Karla Damus, RN MSPH PhD
Ob/Gyn and Women’s Health, AECOM, Bronx, NY
Office of the Medical Director
March of Dimes Birth Defects Foundation, White Plains, NY kdamus@marchofdimes.com 914 997 4463

• 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

• HP2000- Increase the proportion of women receiving appropriate preconceptional care to 60%
• HP2010- Removed- unable to measure and track objective

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

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 infant’s life and throughout the woman’s childbearing years
• Preconceptional health is the cornerstone of healthy infants, children, families and communities

• Preconception care is comprised of biomedical and behavioral interventions that aim to identify and address reversible risks to a woman’s 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 wellwoman care.
8/29 DRAFT SUMMARY OF RECOMMENDATIONS TO IMPROVE PRECONCEPTION HEALTH

• 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

• To reduce the risk of adverse health effects for the woman, fetus, or neonate by optimizing the woman’s health and knowledge before planning and conceiving a pregnancy.
• Because reproductive capacity expands almost four decades for most women, optimizing women’s 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

•
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

• 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

Weeks gestation from LMP
Most susceptible time for major malformation
Critical Periods of Development
4 5 6 7 8 9 10 11 12
Missed Period Mean Entry into Prenatal Care

•
•
•

• 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.

• 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)

Birth Weight and Coronary Heart Disease
Barker Hypothesis
1.75
1.5
1.5
1.25
1.25
1.15
1
1 0.9
0.7
0.75
0.5
0.25
0
<5.0
5.0-5.5
5.6-7.0
7.1-8.5
8.6-10.0
>10.0
Birthweight (lbs)
Rich-Edwards 1997

Birth Weight and Insulin Resistance Syndrome
Barker Hypothesis
20
18
15
10
5
Barker 1993
0
<5.5
8.4
8.5
4.9
2.2
5.6-6.5
6.6-7.5
7.6-8.5
Birthweight (lbs)
8.6-9.5
1
>9.5

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

www.marchofdimes.com/peristats

15
10
Preterm Birth Rates
United States, 1983, 1993, 2003
Percent
12.3
11.0
9.6
7.6
5
0
1983 1993
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
2003
HP 2010
Objective

Distribution of Live Births by Gestational Age
United States, 1990 and 2001
1990
Live Births n = 4,111,396*
2001
Live Births n = 3,986,102*
Not Preterm (89.4%) Not Preterm (88.4%)
Moderately
Preterm
(8.7%)
Very
Preterm
(1.9%)
Total Preterm = 10.6%
* 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
Moderately
Preterm
(10.0%)
Very
Preterm
(1.9%)
Total Preterm = 11.9%

Distribution of Preterm Births by Gestational Age, US, 2002
(36 Weeks)
37.1
~60% of PTB
35 - 36 weeks
21.1
(35 Weeks)
(<32 Weeks)
16.2
5 (32 Weeks)
7.6
(33 Weeks)
12.9
(34 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 atrisk neonatal population.”
Wang, et al. Clinical Outcomes of Near-Term
Infants, Pediatrics (114) 372-6, 2004 .
Source: National Center for Health Statistics, 2002 natality file
Prepared by the March of Dimes Perinatal Data Center, 2004

TYPE
Spontaneous
Preterm Labor
Spontaneous
Premature Rupture of the Membranes
50%
25-30%
25-30%
Preterm
Birth
Iatrogenic
(Medical
Indication)
While this suggests distinct pathways, many of the risk factors for all 3 are similar

100
80
60
Percent
PLURALITY
Preterm and Low Birthweight Births
By Plurality, United States, 2002
Twins
58.2
92.7
Higher
Order
Twins
55.4
94.6
Higher
Order
40
20
Singleton
10.4
0
Preterm Birth
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
Singleton
6.1
Low Birthweight

25
MATERNAL AGE
Preterm Births by Maternal Age
Among Singletons, US, 1990 and 2001
Percent
23.3
21.5
20
15 13.7
13.1
10.2
10.8
8.3
9.4
8.4
9.2
9.7
10.6
11.5
12.8
10
5
0
<15 15-19 20-24 25-29
1990 2001
30-34 35-39 40+
Source: National Center for Health Statistics
Prepared by March of Dimes Perinatal Data Center, 2004

20 Percent
RACE ETHNICITY
Preterm Births by Race/Ethnicity, US, 1990 and 2001
18.9
17.6
15
12
13.2
11
11.4
10
8.5
10.8
10.1
10.3
10.6
11.9
5
0
White Black Native
American
Asian or
Pacific
Islander
1990 2001
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
Hispanic All Races/
Ethnicities

