Endocrinology of Parturition Prof. Errol R. Norwitz

Endocrinology of Parturition

Prof. Errol R. Norwitz

The screen versions of these slides have full details of copyright and acknowledgements 1

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Errol R. Norwitz, M.D., Ph.D.

Dept. of Obstetrics, Gynecology & Reprod. Sciences

Yale University School of Medicine


. .

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• Understand the molecular mechanisms

responsible for onset of labor at term

• Appreciate why these mechanisms fail leading

to preterm or post-term birth

• Discuss rationale behind interv entions designed

to prev ent and/or treat abnormalities of labor

Objectives

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• The physiological process by which products

of conception are passed from uterus to the outside

world, and is common to all v iv iparous species

• Labor is a clinical diagnosis characterized by:

� Regular painful uterine contractions

� Progressive cervical effacement and dilatation

(or an initial examination of ≥80% effacement,

or ≥ 2 cm dilatation in a null iparous patient)

What is labor?




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• The uterus undergoes a dramatic increase in weight and v olume

• The number of myometrial cells increases in early pregnancy, but thereafter remains stable

• Myometrial growth in the latter half of pregnancy results from an increase in cell size; This is accompanied by an increase in fibers, connectiv e tissue, blood v essels and lymphatics

• In the latter half of pregnancy, graduate thinning of the uterine wall occurs, forming the lower uterine segment

• The increase in size is accompanied by a 10-fold

increase in uterine blood flow; 80-90% of uterine blood flow goes to the placenta

• This increase parallels increase in placental size

and decrease in placental v ascular resistance

• In contrast to the uterus, which is made upof smooth muscle cells, the cerv ix is composed of fibrous

connectiv e tissue containing an extra cellular matrix

The reproductive tract changesin pregnancy

Corpus (body)

of the uterus

Cerv ix (neck)

of the uterus

5Term, labor

Term, no labor20 weeks

The cervix undergoes extensive remodeling during pregnancy

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“The foetus in the womb”

Leonardo Da Vinci, circa 1510

What causes labor?




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Labor timing

• In most mammalian species the fetus is in control

of the timing of labor

• Mechanical approach to labor

• Endocrine ev ents

• Paracrine/autocrine ev ents

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Species-specific obstacles to reproduction

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Uterus

Ov ary

SP-A from the fetal

lungs causes

activation and migration

of AF macrophages

into uterus leading to ↑↑↑↑ IL-1ββββ ,

NF-κB activation and labor

Condon J, et al., Proc. Natl. Acad. Sci. USA 2004, 101: 4978-83

Progesterone

Labor

X

PGF2αααα

X

*****




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cholesterol

5 -pregnenolone

17αααα -hydroxypregnenolone

Fetus Mother

dehydroandrostenedione

?

↓↓↓↓ progesterone

Membrane phospholipids

estrone

17ββββ -estradiol

17-oxido-reductase

4 -androstenedione

PLA2

AA

PGE2

PGEM

15-OH PGDH

Hypothalamus

Posteriorpituitary

OT

aromatase

3ββββ -hydroxysteroid dehydrogenase

PGE2

Placenta/fetal membranes

COX-2

Hypothalamus

Anteriorpituitary

CRH

Cortisol

↑↑↑↑ PG receptors↑↑↑↑ OT receptors↑↑↑↑ gap junctions

+

+

-

17ββββ -estradiol

Adrenalgland

ACTH

+

PGF2αααα

LABOR

Uterus

PGE2

+

↓↓↓↓

+

17αααα hydroxylase/

17,20-lyase


17,20-lyase

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• The end result is a progressiv e increase

in conj ugated estrogen in maternal plasma

during the latter part of gestation,

preceding the sharp rise

in estrogen that occurs prior to deliv ery

in response to cortisol mediated induction,

other cytochrome P450 enzyme in ruminants

and other non primate species

• It is likely that a parturition cascade exists

in humans, responsible for the remov al

of mechanisms maintaining uterine quiescence and for promoting uterine activ ity

• Giv en its teleological importance, such a cascade would likely hav e multiple

redundant loops to ensure a fail safe mechanism of securing pregnancy success

• In such a model, each element is connected to the next and many

of the elements demonstrate positiv e feed forward characteristics typical

of a cascade mechanism

• It may not be possible to identify one signaling mechanism uniquely responsible

for the initiation of labor; It may be prov en to describe

such mechanisms as being responsible for promoting labor

• Human labor is a multi factorial physiological ev ent inv olv ing an integrated set

of changes which occur gradually ov er a period of days to weeks Norwitz ER, et al., N. Engl. J. Med., 1999, 341: 660-6

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16-OH-DHEAS from fetal adrenal

