Recent Advances in the Prevention of Preterm Birth

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Recent Advances in the Prevention of Preterm Birth

• M. Sean Esplin, M.D.
• University of Utah
• Division of Maternal-Fetal Medicine

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Statistics

• Leading cause of long term morbidity
• Learning disabilities, seizures, MR, CP
• Costly
• 20,000-100,000 average NICU Cost
• 500,000 per child lifetime cost

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Epidemiology of Preterm Birth

• Twelve-plus percent of all births
• estimated 500,000 in US in 2005
• At least 75 of all neonatal deaths of otherwise
  normal babies.
• 70-80 are spontaneous. 20-30 are indicated.

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In an Average Week in the U. S.

• 78,058 babies are born
• 8,985 babies are born preterm
• 538 babies will die before their first birthday
• In 2001 476,000 babies were born preterm

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Preterm babies in 2001

• Prematurity related infant stays resulted in
  costs of 13,200,000,000
• The average hospital charge was 35,000 per baby
• The average length of stay was 13 days

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Comparative Costs

• Infants born at 25-27 weeks cost 28 times the
  cost of those born at 39-42 weeks gestation
• 280,146 vs. 9,803

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Utah Prematurity Rates

• Overall 2002 prematurity rate 10.5
• (N 5,152)
• An increase of 42 from 1991 (7.7)
• (N 3,219)
• Represent 80 of neonatal deaths in Utah
• Associated with decreasing maternal age and
  education, non-married status and lower income.

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Utah Prematurity Costs (43,002 live births in
1997)

• Total Avg Cost Avg. Stay
• Term 39,525 866 1.5 d
• (34,228,650) (59,287 d)
• All Preterm 3,477 17,995 12.5 d
• (62,568,615) (43,462 d)
• lt 28 Weeks 278 65,907 29.3 d
• (18,322,146) (8145 d)

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Survival According to Gestational Age
30
25
20
Survival,
Distribution of Births,
15
10
5
0
Gestational Age (weeks)
St John Am J Obstet Gynecol. 2000
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Neonatal Survival Rates
100
80
60
Survival Rate ()
40
20
0
23
25
27
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Weeks Gestation
Bottoms et al. Am J Ob Gyn 1999
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Short Term Outcomes in VLBW Infants (BW lt 1500
gms)
Outcome
Affected
BPD
23
25
Apnea
PDA
30
IVH
32
Severe IVH
11
NEC
10
25
Sepsis
66
ROP
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Long-term Outcomes of VLBW Infants

• Comparison of Infants delivered between 1977-1979
• VLBW group
• N242
• Mean Birth Weight 1179 gms
• Mean GA at del 29.7
• Controls
• N233
• Evaluated at age 20

Bhutta AT et al. JAMA 2002 Aug 14
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Long-term Outcomes in VLBW Infants (BW lt 1500 gms)
Outcome
VLBW
CTL
87
92
Mean IQ
74
83
HS Graduation
Neurosensory impairment
10
lt1
10
5
Short Stature
Bhutta AT et al. JAMA 2002 Aug 14
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If you cant do something well, learn to enjoy
doing it poorly
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True Endpoints of Efficacy

• Reduced short-term or Long-term morbidity or
  mortality
• Reduced healthcare cost

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Surrogate End Points for Efficacy

• Delay in delivery
• Increased birth weight
• Need for additional therapy

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The secret to success is knowing who to blame for
your failures.
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Does anything really prevent preterm birth?
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Prevention Strategies

• Primary Prevention
• Provide prenatal care to general popuation to
  prevent disease
• Secondary Prevention
• Provide care for high-risk patients who do not
  have symptoms of active disease
• Tertiary Prevention
• Treatment of patients after the onset of symptoms

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ProgesteroneThe new (old) option

• 5 Studies performed between 1964 and 1985
• 3 positive effect
• 2 negative effect
• Studies were limited by small numbers and
  contradictory findings

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ProgesteroneThe new (old) option

• Meta-analysis (1989) 15 randomized controlled
  trials
• 1953-1985
• 819
• Multiple types of progestins
• No significant reduction in rates of preterm birth

Goldstein P.. BJOG 1989 96265
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ProgesteroneThe new (old) option

• Meta-analysis (1990) 7 randomized controlled
  trials (1964-1985)
• Only 17 alpha Hydroxyprogesterone
• Women enrolled for either risk of recurrent SAB
  or previous PTB