United States, 19152002
120
Rate per 1,000 live births
100
80
60
40
20
0
1915 1925 1935 1945 1955 1965 1975 1985 1995
Source: National Center for Health Statistics, final mortality data
Prepared by March of Dimes Perinatal Data Center, 2002

• Unexpected findings- most of increase due to:
– non Hispanic white
– >30 years
– married
– >high school
– onset PNC first trimester
– nonsmoker
– private insurance www.cdc.gov/mmwr

Three Leading Causes of Infant Mortality
United States, 1990 and 2002
Rate per 100,000 live births
198.1
Birth Defects
140.7
Preterm / LBW
96.5
114.4
130.3
1990
2002
SIDS
50.6
0 50
Source: National Center for Health Statistics
Prepared by March of Dimes Perinatal Data Center, 2004
100 150 200 250

Leading Cause-specific IMR and % Change
United States, 2001 and 2002
% change Cause of
Infant Death
Birth defects
Prematurity/LBW
SIDS
Maternal complications
2001 final rate
136.9
109.5
55.5
37.2
2002 prelim rate
140.7
114.4
50.6
42.9
+ 3%
+ 5%
- 8%
+15%
Rates are per 100,000 live births

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
– multifetal pregnancy
– obesity
– maternal age (<17 and >35 yrs)
– infections
– black race
– bleeding
– low SES
– anemia
– unmarried
– major stress
– previous fetal or neonatal death
– lack of social supports
– 3+ spontaneous terminations
– tobacco use
– uterine abnormalities
– illicit drug use
– incompetent cervix
– alcohol abuse
– genetic predisposition
– 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
• Alzheimer’s Disease

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
• Lactation
600 µg synthetic + food
500 µg any source

Folic Acid Knowledge and Behavior
1995 and 2004
Aware of folic acid
52
77
Knew folic acid can prevent birth defects
Knew folic acid should be taken before pregnancy
2
4
12
Take folic acid daily
24
28
40
0 10 20 30 40
Percentage of women ages 18-45
50 60 70 80 90
1995
2004

Things Women Reported Might Encourage them to Take a
Multivitamin Daily
March of Dimes Folic Acid Survey, 2003
Advised by a health care provider
Change in health
Feeling run down
Needed vitamins
Remembered to take
Someone to remind me
If pregnant
If not in pill form
9
33
4
4
4
4
4
4
0 5 10 15 20 25 30 35
Percentage of women ages 18-45 who do not take vitamins daiily

Prevent some birth defects
Prevent some cardiovascular events
Prevent osteoarthritis
Decrease risk of Alzheimer's
Lower risk of colorectal cancer
Decreases homocysteine levels
Most grain products in US are fortified with folic acid
Because grain supply is fortified with folic acid, women of childbearing age do not need folic acid supplements
True False Not Sure
OB/G FP OB/G FP OB/G FP
98% 96% 0% 0% 2% 3%
56% 70% 12% 8% 33% 23%
7% 8% 35% 50% 58% 42%
20% 32% 24% 32% 55% 36%
35% 37% 19% 27% 47% 36%
51% 70% 8% 5% 40% 25%
58%
8%
56%
5%
20%
82%
18%
82%
22%
11%
26%
13%
Q. 14 “Please tell me whether each statement is true or false, or if you are not sure.” Note: Correct responses are outlined.

When Do Physicians Recommend Multivitamins/Folic Acid?
Always Usually Occasionally Never
OB/G FP OB/G FP OB/G FP OB/G FP
Among patients who express interest in becoming pregnant
At annual GYN exams with non-pregnant women
At other types of visits by non-pregnant women, regardless of the reason for the visit
89% 78% 9% 16% 2% 4% 0% 2%
27% 21% 34% 34% 32% 41% 8% 4%
13% 9% 27% 22% 50% 60% 9% 9%
Q. 15 “In your practice, do you always, usually, occasionally, or never recommend multivitamins or folic acid supplementation:…?”

