Statistics,
final natality data Prepared by March of Dimes
Perinatal Data Center, 2003
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Distribution of Preterm Births by Gestational
Age, US, 2002
(lt32 Weeks)
Near term infants had significantly more medical
problems and increased hospital costs compared
with contemporaneous full term infants Near term
infants may represent an unrecognized at-risk
neonatal population. Wang, et al. Clinical
Outcomes of Near-Term Infants, Pediatrics (114)
372-6, 2004.
(36 Weeks)
(32 Weeks)
(33 Weeks)
60 of PTB 35 - 36 weeks
(34 Weeks)
(35 Weeks)
Source National Center for Health Statistics,
2002 natality file Prepared by the March of Dimes
Perinatal Data Center, 2004
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TYPE of Preterm Birth
Spontaneous Preterm Labor
50
Spontaneous Premature Rupture of the Membranes
25-30
Preterm Birth
25-30
Iatrogenic (Medical Indication)
While this suggests distinct pathways, many of
the risk factors for all 3 are similar
25
PLURALITYPreterm and Low Birthweight Births By
Plurality, United States, 2002
Percent
Higher Order
Higher Order
Twins
Twins
Singleton
Singleton
Preterm is less than 37 weeks gestation Low
birthweight is less than 2500 grams or 5 1/2
pounds Source National Center for Health
Statistics, final natality data Prepared by March
of Dimes Perinatal Data Center, 2002
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MATERNAL AGEPreterm Births by Maternal AgeAmong
Singletons, US, 1990 and 2001
Percent
Source National Center for Health
Statistics Prepared by March of Dimes Perinatal
Data Center, 2004
27
RACE ETHNICITYPreterm Birthsby Race/Ethnicity,
US, 1990 and 2001
Percent
People of Hispanic ethnicity may be any race all
other categories are non-Hispanic Source
National Center for Health Statistics Prepared by
March of Dimes Perinatal Data Center, 2004
28
Infant MortalityUnited States, 1915-2002
Rate per 1,000 live births
Source National Center for Health Statistics,
final mortality data Prepared by March of Dimes
Perinatal Data Center, 2002
29

• Unexpected findings- most of increase due to
• non Hispanic white
• gt30 years
• married
• gthigh school
• onset PNC first trimester
• nonsmoker
• private insurance

www.cdc.gov/mmwr
30
Three Leading Causes of Infant Mortality United
States, 1990 and 2002
Rate per 100,000 live births
Source National Center for Health
Statistics Prepared by March of Dimes Perinatal
Data Center, 2004
31
Leading Cause-specific IMR and ChangeUnited
States, 2001 and 2002
Rates are per 100,000 live births
32
Risk Factors for Preterm Labor/Delivery

• The best predictors of having a preterm birth
  are
• current multifetal pregnancy
• a history of preterm labor/delivery or prior low
  birthweight
• mid trimester bleeding (repeat)
• some uterine, cervical and placental
  abnormalities
• Other risk factors

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

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

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Folic Acid Deficiency

• Predisposes to
• NTDs
• Other birth defects (cleft lip/palate, cardiac,
• limb reduction, urinary tract, omphalocele,
  trisomies)
• Early and recurrent pregnancy loss
• Low birth weight and prematurity
• Gestational hypertension, preeclampsia in Black
  women
• Atherosclerotic vascular disease (stroke, CAD)
• Colorectal and cervical cancer
• Acute Lymphocytic Leukemia
• Alzheimers Disease

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Folic Acid Recommendations

• Prevent Recurrence, 1991
• All women with a previous NTD pregnancy should
• take 4 mg or 4000mcg interconceptionally
• Prevent Occurrence, USPHS September, 1992
• All women of childbearing potential should
• consume 0.4 mg (400 micrograms) of folic acid
  daily
• Food Nutrition Board of IOM, 1998
• Men (14 yr older) 400 µg any source
• Women (14 yr older) 400 µg synthetic food
• Pregnancy 600 µg synthetic food
• Lactation 500 µg any source

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Folic Acid Knowledge and Behavior 1995 and 2004
Percentage of women ages 18-45
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Things Women Reported Might Encourage them to
Take a Multivitamin DailyMarch of Dimes Folic
Acid Survey, 2003
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Perceived Benefits of Folic Acid
Q. 14 Please tell me whether each statement is
true or false, or if you are not sure. Note
Correct responses are outlined.
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When Do Physicians Recommend Multivitamins/Folic
Acid?
Q. 15 In your practice, do you always, usually,
occasionally, or never recommend multivitamins or
folic acid supplementation?
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Prevention or Well-Woman Care

