預防早產新觀念
Prevention of preterm parturition
2014.04.26
高雄長庚婦產部
產科主任 蔡慶璋
Introduction
• Preterm birth refers to a delivery that occurs before
370/7ths weeks of gestation
• 12% of births in USA
• 20 % of preterm deliveries are iatrogenic; performed
due to medical or obstetrical complications that are
believed to put the health of the mother or fetus in
jeopardy (eg, intrauterine growth restriction,
preeclampsia, placenta previa, nonreassuring antenatal
fetal testing).
• 80 % preterm deliveries are spontaneous, related to
preterm labor or preterm premature rupture of the
membranes.
Classification — Subtypes of preterm birth
By gestational age :
• Moderate preterm: 32 to <37 weeks
Late preterm: 340/7ths to 366/7ths weeks
• Very preterm: 28 to <32 weeks
• Extremely preterm: <28 weeks
By birth weight :
• Low birth weight (LBW): <2500 grams
• Very low birth weight (VLBW): <1500 grams
• Extremely low birth weight (ELBW): <1000 grams
Pathogenesis of spontaneous preterm birth
•
Activation of the maternal or fetal hypothalamicpituitary-adrenal axis associated with either
maternal anxiety and depression or fetal stress
• Infection : Some organisms
eg, Pseudomonas, Staphylococcus, Streptococcus,
Bacteroides, and Enterobacter) produce proteases,
collagenases, and elastases that can degrade the
fetal membranes. Bacteria also produce
phospholipase A2 (which leads to prostaglandin
synthesis) and endotoxin, substances that stimulate
uterine contractions and can cause PTL
• Decidual hemorrhage: damaged decidual blood
vessels and presents clinically as vaginal bleeding or
retroplacental hematoma formation
• Pathological uterine distention
Multiple gestation, polyhydramnios,
• Pathologic cervical change
Cervical insufficiency
Significance — Preterm birth
• the leading direct cause of neonatal death
(death in the first 28 days of life).
• It is responsible for 27 %of neonatal deaths
worldwide
• The risk of neonatal mortality decreases as
gestational age at birth increases( figure)
• The burden of preterm birth includes
neonatal morbidity and long-term sequelae,
including neurodevelopmental deficits (eg,
cerebral palsy, impaired learning, visual
disorders) and an increased risk of a
spectrum of diseases in adulthood
• In addition, preterm birth is the second
most common cause of-death (after
pneumonia) in children younger than 5
years
UNPROVEN INTERVENTIONS
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Diagnosis and treatment of genital tract infection
Treatment of periodontal disease
Weight management
Assessment of uterine activity
Bed rest and hospitalization
Abstinence
Prophylactic tocolytic drugs
Enhanced prenatal care
Social support and relaxation therapy
Thyroid hormone
POTENTIALLY EFFECTIVE
INTERVENTIONS
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Supplemental progesterone
Inhibition of acute preterm labor
Diagnosis and treatment of asymptomatic bacteriuria
Smoking cessation
Avoidance of cocaine
Decrease the rate of multiple gestation from ART
Cervical cerclage
Pessary
Reduce occupational fatigue
Nutritional intervention
Avoiding a short interpregnancy interval
Avoidance or treatment of malaria
Ultrasound Assessment of
The Cervix
NORMAL CERVICAL LENGTH
• Cervical length measurements before 15 weeks of
gestation have no clinical value
• Cervical length normally declines slightly between
20 and 32 weeks, and more substantially after 32
weeks.
• The median cervical length is
40 mm before 22 weeks,
35 mm at 22 to 32 weeks,
30 mm after 32 weeks.
• Cervical length is not significantly affected by parity.
TECHNIQUE
• Transvaginal ultrasound is the most
reproducible technique for cervical
assessment.
• Transabdominal images of the cervix are less
reproducible; thus, they should not be used
for clinical management
Procedure
• The maternal bladder is emptied prior to initiating the
examination.
• The cervix is often easier to locate sonographically if a digital
examination is performed before the procedure, as gel from the
examiner's glove left in the cervical canal makes the external os
more echogenic.
