KELAINAN LAMA USIA

KEHAMILAN

Puja Agung Antonius

pujaagungantonius@yahoo.com

Department of Obstetrics and Gynecology

Faculty of Medicine Andalas University
NO ESTROGEN ?
Endocrinology of parturition
Hirota Y., et al. Nature Med 2010;16:529-31
 Aromatase

Aromatase
 Estrogen - Gap junctions

Myometrium cells is a single unit smooth muscle cell

Action potentials generated in one cell can activate adjacent cells by ionic currents spreading
rapidly over the whole organ and securing a co-ordinated contraction as though the tissue were
a single unit or a syncytium
Estrogen – Oxytocin receptor
R: oxytocin G-protein coupled receptor; G: G-protein; PLC: phospholipase C; PIP2: phosphatidyl-inositol
biphosphate; IP3: inositol tri-phosphate; ER: endoplasmic reticulum; VOCC: voltage operated calcium
channels; Ca2+: ionised calcium; Ca2+i: free intracellular ionised calcium; MCLK-P myosin light chain kinase
phosphate.
 Endogenous anti-progestin Concept of P
which prevents the
physiological action of P withdrawal

A change in the number,

affinity, or distribution of the CAP = Contraction Associated Protein
progesterone receptor (PR)

A change in local synthesis,

metabolism or sequestration
by a binding protein

Mesiano S., et al. Semin Cell Dev Biol 2007;18:321-31

Myometrium relaxation Astle S., et al. Eur J Obstet Gynaecol 2003;108:177-81
Young IR., et al. The comparative physiology of parturition in mammals: hormones and parturition in mammals
Young IR., et al. The comparative physiology of parturition in mammals: hormones and parturition in mammals
Mazaki-Tovi S., et al. Semin Perinatol 2007;31:142-58
SUMMARY

LATE PREGNANCY

Effects on embryo allogeneic antigen, endometrium

and maternal immune modulation

EARLY PREGNANCY
R: oxytocin G-protein coupled receptor; G: G-protein; PLC: phospholipase C; PIP2: phosphatidyl-inositol
biphosphate; IP3: inositol tri-phosphate; ER: endoplasmic reticulum; VOCC: voltage operated calcium
channels; Ca2+: ionised calcium; Ca2+i: free intracellular ionised calcium; MCLK-P myosin light chain kinase
phosphate.
Maternal CRH Corticotopin realeasing
Hormone
Glukokortikoid

CRH oleh plasenta

Corticotropin oleh hipofisis anterior

Cortisol oleh kortex adrenal

• CRH disekresi masuk ke aliran darah fetus.
• Berikatan dengan reseptor CRH 1.
• CRH reseptor maternal : hipofisis anterior,
miometrium, kelenjar adrenal.
• CRH reseptor fetus : hipofisis anterior, kelenjar
adrenal, paru – paru
peningkatan CRH ini yg menginisiasi
parturition
• Peningkatan CRH tinggi memiliki hub spesifik
dengan resiko preterm, namun pemeriksaan CRH
mempunyai sensitivitas yg rendah untuk prediksi
preterm
• Peningkatan CRH  peningkatan corticotropin 
peningkatan cortisol dan DHEAS
(Dehidroepiandrosteron sulfat) oleh kelenjar
adrenal maternal
• Cortisol  pelepasan CRH dan DHEAS
• DHEAS  substrat pembentukan estrogen oleh
plasenta
• Pada akhir kehamilan reseptor CRH
mengaktifkan Gαq pathway (aktivasi protein C
kinase)  kontraksi efisien spt oksitosin dan
prostaglandin
 CRH fetal
• Dari maternal
• Stimulasi hipofisis anterior  corticotropin,
sintesis cortisol oleh kelenjar adrenal fetus
dan lung maturation.
• Cortisol  memicu dihasilkan surfaktan
protein A dan fosfolipid, sebagai faktor
proinflamasi memicu kontraksi miometrium
melalui peningkatan prostaglandin
 Aktivasi miometrium
• Protein yang berpotensi untuk stimulasi
kontraksi ritmik uterus yg kuat yg mendorong
softening cervix tidak terinisiasi saat
kehamilan.
3 tipe kontraksi :
1. Meningkatkan aktivasi protein aktin dan
miosin yang menyebabkan kontraksi otot
2. Meningkatkan eksitasi sel miometrium
3. Meningkatkan konektivitas interseluler yang
mendukung synchronous contraction
Awalnya aktin yg globuler berubah menjadi
filamen
• Interaksi filamen aktin dan miosis memicu
kontraktilitas miosit
• Miosin akan teraktivasi bila terjadi fosforilasi
oleh miosin light chain kinase yang diaktifkan
oleh calmodulin dan calsium intraseluler.
 Cervical softening

• Faktor inflamasi berpindah ke cervix dan

melepaskan metaloprotease  degradasi
collagen  perubahan struktur cervix
 Progesteron withdrawal

• Penurunan level Progesteron berperan

menginisiasi parturition.
PRETERM
 Definition
• Menurut World Health
Organization (WHO), preterm
birth didefinisikan kelahiran yang
terjadi pada usia kehamilan lebih
dari 20 minggu dan kurang dari
37 minggu