• Only about one-half of the physicians generally
  bring up folic acid (or multivitamins) during an
  annual exam
• Patients are not likely to bring up the issue of
  folic acid on their own, and physicians perceive
  that patients have only moderate compliance
  levels when advised to take folic acid or
  multivitamins
• Physicians suggest that some doctors may not
  address folic acid with their patients primarily
  due to lack of knowledge about folic acid, and
  lack of time during the exam
• Survey responses suggest that folic acid is not
  high on physicians priority list, in light of
  all the other preventive issues they need to
  address with patients

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Perceived Recommended PreconceptionalFolic Acid
Dose for NTD Patients
Q. 21 To the best of your knowledge, what is
the recommended preconceptional daily dose of
folic acid for women who have had a pregnancy
affected by NTD?
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Mean serum and red blood cell folate levels,
before and after folic acid fortification,
NHANES women aged 15-44 years
ng/mL
ng/mL
Serum folate
Red blood cell folate
20
350
265.5
300
15
250
12.8
200
163.0
10
150
5.0
100
5
50
0
0
1988-1994
1999-2000
1988-1994
1999-2000
SOURCE CDC/NCHS, National Health and Nutrition
Examination Surveys, 1988-94 and 1999-2000
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DAILY Take the Good Acids

• Folic acid (at least 400 mcg)
• Vitamin B9
• Ascorbic acid
• Vitamin C
• Omega 3 fatty acid

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Factors that Contribute to Increasing Rates of
Preterm Birth

• Increasing rates of births to women 35 years of
  age
• Independent risk of advanced PATERNAL age
• Increasing rates of multiple births
• Indicated deliveries
• Induction
• Enhanced management of maternal and fetal
  conditions
• Patient preference/consumerism (section on
  demand)
• Substance abuse
• Tobacco
• Alcohol
• Illicit drugs
• Bacterial and viral infections
• Increased stress (catastrophic events, DV, racism)

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Multiple Birth Ratios by Maternal RaceUnited
States, 1980-2002
Ratio per 1,000 live births
Source NCHS, final natality data,
1980-2001 Prepared by March of Dimes Perinatal
Data Center, 2003
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Higher-Order Multiple Birth RatiosBy Maternal
Race, United States, 1980-2002
Ratio per 100,000 live births
Source NCHS, final natality data,
1980-2002 Prepared by March of Dimes Perinatal
Data Center, 2004
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Proportion of Preterm Births by PluralityUnited
States, 1992 and 2002
Percent of preterm births
40 increase in the proportion of
multiple preterm births from 1992 to 2002
Multiple Births 2.4 3.3
Source National Center for Health
Statistics. Prepared by March of Dimes Perinatal
Data Center, 2004.
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Total and Primary Cesarean and VBAC Rates United
States, 1989-2002
49
Singleton Preterm Births by Delivery
Method United States, 1990 and 2001
Percent
Source National Center for Health
Statistics Prepared by March of Dimes Perinatal
Data Center, 2004
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Perinatal Impact of Substance Abuse

• There are many direct and indirect adverse
  perinatal outcomes associated with substance
  abuse
• Substance use (smoking, alcohol, illicit drugs
  and abuse of prescription drugs) is associated
  with many adverse reproductive and perinatal
  outcomes including infertility, unintended
  pregnancy, STIs, miscarriage, fetal death, birth
  defects, developmental disabilities, PROM,
  placental abruption, preterm birth, low
  birthweight, infant mortality, SIDS

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Substance Abuse and Reproductive Health Issues

• Polydrug use is common
• Substance abuse, domestic violence and STIs often
  overlap
• Women often use substances to cope with stress
  and/or depression
• assess and intervene with primary causes
• Substances influence behavior and cognition
• alcohol and other substances are associated with
  unintended pregnancy
• Substances can impair a persons immune system,
  increase susceptibility to infections
• Pregnancy is a time of relative immune suppression

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Provider/Client Opportunity

• Pregnancy is a window of opportunity as 96 of
  women in the US are seen by a healthcare provider
  during their pregnancy and seen multiple times
• Internatal (preconceptional and
  interconceptional) periods are also opportunities
  to address substance abuse issues with more
  pharmocotherapy options
• Women are more likely to change their behavior
  during pregnancy than at any other time in their
  lives and the changes can have life long health
  benefits
• Women are more likely to stop substance abuse
  during pregnancy or when they are planning to
  become pregnant, both spontaneously and with
  assistance, than at any other time in their
  lives.