• 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

Perceived Recommended Preconceptional
Folic Acid Dose for NTD Patients
"400 micrograms"
8%
9%
OB/GYN
FP
"1 milligram"
40%
57%
"4 milligrams"
46%
16%
"5 milligrams"
4%
4%
DK/Not sure
3%
14%
0% 10% 20% 30% 40% 50% 60%
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?”
70%

ng/mL
20
Mean serum and red blood cell folate levels, before and after folic acid fortification,
NHANES women aged 15-44 years
Serum folate Red blood cell folate ng/mL
350
265.5
300
15
250
12.8
163.0
200
10
150
5.0
5
100
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

•
–
•
–
•

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)

Multiple Birth Ratios by Maternal Race
United States, 1980-2002
Ratio per 1,000 live births
40
35
30
25
20
19.3 19.7 19.9
20.3 20.3 21.0
21.6 22.0
22.4 23.0
23.3
23.9 24.4
25.2 25.7
26.1
27.4
28.6
30.0 30.7
31.1
32.0
33.0
15
10
5
0
1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
All Races White Black
Source: NCHS, final natality data, 1980-2001
Prepared by March of Dimes Perinatal Data Center, 2003

Higher-Order Multiple Birth Ratios
By Maternal Race, United States, 1980-2002
240
Ratio per 100,000 live births
200
160
120
80
40
37.0 38.2 40.3
43.3 45.1
51.2 48.3
56.2 61.0
69.2
72.8
81.4
95.5
104.2
116.2
127.5
152.6
173.6
193.5
184.9
180.5
185.6
184.0
0
19
80
19
81
19
82
19
83
19
84
19
85
19
86
19
87
19
88
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
All races White Black
Source: NCHS, final natality data, 1980-2002
Prepared by March of Dimes Perinatal Data Center, 2004

Proportion of Preterm Births by Plurality
United States, 1992 and 2002
100
Percent of preterm births
Singletons
Multiples
75
88.3
83.6
50
40% increase in the proportion of multiple preterm births from
1992 to 2002
25
11.7
0
1992
% Multiple Births 2.4%
Source: National Center for Health Statistics.
Prepared by March of Dimes Perinatal Data Center, 2004.
16.4
2002
3.3%

Total and Primary Cesarean and VBAC Rates
United States, 1989-2002

5
0
Singleton Preterm Births by Delivery Method
United States, 1990 and 2001
15
Percent
13.4
11.2
10.2
9.3
9.5
9.2
10
Vaginal VBAC
1990 2001
C-Section
Source: National Center for Health Statistics
Prepared by March of Dimes Perinatal Data Center, 2004

• 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

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 person’s immune system, increase susceptibility to infections
• Pregnancy is a time of relative immune suppression

• 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.

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

Source: SAMHSA
2002-2003 NSDUH www.oas.samhsa.gov
Substance Abuse in
Pregnant and NonPregnant Women in the US, 2002-2003

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.samhsa.gov

Past Month Cigarette Use among Women Aged 15 to 44 by Pregnancy Status, Age, and Race/Ethnicity, 2002 -2003
Source: SAMHSA
2002-2003 NSDUH www.oas.samhsa.gov

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

• 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

LBW (<2500 g) and PTD (<37 wks) by Smoking Status and by Race/Ethnicity, CT, 1998
25
20
15
10
12
Percent
17.7
13.1
17.8
8.7
5.9
5
11.7
8.6
23.1
13.3
19.3
11.9
0
White
NonHisp
Black
NonHisp
Low Birthweight
Hispanic
Yes No
White
NonHisp
Black
NonHisp
Preterm
Hispanic
Prepared of PDC, MOD
Source: Connecticut Dept of Public Health, OPPE

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 (RR=1.4-1.6)
– Risk increases with increased amount smoked
• Smoking during and after pregnancy increases risk for
SIDS by 3-fold

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

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

• 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.

• 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

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

Chromosomal Instability in Amniocytes from 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.

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, 171:1032-9, 2005.

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).

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. BMJ:328, 977-83, 2004. bmj.com

• 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

Smoking Cessation and Preterm Birth
(Cochrane Review)
• 64 trials (51 RCTs of 20,931 women) and 6 clusterrandomised 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.

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 Clinician’s Guide to Helping Pregnant Women Quit Smoking http://iml.dartmouth.edu/education/cme/Smoking

• 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)

Common Reasons why Providers Don’t
Promote Behavioral Interventions
• Don’t believe it works
• Not enough time
• No reimbursement
• No system in place for implementation

http://iml.dartmouth.edu/education/cme/Smoking

Brain of healthy baby Brain of baby with FAS

35
LBW (<2500 g) and PTD (<37 wks) by Alcohol Use and by Maternal Race/Ethnicity, CT, 1998
Percent
32.8
29.2
29.4
30
25
23.3
20
16.7
14
15
10
13.1
13.3
12.5
6.4
9.3
8.8
5
0
White
NonHisp
Black
NonHisp
Hispanic White
NonHisp
Black
NonHisp
Hispanic
Low Birthweight Yes No Preterm
Prepared of PDC, MOD
Source: Connecticut Dept of Public Health, OPPE

Effects of Alcohol on Pregnancy
Fetal Alcohol Spectrum Disorder (FASD)
• Miscarriage
• Preterm birth
• Low birth weight
• FAS
• ARBD - Alcohol-Related Birth Defects
• ARND - Alcohol-Related
Neurodevelopmental Disorders
• Birth complications

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.