Keirse MJ. BJOG 1990 Feb97(2)149
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ProgesteroneThe new (old) option

• Meta-analysis (1990) 7 randomized controlled
  trials (1964-1985)
• Reduction in rates of preterm birth. Odds ratio
  was 0.50, 95 CI 0.30-0.85
• Reduction in rates of low birthweight, Odds ratio
  was 0.46, 95 CI 0.27-0.80
• No difference in neonatal morbidity and mortality

Keirse MJ. BJOG 1990 Feb97(2)149
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17 alpha Hydroxyprogesterone

• Naturally produced in the corpus luteum and
  adrenal glands
• Weaker than natural progesterone
• More sustained duration of action

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ProgesteroneThe new (old) option

• Why would this work?
• Progesterone decreases the inflammatory response
• Potent smooth muscle relaxant
• Blocks the effect of prostaglandin-F2? and
  oxytocin
• Some suggest there is a decrease in the
  progesterone to estrogen ratio at time of
  delivery

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Actions of Progesterone on the Myometrium

• Decreases conduction of contractions
• Increases threshold for stimulation
• Decreases spontaneous activity
• Decreases number of oxytocin receptors
• Prevents formation of gap junctions

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ProgesteroneThe new (old) option

• Prospective, randomized trial by MFMU network
• Inclusion criteria
• Previous delivery lt37 weeks
• Singleton pregnancy between 18 and 20 weeks
• No previous progesterone treatment
• No heparin, cerclage, HTN, seizures

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Prevention of Preterm Birth with17-alpha
Hydroxyprogesterone

• 2980 potentially eligible women screened
• 1035 found eligible 533 refused to consent and
  43 declined trial after trial injection
• 463 consented and randomized

Meis et al and MFM Units Network, 2003
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ProgesteroneThe new answer?

• 463 patients enrolled in the study
• 310 in treatment arm
• 153 in control arm
• 17-? Hydroxyprogesterone caproate im Q wk between
  20 and 36 weeks gestation

Meis et al and MFM Units Network, 2003
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Prevention of Preterm Birth with17-alpha
Hydroxyprogesterone

• Multicenter RCT
• 17-alpha OHP in castor oil or placebo of castor
  oil
• Inclusion criteria
• History of spontaneous PTB lt37 weeks in a
  previous pregnancy
• Current GA 15-20 weeks

Meis et al and MFM Units Network, 2003
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Prevention of Preterm Birth with17-alpha
Hydroxyprogesterone

• Primary outcome PTBlt37 weeks
• Secondary outcomes
• PTB at other GAs
• Birth weight
• Neonatal course characteristics
• Pregnancy complications

Meis et al and MFM Units Network, 2003
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Progesterone TrialPatient Characteristics
Treatment (n310)
Control (n153)
GA of Prev PTD
30.5 weeks
31.2 weeks
GA at Random
18.4 weeks
18.4 weeks
Mat Age
26.0 years
26.5 years
BMI
26.9
25.9
Meis et al and MFM Units Network, 2003
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Prevention of Preterm Birth with17-alpha
Hydroxyprogesterone
17-?OHP N306
Placebo N153
RR (95 CI)
Outcome
Meis et al and MFM Units Network, 2003
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Prevention of Preterm Birth with17-alpha
Hydroxyprogesterone
17-?OHP N306
Placebo N153
RR (95 CI)
Outcome
Meis et al and MFM Units Network, 2003
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Prevention of Preterm Birth with17-alpha
Hydroxyprogesterone
17-?OHP N306
Placebo N153
RR (95 CI)
Outcome
Meis et al and MFM Units Network, 2003
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Prevention of Preterm Birth withVaginal
Progesterone

• RCT in single SA center
• Vaginal P suppository or placebo
• Inclusion criteria
• History of spontaneous PTB lt37 weeks in a
  previous pregnancy
• Prophylactic cerclage
• Uterine malformation

da Fonseca et al, Am J Obstet Gynecol
2003188419-24
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Prevention of Preterm Birth withVaginal
Progesterone

• Exclusion criteria
• Multiple gestation
• Known fetal anomaly

da Fonseca et al, Am J Obstet Gynecol
2003188419-24
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Prevention of Preterm Birth withVaginal
Progesterone