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Substance Abuse in Pregnant Women in the US

• Women aged 15 to 44 who were currently pregnant
  were less likely than nonpregnant women in this
  age group to currently use
• an illicit drug, smoke cigarettes, or drink
  alcohol
• Pregnant women 15-25 years were more likely to
  have smoked cigarettes in the past month and to
  have used an illicit drug during the past month
  than pregnant women aged 26 to 44.
• Among pregnant women aged 15 to 44, 10 reported
  drinking alcohol during the past month, 4
  reported binge alcohol use, and less than 1
  reported heavy alcohol use.
• Among pregnant women aged 15 to 44, whites were
  more likely to have smoked cigarettes during the
  past month than blacks or Hispanics

Source The NSDUH Report Substance Use During
Pregnancy 2002 and 2003 Update www.oas.samhsa.gov
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Substance Abuse in Pregnant and NonPregnant
Women in the US, 2002-2003
Source SAMHSA 2002-2003 NSDUH www.oas.samhsa.gov
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Past Month Substance Use among Women Aged 15 to
44 by Pregnancy and Recent Motherhood Status,
2002-2003
Source SAMHSA 2002-2003 NSDUH Update www.oas.samh
sa.gov
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Past Month Cigarette Use among Women Aged 15 to
44by Pregnancy Status, Age, and Race/Ethnicity,
2002 -2003
Source SAMHSA 2002-2003 NSDUH www.oas.samhsa.gov
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Health Consequences of Smokingfor Women

• Evidence confirms that in addition to adverse
  health outcomes such as cancer, cardiovascular
  and pulmonary diseases, women smokers face
  gender-specific health risks related to
  reproduction and menopause.

Women and Smoking A Report of the Surgeon
General. USPHS 2001 effects of smoking on
reproductive outcomes Preventing Maternal
Smoking. National Governors Association Issue
Brief 2001 interventions and state best practices
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Pregnancy Related Smoking Risks

• Ectopic Pregnancy (RR 1.5-2.5)
• Infertility (RR 1.5-3.0)
• Conception Delay (RR 1.4-2.4)
• Spontaneous Abortions (RR 1.1-3.4)
• PPROM (RR 2.0-5.0)
• Preterm labor (RR 1.2-2.0)
• LBW (RR 1.5-3.5)
• SGA (RR 1.5-10)
• References
• U.S. Department of Health and Human Services.
  Women and
• Smoking A Report of the Surgeon General. 2001

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LBW (lt2500 g) and PTD (lt37 wks) by Smoking
Status and by Race/Ethnicity, CT, 1998
Percent
Low Birthweight
Preterm
Prepared of PDC, MOD Source Connecticut Dept of
Public Health, OPPE
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Impact of Smoking

• Smoking during pregnancy is responsible for
• 20 of all LBW
• 8 of preterm births
• 5 of all perinatal deaths
• Pregnant smokers compared to nonsmokers are
• 2.0-5.0 times as likely to experience PPROM
• 1.2-2.0 times as likely to deliver preterm
• 1.5-10 times as likely to deliver a SGA infant
• 1.5-3.5 times as likely to deliver a LBW infant
• Smoking increases risk of stillbirth (RR1.4-1.6)
• Risk increases with increased amount smoked
• Smoking during and after pregnancy increases risk
  for SIDS by 3-fold

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Cigarette Smoke Contains

• Nicotine
• Polycyclic aromatic hydrocarbons
• Tar
• Carbon particles
• Carbon monoxide

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Biotransformation of Compounds in Cigarette Smoke

• Phase 1 Reactive intermediates are formed
• CYP1A1 enzyme
• Phase 2 Conjugation of reactive intermediates
  for detoxification
• GST enzymes

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Metabolic Genes and Cigarette Smoking

• Maternal smoking was associated with a mean birth
  weight reduction of 377 g
• CYP1A1 was associated with a 252 g reduction for
  the AA genotype group, and 520 g for the Aa/aa
  genotype
• GSTT1 was associated with a 285 g reduction and
  642 g for the present and absent genotypes
• If both were present, there was a 1285 g
  reduction in birth weight and a 5.5 wk reduction
  in gestational age
• Wang X (PERI grantee), Zuckerman B, Pearson
  C, et al. Maternal cigarette smoking, metabolic
  gene polymorphism, and infant birth weight.
  JAMA, 2002, 287(2) 195-202.

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CYP1A1

• Isoenzyme cytochrome P450 1A1 (CYP1A1)
• Important in the bioactivation of benzopyrene and
  other aromatic hydrocarbons in cigarette smoke
• Gene for CYP1A1 is on chromosome 15
• Contains 7 exons
• Polymorphism reported in exon 7
• Valine replaces isoleucine
• Protein structure is altered
• Homozygotes or heterozygotes for this variant
  have
• higher enzyme activity than wild-type carriers
• increased production of toxicants

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Glutathione S-transferases (GSTs)