• the transducer is gently placed in the anterior fornix until the
cervix is visualized.
• The image is enlarged to fill at least one-half of the ultrasound
screen
• the anterior and posterior lips of the cervix are of equal thickness
• It is the distance between calipers placed at the notches made by
the internal os and external os
• three measurements have been obtained that satisfy
measurement criteria and vary by less than 10 percent, the
shortest of these is chosen and recorded as the "shortest best."
預防早產的利器
• 黃體素
• 子宮頸環紮手術
Progesterone supplementation to reduce
the risk of spontaneous preterm birth
ROLE OF PROGESTERONE IN
PREGNANCY MAINTENANCE
• Progesterone is a steroid hormone initially produced by the corpus luteum.
Early pregnancy
•
It is critical for the maintenance of early pregnancy until the placenta takes over this function at 7
to 9 weeks of gestation
•
pro-gestational steroidal ketone. Indeed, removal of the source of progesterone (the corpus
luteum) or administration of a progesterone receptor antagonist readily induces abortion before 7
weeks (49 days) of gestation.
Late pregnancy
• The role of progesterone later in pregnancy less clear.
• important in maintaining uterine quiescence in the latter half of pregnancy, possibly by limiting the
production of stimulatory prostaglandins and inhibiting the expression of contraction-associated
protein genes within the myometrium, including ion channels, oxytocin and prostaglandin
receptors, and gap junctions .
• Although levels of progesterone in the maternal circulation do not change significantly in the
weeks preceding labor, the onset of labor both at term and preterm is associated with a functional
withdrawal of progesterone activity at the level of the uterus
• Progesterone has been shown to prevent apoptosis in fetal membrane explants, under both basal
and pro-inflammatory conditions . This may help to prevent preterm premature rupture of
membranes (PPROM), which is a common cause of preterm birth.
PROGESTERONE PREPARATIONS,
ROUTES, AND DOSES
• Oral progesterone — An oral micronized
preparation of natural. Daily doses of 900 to 1600
mg have been given. Reported side effects include
sleepiness, fatigue and headache
• Vaginal progesterone preparations —
100 mg micronized progesterone vaginal tablet or an 8
%vaginal gel containing 90 mg micronized progesterone per
dose (crinone) .
The advantage of vaginal progesterone is its high uterine
bioavailability. It also has few systemic side effects, but
vaginal irritation can be bothersome and the drug needs to
be administered daily. Doses of 90 to 400 mg have been
effective, beginning as early as 18 weeks of gestation
Vaginal progesterone
reduces the rate of preterm birth in women
with a sonographic short cervix
• OBJECTIVE: To determine whether the use of
vaginal progesterone in asymptomatic women
with a sonographic short cervix (≤25 mm) in
the mid-trimester reduces the risk of preterm
birth and improves neonatal morbidity and
mortality.
• STUDY DESIGN: Individual patient data metaanalysis of randomized controlled trials
Introduction
• Progesterone is considered a key hormone for pregnancy
maintenance, A decline of progesterone action is implicated in
the onset of parturition.
• A blockade of progesterone action can lead to the clinical,
biochemical and morphologic changes associated with
cervical ripening
• Administration of vaginal progesterone was proposed for the
prevention of preterm birth in women with a sonographic
short cervix in the mid-trimester based on its biologic effects
on the cervix, myometrium, and chorioamniotic membranes
• The precise mechanism by which progesterone prevents
preterm delivery in women with a short cervix has not been
established. A local effect is likely
RESULTS:
Five trials of high quality were included
• 775 women and 827 infants.