• Study design
• GA confirmed by US X 2
• All patients screened for infection and, if
  positive, treated
• Treatment placebo
• 100 mg P in vaginal suppository
• Identical-looking placebo suppository
• Nightly from 24 to 34 weeks

da Fonseca et al, Am J Obstet Gynecol
2003188419-24
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Prevention of Preterm Birth withVaginal
Progesterone

• Primary outcome PTBlt37 weeks
• Secondary outcomes
• Frequency of UCs (weekly)
• Admissions for symptomatic UCs

da Fonseca et al, Am J Obstet Gynecol
2003188419-24
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Prevention of Preterm Birth withVaginal
Progesterone

• No mention of eligible patients seen or contacted
• 157 women randomized
• 15 women lost to follow-up or withdrew
• 142 women completed study
• 72 in P group
• 70 in placebo

da Fonseca et al, Am J Obstet Gynecol
2003188419-24
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Prevention of Preterm Birth withVaginal
Progesterone

• Subjects in treatment and control arms did not
  differ with regard to
• Mean GA at randomization
• Infection
• Mean age
• Risk factors for PTB
• Obstetric history
• Ethnicity
• Educational level
• Socioeconomic status

da Fonseca et al, Am J Obstet Gynecol
2003188419-24
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Prevention of Preterm Birth withVaginal
Progesterone
Vaginal P N72
Placebo N70
Outcome
P value
PTB lt37 wks
13.8
28.5
PTB lt34 wks
2.8
18.6
Adm for PT UCs
19.4
31.4
da Fonseca et al, Am J Obstet Gynecol
2003188419-24
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Comparison of Dosing
Obstet Gynecol, 2000. 95(3) p. 403-6 Am J
Obstet Gynecol, 1999. 180((6 Pt 1)) p. 1480-3.
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Comparison of Efficacy
Note These values are calculated and not in the
original manuscript
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Acceptance of Treatments
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Comparison of Morbidity
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Are there any other options?
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Omega Fatty Acids

• Arachadonic acid derived eicosanoids (Omega-6)
• Favor pro-inflammatory cytokines
• Associated with septic shock and chronic
  inflammatory disease
• Omega-3 polyunsaturated fatty acids (PUFAs),
  ecosapentaenoic acid (EPA), and docosahexanoic
  acid (DHA)
• Supress pro-inflammatory cytokines

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Treatment?-3 Fatty Acids

• Minimum of 1.2 gm/d of eicosapentanoic acid and
  docosahexaenoic acid for 6 wks
• Reduced monocyte, lymphocyte and neutrophil
  function
• Decreased IL-1, IL-2, IL-6, TNF-alpha
• Have been used to treat inflammatory and
  autoimmune diseases

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Treatment?-3 Fatty Acids

• Decreased in patients with PTD
• May play an competitive inhibitory role on the
  synthesis of eicosanoids and arachadonic acid
  (prostaglandin, leukotriene and thromboxane)

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Omega 3 Fatty Acids and Preterm Birth

• Multi-center European randomized, controlled
  trial
• 898 women at high risk of preeclampsia or preterm
  birth
• Enrolled at 20 weeks gestation
• Preterm birth was reduced by 50
• OR 0.54, 95 C.I. 0.3-0.98

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Omega 3 Fatty Acid Supplementation

• MFMU network trial
• Prospective, controlled trial of Omega 3
  supplementation in addition to progesterone

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Conclusions

• Promises
• 17-alpha OHP or vaginal P may
• Reduce the rate of PTD by 30-50
• Reduce the rates of neonatal complications by 50
  or more
• Save a ton of money in obstetrical/neonatal care

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Conclusions

• Problems
• 17-alpha OHP study
• The rate of failed enrollment was high (gt50)
• The rate of PTD in the control group was high
  (55)
• No long-term follow-up of infants available
• Vaginal P study
• Design not as rigorous as the 17-alpha OHP study
• No mention of relevant secondary outcomes
• No long-term follow-up of infants available
• PTD is multifactorial no treatment will likely
  work the same in all populations
• Multifetal gestation

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Conclusions

• Optimal dosing and route of administration remain
  unclear
• Addition of Omega 3 fatty acid may improve
  outcomes
• Patients with a history of preterm birth should
  be offered a chance to participate in current
  studies

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Quitters never win and winners never quit But
those who never win and never quit are idiots.