• Phase 2 detoxification enzymes
• Protect cells from toxicants by conjugation with
  glutathione
• GSTT1 GST theta 1-1
• GSTT1 is involved in the biotransformation of low
  molecular weight halogenated compounds and
  reactive epoxides produced after metabolization
  of aromatic hydrocarbons present in cigarette
  smoke
• Gene for GSTT1 is on chromosome 22
• A deletion has been identified in the gene
• Homozygotes of GSTT1-null genotype do not express
  the gene, consequently do not have any GSTT1
  enzyme activity
• Prevalence of the null polymorphism ranges from
  12-20 in Europeans to 65 in Asian populations

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Chromosomal Instability in Amniocytesfrom
Fetuses of Mothers Who Smoke

• Does maternal smoking have a genotoxic effect on
  amniotic cells?
• Prospective study, amniocytes were obtained by
  routine amniocentesis for prenatal diagnosis from
  25 controls and 25 women who smoke (10 cig/d for
  10 yrs)
• Maternal smoking is associated with increased
  chromosomal instability in amniotic fluid cells,
  expressed as chromosomal lesions (gaps and
  breaks) and structural chromosomal abnormalities
• Band 11q23, involved in leukemogenesis, seems
  especially sensitive to genotoxic compounds
  contained in tobacco.

de la Chica, etal. JAMA 293 (10)1212-22, March
2005.
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Vitamin C May Cut Pregnant Smoking Risks

• Primate model experimental design at OHSU with 3
  groups
• 7 monkeys born to mothers who received 2 mgm qd
  of nicotine, comparable to a smoking mother
• 7 monkeys born to mothers who received both
  nicotine and 250 mgm vitamin C qd
• 6 control monkeys- neither nicotine nor vitamin C
  
• The monkeys given nicotine and vitamin C had lung
  air flow close to that of a normal animal
• The researchers note that vitamin C did not
  counteract other negative effects of smoking
  during pregnancy, such as abnormal brain
  development and decreased body weight.

Proskocil BJ, et al. Am J Resp and Crit Care Med,
1711032-9, 2005.
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Vitamin C May Cut Pregnant Smoking Risks (cont)

• The study showed that smoking had a much more
  adverse effect on fetal development than was
  previously thought, with smoking mothers causing
  changes in their babies' lungs.
• "What happens to you as a fetus is
  extraordinarily important as to what diseases you
  may be susceptible to as an adult.
• If I can't get patients who smoke to quit during
  pregnancy, I plan to start telling them to take
  vitamin C.

Interview with Dr. Michael Gravett, Chief MFM
OHSU (Oregon Health and Science University)
School of Medicine, May 2005.
"The single most important thing is for pregnant
women to stop smoking," said Dr. Eliot Spindel
(co-author).
69
Warning From the CDC

• Stay away from tobacco smoke if you are at
  risk for heart disease (common complex
  disorders)!
• "We don't make these kind of statements lightly. 
  What we are seeing in the data is a substantial
  biological change that occurs with even 30
  minutes of exposure to secondhand smoke."
  Terry Pechacek, Assoc Director of Science,
  CDC's Office on Smoking and Health
• The number of heart attacks in Helena, MT,
  decreased substantially after the city banned
  indoor smoking, then rose quickly to its former
  level after the law was struck down in court
• During the six-month period in 2002 when the ban
  was in effect, the number of heart attacks
  reported by Helena's heart hospital fell by 40 .
• Sargent RP, Shepard RM, Glantz SA. Reduced
  incidence of admissions for myocardial infarction
  associated with public smoking ban before and
  after study. BMJ328, 977-83, 2004.
  bmj.com

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9 States with Smokefree Workplace Legislation for
All Workers

• California
• Delaware
• New York
• Connecticut
• Maine

• Massachusetts
• Rhode Island
• Vermont
• Montana (2009)

including restaurant and bar workers as of
9/05 5 other states (FL, UT, ID, HI, ND) are
smokefree but exclude bars WA and MD have
smokefree offices
71
Smoking Cessation and Preterm Birth (Cochrane
Review)

• 64 trials (51 RCTs of 20,931 women) and 6
  cluster-randomised trials (over 7500 women)
  provided data on smoking cessation and/or
  perinatal outcomes
• Smoking cessation interventions reduced low
  birthweight (RR 0.81, 95 CI 0.70 to 0.94) and
  preterm birth (RR 0.84, 95 CI 0.72 to 0.98)
• One intervention strategy, rewards plus social
  support, resulted in a significantly greater
  smoking reduction than other strategies (RR 0.77,
  95 CI 0.72 to 0.82).
• Smoking cessation programs in pregnancy reduce
  the proportion of women who continue to smoke,
  and reduce low birthweight and preterm birth.