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 provider’s advice

• 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

• Have you used drugs or alcohol during this
P regnancy
• Have you had a problem with drugs or alcohol in the P ast?
• Does your P artner have a problem with drugs or alcohol?
• Do you consider one of your P arents to be an addict or alcoholic?
• + In the month before you knew you were pregnant how many cigarettes did you smoke?

• 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

Effects of Domestic Violence on
Preterm 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, p<.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.

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.

Sexually Transmitted infections Categories
New York and US, 2002
Sexually transmitted infections are risk factors for adverse perinatal outcomes such as miscarriage, ectopic pregnancy, stillbirth, preterm delivery, birth defects, newborn illness and death.
While prenatal screening for STIs is important, preconception and interconception screening and treatment are also important to reducing the impact of recurrent infections on birth outcomes.
ACOG/CDC HIV Guidelines

• Spontaneous abortion
• Ectopic pregnancy
• PID
• Infertility
• Preterm delivery
• PROM
• Puerperal sepsis
• Postpartum infection
• Wound and pelvic infections after c section
• Postpartum endometrosis
• Neurosyphilis
• Disseminated gonococcal infection (DGI)
• Septic tertiary syphilis
• Cervical cancer
• Vulvar cancer
• Vaginal cancer
• Anal cancer
• Liver cancer
• Kaposis’s sarcoma
• T cell leukemia
• Body cavity lymphoma
• Chronic liver disease, cirrhosis

• 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

• 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
40
30
20
10
0
10.5
Preterm Births by Prenatal Care and Race/Ethnicity, US, 2001
16.8
11 10.8
16.1
10.7
25.8
36.7
Early care Late care
White Black Hispanic
No care
22.9

• 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

• 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

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

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

Activation of
Maternal/Fetal HPA
Axis
• Maternal-Fetal
Stress
•Premature Onset of Physiologic
Initiators
Inflammation
• Infection:
- Chorion-Decidual
- Systemic
CRH
E1-E3
CYP1A1
GSTT1
Decidual
Hemorrhage
Abruption
Pathological
Uterine
Distention
Interleukins
TNFα
Fas L
Chorion
Decidua
Prothrombin G20210A
Factor V Leiden
Protein C, Protein S
Type 1 Plasminogen
MTHFR
Gap jct
IL-8
PGE2
Oxytocin recep
+
CRH
• Multifetal Pregnancy
• Polyhydramnios
• Uterine abnormalities
Mechanical stretch
Susceptibility to environmental toxins proteases
+ MMPs 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)

Common Complex Disorder

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

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 Epidemiology
Proteomics, Metabolomics www.marchofdimes.com/gyponline www.cdc.gov/genomics genome.gov

• 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

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

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 112:173-181, 2005.

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)

“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)

• “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.

“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.

• 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

• 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

• 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. 348:2379-85, 2003.
– Brazil, da Fonesca
•  by 50%+
• daFonesca, et al. AJOG. 188(2):419-24, 2003.

Use of Progesterone to Reduce Preterm Birth
ACOG 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 <34 wks, SMFM 2005

• If all eligibles had received 17P therapy, nearly
10,000 spontaneous PTB out of about 480,000
PTB’s would have been prevented in 2002
• Nationally, the PTB rate would have been reduced by about 2% from 12.1% to 11.8% (p<0.001).
Petrini J, et al. Obstet Gynecol, Feb 2005

Early
Intervention
Primary Care for Children
Prenatal
Care
Age 0 5
Primary Care for Women
Prenatal
Care
Internatal
Care
Poor Birth Outcome
Puberty Pregnancy
White
African
American

• 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

• 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

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%

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

www.marchofdimes.com
Pregnancy and Newborn Health Education Center askus@marchofdimes.com

The answers can’t come soon enough

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@marchofdimes.com
www.marchofdimes.com
Thank you for your attention www.jjpi.com