•
Treatment with vaginal progesterone was associated with
Significant reduction in the rate of
• Preterm birth <33 weeks (RR 0.58, 95% CI 0.42-0.80),
<35 weeks (RR 0.69, 95% CI 0.55-0.88)
<28 weeks (RR 0.50, 95% CI 0.30-0.81),
• Respiratory distress syndrome (RR 0.48, 95% CI 0.30-0.76),
•
composite neonatal morbidity and mortality (RR 0.57, 95% CI 0.40-0.81),
• birth weight <1500 g (RR 0.55, 95% CI 0.38-0.80)
• admission to NICU (RR 0.75, 95% CI 0.59-0.94)
• requirement for mechanical ventilation (RR 0.66, 95% CI 0.44-0.98).
No significant differences between the vaginal progesterone and placebo
groups in the rate of
• adverse maternal events
• congenital anomalies.
CONCLUSION
Vaginal progesterone administration to
asymptomatic women with a sonographic
short cervix reduces the risk of preterm birth
and neonatal morbidity and mortality
17-alpha-hydroxyprogesterone
caproate (17OHPC)己酸孕酮
• a synthetic progestogen with minimal to no
androgenic activity
• In February 2011, FDA approved the use of
progesterone supplementation to reduce the
risk of recurrent preterm birth in women with
a singleton pregnancy who have a history of a
prior spontaneous preterm delivery
• Makena®
The safety of 17-OHPC in pregnancy
• Supported by numerous epidemiologic studies and clinical
trials
In some small studies
• risk of miscarriage and stillbirth
• risk of hypospadias in male offspring exposed to exogenous
progestins ; even if confirmed, this risk is limited to
exposure prior to 11 weeks of gestation and thus is not
relevant to women with prior preterm delivery, as they will
receive the drug after 16 weeks of gestation.
• three-fold increase in risk of developing gestational
diabetes, but this finding was not confirmed in analysis of
data from another large study.
Cerclage for the Management of
Cervical Insufficiency
Definition---what is cervical insufficiency ?
 inability of the uterine cervix to retain a
pregnancy in the absence of the signs and
symptoms of clinical contractions, or labor,
or both in the second trimester.
Pathophysiology
• still poorly understood
• Factors that may increase the risk
– surgical trauma
• Conization, loop electrosurgical excision
procedures
• mechanical dilation of the cervix during
pregnancy termination
– obstetric lacerations
Pathophysiology
• Other proposed etiologies
– congenital müllerian anomalies
– deficiencies in cervical collagen and elastin,
– in utero exposure to diethylstilbestrol (DES
daughters
Diagnosis
 a lack of objective findings and
clear diagnostic criteria
 Diagnosis is based on a history
▪ painless cervical dilation after the first trimester
▪ subsequent expulsion of the pregnancy in the
second trimester
 typically before 24 weeks of gestation, without
contractions or labor and in the absence of other
clear pathology
True or not?
 cervical length in the second trimester
▪ ultrasonographic diagnostic marker  cervical
shorteningcervical insufficiency ?
 short cervical length has been shown to be a marker
of preterm birth in general
 rather than a specific marker of cervical
insufficiency!!!
 Nonetheless, cerclage may be effective in particular
circumstances
diagnostic tests?
 Various diagnostic tests in the nonpregnant
woman
 Hysterosalpingography
 Radiographic imaging of balloon traction on the
cervix
 Assessment of the patulous cervix with Hegar or Pratt
dilators
 Graduated cervical dilators to calculate a cervical
resistance index .
 However, none of these tests have been
validated in rigorous scientific studies, and they
should not be used to diagnose cervical
insufficiency
Treatment Options
• nonsurgical approaches
– activity restriction
– bed rest
– pelvic rest
• Have Not been proved to be effective for the treatment
of cervical insufficiency and their use is discouraged
– vaginal pessary
• Evidence is limited for potential benefit of pessary
placement in select high-risk patients
Treatment Options
• Surgical approaches
– transvaginal and transabdominal cervical cerclage
• McDonald
• Shirodkar
– McDonald procedure
• purse-string suture of
nonresorbable material
is inserted at the
cervicovaginal
junction
Treatment Options
• Surgical approaches
– Shirodkar procedure
• dissection of the vesicocervical mucosa
•  in an attempt to place the suture as close to the
cervical internal os as might otherwise be possible
•  The bladder and rectum are dissected from the
cervix in a cephalad manner
• the suture is placed and tied
•  mucosa is replaced over the knot
Treatment Options
• Surgical approaches
– Transabdominal cerclage (cervicectomy)
• in whom cerclage cannot be placed because of
anatomical limitations (eg, after a trachelectomy),
• Or in the case of failed transvaginal cervical cerclage
resulted in second-trimester pregnancy loss
– Open laparotomy or operative laparoscopy
– Timeing:
• in the late first trimester
• early second trimester (10–14 weeks of gestation)
• in the nonpregnant state
Transvaginal cervico-isthmic cerclage (TVCIC): The TVCIC is placed above the
cardinal ligaments but isn’t quite as high as the TAC. It closes the cervix about
1/2 cm below the internal os.