Lumley J, et al. Interventions for promoting
smoking cessation during pregnancy. The Cochrane
Database of Systematic Reviews 2004, Oct
18(4)CD001055.
72
The 5 As
1. Ask about tobacco use
2. Advise to quit
3. Assess willingness to make a quit attempt
4. Assist in quit attempt
5. Arrange follow-up
A Clinicians Guide to Helping Pregnant Women
Quit Smoking
http//iml.dartmouth.edu/education/cme/Smoking
73
Compliance with Best Practice

• 100 of Ob/Gyns reported they asked about tobacco
  use
• 98 discussed the harm related to smoking and
  advised smokers to quit
• 66 assessed smokers readiness to quit
• 51 provide social support for cessation within
  the office
• 43 provided pregnancy-specific materials
• 23 helped arranged social support at home
  (assist)

74
Common Reasons why Providers Dont Promote
Behavioral Interventions

• Dont believe it works
• Not enough time
• No reimbursement
• No system in place for implementation

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http//iml.dartmouth.edu/education/cme/Smoking
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LBW (lt2500 g) and PTD (lt37 wks) by Alcohol
Useand by Maternal Race/Ethnicity, CT, 1998
Percent
Low Birthweight
Preterm
Prepared of PDC, MOD Source Connecticut Dept of
Public Health, OPPE
78
Effects of Alcohol on PregnancyFetal Alcohol
Spectrum Disorder (FASD)

• Miscarriage
• Preterm birth
• Low birth weight
• FAS
• ARBD - Alcohol-Related Birth Defects
• ARND - Alcohol-Related Neurodevelopmental
  Disorders
• Birth complications

79
Maternal Alcohol Use Increases Neonatal
Infection Risk

• A woman who drinks alcohol during pregnancy
  increases the chances of her newborn acquiring an
  infection soon after birth
• Data were analyzed from the Maternal Lifestyles
  and Development Study on 11,656 infants delivered
  at 32-42 wks
• Increasing amounts of maternal alcohol
  consumption at any point during pregnancy and
  during the 3 months before pregnancy --
  significantly increased the risk of neonatal
  infection
• Heavy drinking (7 drinks/wk) during the second
  trimester increased the risk of infection in the
  newborn nearly 7 fold compared with abstaining
  from alcohol.
• Binge drinking during the second or third
  trimester more than quadrupled the risk of
  neonatal infection.

Gauthier, et al. Alcoholism Clinical and
Experimental Research, June 2005.
80
Screening Tools are the Most Effective Way to
Determine Risk

• Quick, brief questionnaires have been
  demonstrated to be effective in prenatal care for
  assessing alcohol and drug use
• Pregnant women describe their health care
  providers as the best source of information
• Pregnant women will generally follow the
  providers advice

81
How to Use Screening Tools

• Choose a screen that fits your style and is
  culturally appropriate for the patients
• Be nonjudgmental and supportive when asking about
  use
• Stress the benefits of abstinence and offer to
  help the patient achieve it
• Know where to refer the patient for further
  assessment
• T-ACE, 4 Ps, TWEAK, AUDIT, TQDH

82
4Ps (5Ps)

• Have you used drugs or alcohol during this
  Pregnancy
• Have you had a problem with drugs or alcohol in
  the Past?
• Does your Partner have a problem with drugs or
  alcohol?
• Do you consider one of your Parents to be an
  addict or alcoholic?
• In the month before you knew you were pregnant
  how many cigarettes did you smoke?

83
History Red Flags

• Maternal chaotic lifestyle
• psychosocial stresses
• spouse/partner of an alcoholic or drug abuser
• domestic violence, physical and sexual
• Psychiatric diagnosis
• depressions, psychosis, anxiety, PTSD
• lack of functional coping skills
• unexplained mood swings, personality changes
• Late or no prenatal care
• missed appointments and compliance problems
• STIs, sexual promiscuity

84
Physical Examination Findings for the Majority of
Substance Abusers
Nothing unusual is the most frequent finding in
users of licit and illicit drugs.
85
Effects of Domestic Violence onPreterm Birth and
Low Birth Weight

• Prospective study of 3149 low income, relatively
  low risk pregnant women (82 Af Am) in Alabama,
  1997-2001
• 3103 completed the Abuse Assessment Screen and in
  the past year
• 27 reported emotional abuse
• 19 reported physical abuse
• 10 reported being beaten, bruised, threatened
  with a weapon or being permanently injured
• Abuse was reported by 6 of women during
  pregnancy
• Logistic regression analysis indicated that
  injury from physical abuse in the past year was
  significantly associated with PTB/LBW
• AOR 1.6 (95 CI 1.1-2.3) for PTB
• AOR 1.8 (95 CI 1.3-2.5) for LBW
• mean birth weight significantly lower (-75.2 g,
  plt.05)
• Injuries resulting from physical abuse are
  associated with both LBW and PTB