Fetus Mother

dehydroandrostenedione

Hypothalamus

Anteriorpituitary

preparesorgan

systemsfor delivery

? Fetaltrigger

Cortisol

Cortisol

Cortisone

11ββββ -HSD

progesterone

Placental OT

Membrane phospholipids

cholesterol

5 -pregnenolone

17αααα -OH-pregnenolone

estrone

17β-estradiol

estriol16-hydroxylase

17-oxido-reductase

4-androstenedione

placental

sulfatase

cortisol

PLA2

AA

(PGF2a) PGE2

(PGFM) PGEM

15-OH-PGDH

Placental vasodilatation LABOR

Hypothalamus

Posteriorpituitary

OT

aromatase


17,20-desmolase

3ββββ -HSD

Adrenalgland

Liver

Placenta/fetal membranes

COX

CRH

ACTH

DHEAS

from fetalzone ofadrenal gland

↑↑↑↑ PG receptors↑↑↑↑ OT receptors↑↑↑↑ gap junctions

PGF2αααα

SROM

fromdefinitiveadrenalcortex

PGE2

? negative feedback loop

-

+

+

+

+

+

+

+

+

Positivefeedback

loop

16-OH-DHEAS to placenta/ fetal membranes

+

placental CRH

• It is fetal 16-hydroxy-DHEAS that serves as a substrate for estrogen production in the human placenta and not progesterone as in other animal species

• This explains why there is no systemic withdrawal of progesterone levels prior to the onset of labor in humans

• Indeed, levels of progesterone measured in the maternal circulation one week prior to the onset of labor is similar to that during labor

• However, circulating progesterone levels are not an accurate reflection

of progesterone activity at the level of the uterus and there is mounting evidence to suggest that withdrawal of progesterone activity at the level of the uterus is a prerequisite for parturition in the human

• This is supported by evidence showing that the administration of a progesterone receptor antagonist at term leads to increased

uterine activity and cervical ripening

• Moreover, antenatal supplementation with progesterone from a 16 to 20 weeks gestation through 34-36 weeks has been shown to reduce the rate of preterm birth in some women at high risk

• Regardless of whether the trigger for parturition begins with the fetus or the placenta, it ends in the tissues of the maternal uterus, leading

to regular phasic uterine contraction and cervical effacement and dilatation




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Cardinalmovements

A. Before engagement

H. Posterior shoulder delivery

F. Restitution

D. Complete rotation, early extension

B. Engagement, flexion, descent

C. Descent, rotation

E. Complete extension

G. Anterior shoulder delivery

Cardinal movements




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Is there a genetic predisposition for PTB?

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Indirect evidence

• Horse-donkey crossbreeding studies show

intermediate gestational length

Liggins GC, Biol. Neonate 1989, 55: 366-94

• Familial clustering of PTB

� PGDH deficiency may account for 15% of PTB

Iams J, et al., Am. J. Obstet. Gynecol. 1998, 178: 1035-40

Winkvist A, et al., Int. J. Epidemiol. 1998, 27: 248-54

Challis JR, et al., J. Perinat. Med. 1999, 27: 26-34

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• Racial predisposition to PTB

� 2- to 4-fold ↑↑↑↑ risk in African-American women

� Disproportionate ↑↑↑↑ risk of PTB < 28 weeks

in African-American women

Indirect evidence (cont.)

Blackmore CA, et al., Ethn. Dis.1993, 3: 372-5

Carmichael SL, et al., Matern. Child Health J. 1998, 2: 67-70

Ekwo E, Moawad A., Assoc. Acad. Minor. Phys. 1998, 9: 16-21

Blackmore C, et al., Matern. Child Health J. 1999, 3: 189-93

Ventura SJ, Bachrach CA, Natl. Vital Stat. Rep. 2000, 48: 1-5




19National Center for Health Statistics; March of Dimes, 2001

• PTB in the U.S. is highest for African-Americans

>> Nativ e Americans > Hispanics > Whites, Asians

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• High rate of recurrent PTB

� If the first delivery was at 20-31 weeks,

the risk of a similar recurrent PTB was 13.4%

(African-American) and 8.2% (Caucasian)

� If the first delivery was at 32-36 weeks,

the risk of a similar recurrent PTB was 3.8%

(African-American) and 1.9% (Caucasian)


Turnbull AC, Obstetrics, 1989, pp. 189-204

Iams J, et al., Am. J. Obstet. Gynecol. 1998, 178: 1035-40

Ekwo E, et al., Assoc. Acad. Minor. Phys. 1998, 9: 16-21

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• Twin studies of pregnancy outcomes suggest

the heritability of PTB to be around 17-36%


Treloar SA, et al., Tw in Res. 2000, 3: 80-2

Claussen B, et al., Br. J. Obstet. Gynaecol. 2000, 107: 375-381

Crider KS, et al., Genet. Med. 2005, 7(9): 593-604

Svensson AS, et al., Am. J. Obstet. Gynecol. 2006, 194: 475-9




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Unlikely to be an example of simple Mendelian genetics