Clinical Considerations and
Recommendations
In which patients is cerclage indicated based on
obstetric history or physical examination findings?
History-Indicated Cerclage
• History-indicated cerclage (prophylactic cerclage)
– In a patient with a history of unexplained
second-trimester delivery in the absence of
labor or abruptio placentae.
– History-indicated cerclages typically are placed
at approximately 13–14 weeks of gestation
Physical Examination-Indicated
Cerclage
• advanced cervical dilation in the absence
of labor and abruptio placentae
– candidates for examinationindicated cerclage (emergency or
rescue cerclage).
– physical examination-indicated
cerclage may be beneficial.
• Nevertheless, given the lack of larger
randomized trials that have
demonstrated clear benefit, women
should be counseled about the potential
for associated maternal and perinatal
morbidity.
Ultrasound-indicated cerclage
• Meta-analyses of multiple randomized trials that compared cerclage
versus no cerclage in patients with short cervical length during the
second trimester have reached the following conclusions
• a current singleton pregnancy
• prior spontaneous preterm birth at less than 34 weeks of gestation
• short cervical length (less than 25 mm) before 24 weeks of
gestation
– Alough not meet the diagnostic criteria for cervical insufficiency
– Cerclage is associated with significant decreases in preterm birth
outcomes, as well as improvements in composite neonatal
morbidity and mortality
Ultrasound-indicated cerclage
 Cerclage placement in women without a history of prior
spontaneous preterm birth and with a cervical length less
than 25 mm detected between 16 weeks and 24 weeks of
gestation has not been associated with a significant
reduction in preterm birth!!
Which patients should Not be
considered candidates for cerclage?
 Incidentally detected short cervical length in the
second trimester in the absence of a prior singleton
preterm, cerclage is not indicated in this setting.
 in asymptomatic women with cervical length less than
or equal to 20 mm before or at 24 weeks of gestation
 Vaginal progesterone is recommended as a
management option to reduce
 the risk of preterm birth
Which patients should Not be
considered candidates for cerclage?
• Cerclage may increase the risk of preterm birth in
women with a twin pregnancy and an
ultrasonographically detected cervical length less than
25 mm and is not recommended
• evidence is lacking for the benefit of cerclage solely
for the following indications: prior loop electrosurgical
excision procedure, cone biopsy, or müllerian anomaly.
Is cerclage placement associated with
an increase in morbidity?
 There is a low risk of complications with
cerclage placement.
 Reported complications include
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rupture of membranes
Chorioamnionitis
cervical lacerations
suture displacement.
Life-threatening complications of uterine rupture
and maternal septicemia are extremely rare but
have been reported with all types of cerclage.