Neggers Y, et al. Acta Obstet Gynecol Scand
83(5)455-60, 2004.
86
Impact of Police-Reported IPV during Pregnancy
on Birth Outcomes

• Population based, retrospective cohort study in
  Seattle WA using police data and state birth
  certificate files, Jan 1995-Sep 1999
• Exposed subjects IPV incident police report
  during pregnancy and who subsequently had a
  singleton live birth of fetal death
• Unexposed controls randomly selected Seattle
  residents with a singleton LB or FD without an
  IPV police report
• Results
• AOR 1.7 (95 CI 1.2-2.4) for LBW AOR 2.5 (95 CI
  1.3-4.9) for VLBW
• AOR 1.6 (95 CI 1.1-2.3) for PTB AOR 3.7 (95 CI
  1.8-7.6) for VPTB
• AOR 3.5 (95 CI 1.4-8.5) for neonatal death
• Police-reported partner violence during pregnancy
  is significantly associate with ah increased risk
  of adverse birth outcomes
• There is a critical need to identify women with
  DV and to provide women health and social service
  information and referrals, particularly to high
  risk pregnancy programs.

Lipsky S, et al. Obstet Gynecol 102(3)557-64,
2003.
87
Sexually Transmitted infections CategoriesNew
York and US, 2002
88
STI Impact on Women

• Disseminated gonococcal infection (DGI)
• Septic tertiary syphilis
• Cervical cancer
• Vulvar cancer
• Vaginal cancer
• Anal cancer
• Liver cancer
• Kaposiss sarcoma
• T cell leukemia
• Body cavity lymphoma
• Chronic liver disease, cirrhosis

• Spontaneous abortion
• Ectopic pregnancy
• PID
• Infertility
• Preterm delivery
• PROM
• Puerperal sepsis
• Postpartum infection
• Wound and pelvic infections after c section
• Postpartum endometrosis
• Neurosyphilis

89
STI Impact on Babies

• Miscarriage
• IUGR
• Stillbirth
• Prematurity
• Low birthweight
• Conjunctivitis
• Pneumonia
• Encephalitis
• GBS meningitis
• Neonatal sepsis
• Vertical transmission
• Hepatitis, cirrhosis
• Chronic HBV infection

• Neurologic damage
• Laryngeal papillomatosis
• Transmission through BF
• Birth defects (brain, spinal cord, eyes, auditory
  nerves)
• Neonatal Death
• CMV, HSV, syphilis associated neurologic problems
• Childhood morbidity
• Liver cancer as an adult

90
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91
Interventions- What works?
92
The Importance of Prenatal Care

• Early, comprehensive, culturally sensitive
  accessible, available prenatal care is always
  important, but studies have not shown that it
  reduces rates of PTB/LBW
• It has been shown to reduce fetal deaths, IMR and
  complications of pregnancy
• Early PNC may be too late to prevent some PTB

Preterm Births by Prenatal Care and
Race/Ethnicity, US, 2001
93
Can Preterm Labor be Prevented?

• Primary prevention is the goal
• especially risk reduction in the preconceptional
  period and early in pregnancy
• Preterm prevention programs have focused on risk
  assessment or prediction of preterm labor
• risk assessment identifies only half of preterm
  births
• during pregnancy most biomarkers, even in
  combination with risk factors, do not have good
  positive predictive values
• Causation is the great unknown

94
Prevention of Preterm Labor, Preterm Delivery and
Prematurity

• Primary prevention
• identifying and managing risks
• risk reduction approach and strategies to
  reproductive health
• prevent PTL
• Secondary prevention
• prevent preterm delivery
• Tertiary prevention
• prevent/minimize complications of prematurity

95
March of Dimes Investment in the Science and
Public Health of Preterm Delivery

• Toward Improving the Outcome of Pregnancy (TIOP
  I)- regionalization of perinatal care
• TIOP II - regionalization, continuum, elimination
  of health disparities
• Perinatal Epidemiological Research Initiative
  (PERI 1998-2004)
• Six innovative research initiatives to define
  biomarkers and mechanisms
• Epidemiologic approaches to test biologically
  plausible hypotheses for the major determinants
  of preterm birth
• Examine the interactions of risk factors
  associated with prematurity and relevant
  biologic samples
• Prematurity Research Initiative -PRI

96
Major Pathways to Preterm Labor

• Inflammation/infection (ascending), 40
• cytokines
• Stress (maternal/fetal), 25
• CRH
• Bleeding (decidual hemorrhage, abruption), 25
• thrombin
• Stretching (uterine distention), 10