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Complex genetic model

• Primarily a single gene disorder

� Variable penetrance of the gene

� Genetic background (gene-gene interactions)

� Gene-environment interactions

• Multiple genes inv olv ed

• Epigenetic factors

� DNA methylation/histone acetylation

� siRNA

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Gene-environment interaction and PTB

• A disproportionate ↑↑↑↑ in IL-1ββββ ov er IL-1ra

in v aginal secretions of pregnant women

with altered v aginal microflora is assoc with PTB

Genç MR, et al., Am. J. Obstet. Gynecol. 2004, 190: 1191- 7

• Maternal carriers of SNP in intron 2 of IL-1ra

is assoc. with ↓↓↓↓ pro-inflammatory IL-1ββββ response

to abnormal v aginal flora and ↓↓↓↓ rate of spont. PTB

(6% vs. 18%, P = 0.02)

Genç MR, et al., Am. J. Obstet. Gynecol. 2004, 191: 1324-30




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• Also ↓↓↓↓ spontaneous PTB rate with maternal carriage

of 896 A>G SNP in TLR4 gene

� Maternal carriers have ↑↑↑↑ in vaginal pH, 10-fold ↑↑↑↑

in Gardnerella vaginalis and gram negative rods,

and an alteration in vaginal IL-1ββββ and IL-1ra levels

Gene-environment interaction and PTB (cont.)

Genç MR, et al., Eur. J. Obstet. Gynecol. Reprod. Biol. 2004, 116: 152-6

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• Maternal carriers of -308 G>A SNP in TNFαααα promoter

are assoc. with ↑↑↑↑ risk of PTB (OR, 2.7; 95% CI,

1.7-4.5), which was further ↑↑↑↑ in presence of BV

(OR, 6.1; 95% CI, 1.9-21.0)

Genç MR, et al., Eur. J. Obstet. Gynecol. Reprod. Biol. 2004, 116: 152-6

Macones G, et al., Am. J. Obstet. Gynecol. 2004, 190: 1504-8

• Kand in African-American women (OR = 17)

Nguyen DP, et al., Obstet. Gynecol. 2004, 104: 293-300

Gene-environment interaction and PTB (cont.)

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When labor goes right

Photo by Diane Arbus

When labor goes wrong




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Preterm birth

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Why all the fuss?

• Preterm birth complicates 8-12% of all deliv eries

• Leading cause of perinatal mortality and morbidity

• There has been no decrease in the incidence

of preterm birth ov er the past 30 years

30March of Dimes Perinatal Data Center, 2006; www.marchofdimes.com

0

2

4

6

8

10

12

14

1990 1992 1994 1996 1998 2000 2002

Percent of all births

2004

Preterm birth < 28 weeks’ gestation < 34 weeks < 37 weeks

10.6%10.8%10.7% 11.0%11.0%11.0%11.0%11.4%11.6%11.8%11.6%11.9%12.1%

12.5%12.9%

Preterm births, 1990-2004




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Preterm births

for maternal

or fetal indication

- Diabetes

- IUGR

- Preeclamp sia

- Placenta previa

- Placental abruption

Tucker JM, et al., Obstet. Gynecol. 1991, 77: 343-7

20%

Preterm birth is a syndrome

• Preterm PROM

• Intra-amniotic

infection

• Idiopathic preterm labor

30%

30%

20%

Spontaneous Iatrogenic

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Intrauterine infection/

inflammation

Preterm labor

Maternal

and/or

fetal stress

Excessiv e uterine

stretch

Hemorrhage

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• Prior preterm birth

• African-American race

• Age < 18 or > 40 years

• Poor nutrition

• Anemia

• Low pre-pregnancy weight

• Low socioeconomic status

• Absent prenatal care

• Bacteriuria or UTI

• Genital/gingival infection

• Cigarette smoking

• Illicit drug use

• Cervical injury or anomaly

• Uterine anomaly or fibroids

• Excessive uterine activity

• Premature cervical dilatation

• Overdistended uterus (twins)

• ? Vaginal bleeding

• ?? Strenuous work

• ?? High personal stress

Risk factors




34

+

+

35Iams JD, et al., N. Engl. J. Med. 1996, 334: 567-72

(n=

2915)

50%le (35 mm)

10%le (25 mm)

90%le (45 mm)