Summary of Recommendations and
Conclusions
 The following recommendations are based on good or
consistent scientific evidence (Level A)
 Although women with a current singleton pregnancy, prior
spontaneous preterm birth at less than 34 weeks of
gestation, and short cervical length (less than 25 mm) before
24 weeks of gestation do not meet the diagnostic criteria for
cervical insufficiency
 available evidence suggests that cerclage placement
significant decreases in preterm birth outcomes, as well as
improvements in composite neonatal morbidity and
mortality
may be considered in women with this combination of
history and ultrasonographic findings
Summary of Recommendations and
Conclusions
 The following recommendations are based on good or
consistent scientific evidence (Level A)
 Cerclage placement in women without a prior
spontaneous preterm birth and a cervical length
less than 25 mm detected between 16 weeks and
24 weeks of gestation has not been associated with
a significant reduction in preterm birth
Summary of Recommendations and
Conclusions
• The following recommendations are based on limited or
inconsistent scientific evidence (Level B):
– nonsurgical approaches, including activity restriction, bed
rest, and pelvic rest have not been proved to be effective
for the treatment of cervical insufficiency
– The standard transvaginal cerclage methods include
modifications of the McDonald and Shirodkar techniques.
The superiority of one suture type over another has not
been established
Summary of Recommendations and
Conclusions
 The following recommendations are based on limited or
inconsistent scientific evidence (Level B):
 Cerclage may increase the risk of preterm birth in women
with a twin pregnancy and an ultrasonographically
detected cervical length less than 25 mm and is not
recommended.
 Neither antibiotics nor prophylactic tocolytics have been
shown to improve the efficacy of cerclage, regardless of
timing or indication.
Summary of Recommendations and
Conclusions
 The following recommendations are based primarily on
consensus and expert opinion (Level C):
 Cerclage should be limited to pregnancies in the second
trimester before fetal viability has been achieved..
 After clinical examination to rule out uterine activity, or
intraamniotic infection, or both, physical examinationindicated cerclage placement in patients who have cervical
change of the internal os may be beneficial.
 In patients with no complications, transvaginal McDonald
cerclage removal is recommended at 36–37 weeks of
gestation.
Summary of Recommendations and
Conclusions
• The following recommendations are based primarily on
consensus and expert opinion (Level C):
– For patients who elect cesarean delivery at or beyond 39
weeks of gestation, cerclage removal at the time of
delivery may be performed; however, the possibility of
spontaneous labor between 37 weeks and 39 weeks of
gestation must be considered.
– In most cases, removal of a McDonald cerclage in the office
setting is appropriate.
Clinical Scenario
• Woman: Prenatal care for 1st trimester of 3rd
pregnancy
1st child: Born at 30 weeks of gestation
after preterm labor
2nd pregnancy: Ended in delivery at 19
weeks of gestation.
• How to reduce risk of preterm birth?!
Recommendation
• Woman: Previous preterm birth x2
Careful history taking : Risk factors.
(Smoking, nutrition, infections…)
17-OHPC 250mg IM weekly from GA16 to
36wks
Transvaginal ultrasonographic (16~24 wks) →
Cerclage if cx length <25mm before GA 24 wks
早產的預防， 目前使用的方法如下：
1.環紮法(cerclage)
• 實驗指出，若一個單胞胎以前有過妊娠34週前自發性早產的病史，而其子宮
頸在妊娠24週前短於25mm，若施以環紮術可以減少30%孕婦在35週前早產的
機會(28% vs 41%，RR 0.7)，亦可減少36%的胎兒出生前後的死亡率與罹病率
(16% vs 25%，RR 0.64) [5]。
2.17α Hydroxy-Progesterone Caproate
• 如果孕婦有早產的病史， 我們從妊娠16-20週起，至36週為止，每星期預防性
的肌肉注射一次17α Hydroxyprogesterone Caproate 250mg 將可以明顯的減少
再一次的早產發生，但目前的證據並不支持它在雙胞胎上的使用，且它亦無
法抑制active preterm labor[6]。
3.黃體素
• 對於沒有任何早產症狀，但卻有很短子宮頸長度的孕婦，使用黃體素有助於
延長妊娠週數，但理想給藥的途徑及劑型尚未定論。在一項實驗中，一群沒
有過去自發性早產病史的單胞胎孕婦，在妊娠24週前經陰道超音波測得子宮
頸長度短於20mm，經陰道給予黃體素，不管是90-mg 凝膠或 200-mg 塞劑，
都可以減少自發性早產的發生和胎兒出生前後的死亡率與罹病率[7]。
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