97
Inflammation
Pathological Uterine Distention
Activation of Maternal/Fetal HPA Axis
Decidual Hemorrhage Abruption
Infection - Chorion-Decidual - Systemic
Maternal-Fetal Stress Premature Onset of
Physiologic Initiators
Multifetal Pregnancy Polyhydramnios Uterine
abnormalities
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)
98
Common Complex Disorder
99
PTB as a Common Complex Disorder

• Common
• 12.1 of all US births in 2002
• Well defined phenotype
• birth before 37 weeks of gestation, dating by LMP
  with ultrasound confirmation
• 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.
• Genetic contribution
• Familial aggregation
• Recurrence of preterm birth
• Racial disparity
• Environmental influences
• Gene-environment interactions

100
Genome All of the genetic material (DNA)
belonging to a particular organism. Genomics
All of the structure and function of an entire
genome (e.g., the human genome), including its
sequences, structures, regulation, interactions,
and products. (SNP, Haplotype mapping)HuGE
Human Genome EpidemiologyProteomics,
Metabolomics
www.marchofdimes.com/gyponline www.cdc.gov/genomic
s genome.gov
101
Candidate Gene Association Study

• Case-control study of 426 SNPs with PTD in 300
  mothers with PTD and 456 mothers with term births
  at Boston MC
• 25 candidate genes in the final haplotype
  analysis, a significant association was found for
  the F5 gene haplotype and PTD
• Ethnic specific analyses revealed
• consistent finding of the F5 gene
• IL1R2 in Blacks
• NOS2A in whites
• OPRM1 in Hispanics
• Results underscore the potentially important role
  of F5 gene variants in the pathogenesis of PTD
• Hao K, Wang X, Niu T, et al. A candidate
  gene association study on preterm delivery
  application of high throughput genotyping
  technology and advanced statistical methods.
  Human Molecular Genetics, 2004, 13(7) 683-91

102
Genomic approaches do not replace but can add to

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

103
Proteomics Help Identify Intra-amniotic
Inflammation

• Proteomic analysis of AF can promptly identify
  biomarkers characteristic of intrauterine
  inflammation
• Results can be available in 50 minutes, useful
  for clinical decision making
• Patients with PTL and evidence of intra-amniotic
  inflammation showed a distinctive proteomic
  profile involving neutrophils defensins -1 and -2
  and calgranulins A and C
• Scoring system developed which has a 92.9
  sensitivity and 91.8 specificity

Buhumschi, et al. Br J Obstet Gynaecol
112173-181, 2005.
104
Metabolomics in PTL A Novel Approach to Identify
Patients at Risk for PTD

• For the first time, researchers have successfully
  profiled the amniotic fluid metabolome (the sum
  of all metabolic processes occurring in the
  amniotic fluid), to identify which women who have
  experienced PTL are also at risk for PTB.
• With PTB rates increasing, the need for tools
  that can identify PTB risk has never been
  greater.
• Romero, et al studied the amniotic fluid of 3
  groups of patients those with PTL who delivered
  at term, those with intra-amniotic inflammation
  who had both PTL and PTD, and those with no sign
  of inflammation who still had PTL and PTD.
• By using metabolomic profiling, 96 of the time
  patients belonging to the appropriate clinical
  group were correctly identified.
• A second study, in a different set of patients
  with a larger sample size, has already confirmed
  the effectiveness of this method.
• Until now, we have never had a way to predict
  the course of preterm labor with such accuracy.
  Metabolomic profiling is providing that tool.

Romero, et al. SMFM, Reno, NV (Feb. 10, 2005)
105
PharmacogenomicsDrugs by Design?
In the very near future, primary care physicians
will routinely perform genetic tests before
writing a prescription because (they will) want
to identify the poor responders. F. Collins
(AAFP Annual Meeting, 1998)
106
Preterm Birth Legislation Introduced

• PREEMIE Act, authorizes expansion of research
  into the causes and prevention of prematurity and
  increases federal support of public and health
  professional education as well as support
  services related to prematurity.
• Prevent Prematurity and Improve Child Health Act
  of 2005, calls for improved access to health
  coverage for pregnant women, infants and
  children. It would provide states increased
  flexibility and federal resources to expand
  access to maternity care for income-eligible
  pregnant women and increased access to health
  coverage for infants and children with special
  health care needs.

107
Innovative Perspectives

• The prevention of preterm delivery will
  require intervention at an earlier stage in the
  processes that lead to it.
• Strategies are needed to prevent infections
• Therapies should be rigorously evaluated in women
  who have recurrent PTD due to disturbances in
  uterine blood vessels and blood flow
• Refine assisted reproductive techniques (ART) to
  reduce the occurrence of twin and higher-order
  multifetal pregnancies
• Lockwood CJ. Predicting premature
  delivery--No easy task. NEJM, 2002, 346
  (4)282-4.