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Markers

• Activin/Inhibin

• Follistatin

• Ferritin

• CRP

• Interleukin-6

• CRH

• Progesterone

• Estrogens

• Metalloproteinases

• Collagenase

• Relaxin

• Fibronectin

Source

• Blood

• Serum

• Saliva

• Amniotic fluid

• Vagina

• Cervix

Biochemical/endocrine markers




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Fetal fibronectin (fFN)

Amnion

Chorion

Fetalfibronectin

Decidua

38Goldenberg RL, et al., Am. J. Public Health 1998, 88: 233-8

1 2 3 4 5 6 7 8 9 1011 12 131415 1617 1819 20 21

Positive fFN

Cervical length < 25 mm

Previous SPTB

BMI < 19.8

Vaginal bleeding

Bacterial vaginosis

Pelvic infection

Black race

RR of spont PTB < 32 weeks

Ris

k f

acto

rs

Contractions

Screening for preterm birth

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Effective strategies for prevention of preterm birth

• Prev ention of multifetal pregnancies

• Cerv ical cerclage, if indicated

• Early diagnosis and treatment

of genitourinary infections and STDs

• Stop smoking and substance abuse

• Progesterone supplementation (?)




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Preventive strategies without proven benefit

• Intensiv e prenatal care

• Bed rest, flexible workforce policies

• Screening asymptomatic women

for genital tract/gingiv al infections

• Broad-spectrum antibiotics

• Uterine tocolytic therapy (?)

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Post-term pregnancy




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2

4

6

8

%

of

all

deli

veri

es

EDC

Term

Post-term

(prolonged)

Gestational age (weeks)

10% (range, 3-14%)

4%(range, 2 7%)

What is the definitionof post-term pregnancy?

0

38 40 42 44

-

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Accurate dating

• Menstrual history is often inaccurate

� Especially if irregular cycles, on hormonal

contraception, or intermenstrual bleeding

• Routine early ultrasound will ↓↓↓↓ incidence

of post-term pregnancy from 10% to 1.5-5%

� Not currently recommended in the U.S.

Warsof SL, et al., Clin. Obstet. Gynecol. 1983, 10: 445-7

Bennett K, et al., Am. J. Obstet. Gynecol. 2004, 190: 1077-81

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Can we identify parturients at risk

of post-term pregnancy?

• Risk factors for post-term pregnancy ...

� Primiparity

� Prior post-term pregnancy

� Fetal anencephaly (without polyhydramnios)

� Congenital adrenal hypoplasia (CAH)

� Placental sulfatase deficiency (rare)

� Male fetus

• The majority of post-term pregnancies

hav e no known cause




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• Perinatal death

(stillbirth)

• Fetal macrosomia

• Meconium

• “Fetal distress”

• Uteroplacental

insufficiency

4- fold ↑↑↑↑ at 43 wks and 5

to 7- fold ↑↑↑↑ at 44 wks (vs. 40 wks)

2.5- 10% (vs. 0.8-1% at 40 wks)

30- 38% (vs. 17% at 40 wks)

8% (vs. 5% at term)

20- 40%

Risks to the fetus

Complication Incidence

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“Antepartum fetal deaths

perinatal deathsmoreaccount for

than do complications

of prematurity

or sudden infant death syndrome (SIDS)”

Cotzias CS, et al., Br. Med. J. 1999, 319: 287-8

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Hilder L, et al., Br. J. Obstet. Gynaecol. 1998, 105: 169-73

Rand L, et al., Obstet. Gynecol. 2000, 96: 779-83

Smith GCS, Am. J. Obstet. Gynecol. 2001, 184: 489-96

Stillbirth

Infant mortality

Stillbirth

Infant mortality

PNMR per 1,000 liv e births PNMR per 1,000 ongoing pregnancies




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Also increased risk of perinatal morbidity

• Post-term pregnancy is a risk factor for:

�Apgar score < 4 at 5 min (OR 3.6; 95% CI, 1.5-8.7)

�Neonatal convulsions(OR 3.4; 95% CI, 1.5-7.6)

�Meconium aspiration (OR 3.0; 95% CI, 2.6-3.7)

Clausson B, et al., Obstet. Gynecol. 1999, 94: 758-62

• Also an independent risk factor for newborn

encephalopathy (OR 13.2; 95% CI, 5.03-34.83)

Badawi N, et al., Br. Med. J. 1998, 317: 1549-53

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• The timing of labor and birth is a critical

determinant of perinatal outcome

• The factors responsible for the onset of labor

at term remain poorly understood

• A better understanding of the factors responsible

for labor will improv e our ability to manage

abnormalities of labor

Conclusions

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“Children are one third of our population and all of our future”

Select Panel for the Promotion of Child Health

U.S. Dept of Health and Human Services

W ashington, DC, 1981




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Endocrinology of Parturition Prof. Errol R. Norwitz

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