108
Interventions that Work

• Early, comprehensive, accessible prenatal care
• Educate all pregnant women about preterm labor
  signs and symptoms
• Screen and treat all UTIs and STIs
• Identify cigarette smokers and intervene (5As)
• Assess for alcohol use and intervene
• Identify illicit substance users and intervene
• Assess for domestic violence and intervene
• Eliminate folic acid deficiency
• Reduce major stress levels early and throughout
  pregnancy

109
Interventions that Work

• Provide culturally sensitive, age appropriate
  pre/interconceptional care (risk reduction
  focus)
• Prevent unintended pregnancy
• Promote optimal weight
• Appropriate exercise and activity
• Good mental health
• Manage all chronic conditions (hypertension,
  diabetes)
• Oral health and periodontal disease
• Omega 3 fatty acid
• Progesterone to prevent recurrent preterm birth
  for some women

110
Promising Research Directions

• Clotting abnormalities (Thrombophilia) - Yale
• Genetic
• Can screen
• Can treat
• Stress research - CDC, MOD (PERI), others
• Progesterone (high risk by history)
• Multisite US, MFMU-NICHD
• ? by 33
• Meis P, et al. NEJM. 3482379-85, 2003.
• Brazil, da Fonesca
• ? by 50
• daFonesca, et al. AJOG. 188(2)419-24, 2003.

111
Use of Progesterone to Reduce Preterm BirthACOG
Committee Opinion, No 291, November 2003

• Further studies are needed to evaluate
  progesterone use in patients with other
  high-risk obstetric factors (multiple gestation,
  short cervical length, positive test results for
  cervicovaginal fetal fibronectin)
• Unresolved issues, such as optimal delivery of
  the drug and its long-term safety, still remain
• When progesterone is used, restrict use to only
  women with a documented history of a previous
  spontaneous preterm birth less than 37 weeks of
  gestation
• previous preterm lt34 wks, SMFM 2005

112
Estimated Impact of 17P

• If all eligibles had received 17P therapy, nearly
  10,000 spontaneous PTB out of about 480,000 PTBs
  would have been prevented in 2002
• Nationally, the PTB rate would have been reduced
  by about 2 from 12.1 to 11.8 (plt0.001).

Petrini J, et al. Obstet Gynecol, Feb 2005
113
Life Course Perspective
White
African American
Primary Care for Children
Early Intervention
Prenatal Care
Prenatal Care
Internatal Care
Primary Care for Women
Poor Birth Outcome
0
5
Age
Pregnancy
Puberty
114
Take Home Messages

• Preterm birth is a common complex disorder
  meeting criteria for high public health priority
• Intervene throughout the continuum of
  reproductive health for women and men with
  culturally sensitive risk reduction interventions
• All providers have a major role in the success of
  primary and secondary prevention
• All pregnant women are at risk for preterm labor
  and birth and should be taught the signs and
  symptoms beginning about 20 weeks of gestation
• A multidisciplinary approach is needed
• Everyone can make a difference

115
Prevent the Preventable

• Ø Unintended pregnancies
• Ø Folic acid deficiency
• Ø Alcohol
• Ø Tobacco
• Ø Illicit drugs
• Ø Infections (UTIs, STIs, periodontal disease)
• Ø Extremes of weight
• Ø Some Prescription Drugs
• Ø Environmental toxins
• Ø Known genetic/familial risks
• Ø Unnecessary interventions resulting in preterm
  birth

116
Campaign Goals

• 1. Increase public awareness of the problems of
  prematurity to at least 60 for women of
  childbearing age and 50 for the general public
  by 2010
• 2. Reduce the rate of preterm birth from 12.3 in
  2003 to the HP2010 objective of 7.6

117
March of Dimes Prematurity Campaign Aims

• 1. Generate concern and action around the problem
  of prematurity
• 2. Educate women of reproductive age about risk
  reduction and warning signs
• 3. Provide affected families with information,
  emotional support, and opportunities to help
  other families
• 4. Assist health practitioners to improve
  prematurity risk detection and address risk
  -associated factors
• 5. Invest more public and private research
  dollars to identify causes of preterm labor and
  prematurity, and to identify and test promising
  interventions
• 6. Expand access to health coverage in order to
  improve maternity care and infant health outcomes

118
March of Dimes

www.marchofdimes.com Pregnancy and Newborn Health
Education Center askus_at_marchofdimes.com
119
Premature BirthThe answers cant come soon
enough
120
Thank you for your attention
this continuing education presentation is
sponsored by the March of Dimes - Johnson
Johnson Pediatric Institute Grand Rounds
Program as part of the
March of
Dimes National Prematurity Campaign
Additional Resources Pregnancy and Newborn Health
Education Center askus_at_marchofdimes.com
www.marchofdimes.com
www.jjpi.com