Preterm Labour
Preterm Labour
 ETIOLOGI

1. Ruptura spontan selaput ketuban

• Ketuban pecah dini secara umum terjadi
pada 3% dari seluruh kehamilan
• Umumnya terjadi spontan tanpa
penyebab yang jelas, akan tetapi sering
disebabkan oleh infeksi
• Ketuban pecah dini bertanggung jawab
terhadap 1/3 kehamilan preterm
2. Infeksi
Invasi bakteri pada ruang
koriodesidua akan
mengaktivasi desidua dan
selaput ketuban untuk
memproduksi cytokine,
termasuk TNF, IL 1, IL6,
IL8 dan granulocyte colony-
stimulating factor, kemudian
cytokines tersebut akan
merangsang prostaglandin
dan juga menginisisasi
kemotaksis dan ilfitrsi
neutrofil, yang
merangsang sintesa
metaloprotease, dan
akhirnya menyebabkan
rupturnya selaput ketuban
serta terjadi pematangan
serviks
3. Anomali hasil pembuahan
4. Persalinan preterm sebelumnya
5. Uterus yang overdistensi
6. Dilatasi serviks
7. Anomali uterus
8. Gangguan atau kelainan pada
plasentasi
9. Kelainan maternal yang serius
Preterm Labour
 Risks Factors (Antepartum)
Twins, triplets
PROM
Polyhydramnion
Antepartum hemorrhage
Urinary tract infection
Tobacco or coccain use
Serious maternal infection
Physical/emotional trauma

Preterm Labour
 USG
 Meneliti pada pasien
dengan riwayat
preterm–prediksi bila
USG dilakukan pada 20-
28 minggu
 Perhatian : panjang dan
cekungan (funneling)
 PPV=20%
USG transvaginal (II-2B)
Asimptomatik : Risiko
relatif 4x bila panjang <
30mm
Iams et al. N Eng J Med 1996;334:567
Panjang < 22 mm
Preterm <35 mgg
Andrews et al. Obstet Gynecol
2000;95:222

Preterm Labour
 Approaches to ANC
• Preconception preparation: nutritional
status, avoidance of smoking and drugs,
supportive environment
• Treatment of symptomatic vaginal
infection
• In the very rare occasion of women with
a history of cervical insufficiency 
cervical cerclage has been effective

Preterm Labour
 Corticosteroids
• Reduces the risk of death, RDS,
and intraventricular hemorrhage

Betamethasone is the drug of choice and is

the only medication shown in clinical trials to be effective
Betamethasone : 12 mg IM, 2 doses at 24 hour interval
At the presence time, many practitioners still use
Dexamethasone 6 mg IM (widely available and cheaper)

Preterm Labour
Tocolytic ACOG

Preterm Labour
 Tocolytic
• At the presence time, tocolytic
therapy can only delay delivery for
- Acquiring time for better neonatal
care
- Lung maturation by corticosteroid
- Antibiotic administration for
preventing neonatal infection.
Preterm Labour
Type of drugs Mechanism of action
Magnesium sulfate Antagonis Ca intrasel
Terbutaline (Bricanyl) Reseptor Beta2 adrenergik
agonis (simpatomimetik)
mengurangi ion Ca bebas
intrasel
Ritodrine (Yutopar) Sama dengan terbutaline
Nifedipine Calcium channel blocker
(Procardia)
Indomethacin Inhibitor prostaglandin
(Indocin)
Preterm Labour
Dosage
Dosis loading 4-6 g,
dilanjutkan 2-4 g IV per
jam
0.25-0.5 mg SK setiap
3-4 jam
Atau
- 2,5 -10 µg/menit IV,
maksimal 80µg/menit IV
0.05-0.35 mg per menit IV
5-10 mg SL tiap 15-20
menit (sampai 4 kali),
dilanjutkan 10-20 mg oral
tiap 4-6 jam
50-100 mg suppositoria,
dilanjutkan 25-50 mg oral
tiap 6 jam
Preterm Labour
 Contraindications
toTocolysis
• Non-reassuring fetal heart
• Lethal fetal anomaly
• Intrauterine fetal death
• Chorioamnonitis
• Severe gestational hypertension
with adverse conditions
• Severe IUGR
Preterm Labour
Sites of Action of Commonly Used Tocolytic Drugs
β-Adrenergic receptor agonist
Binding to β2-Adrenergic Side Effects:
receptor agonist • Tachycardia
• Hipotension
• Tremor
• Shortness of breath
Intracelullar cAMP • Chest discomfort
• hypokalemia

Inactivates myosin light chain

Activates protein kinase
kinase

Myometrial relaxation
 Ca Channel Blocker
Side Effects:
• Dizziness
Block Ca channel • Hipotension
• Flushing
• Suppression of HR

Inhibit Ca influx through the cell &

release of intracellular Ca from the sarcoplasmic reticulum

Inactivates myosin light chain

 Intracellular free Ca kinase

Myometrial relaxation
 Magnesium Sulphate
Side Effects:
• Diaphoresis
• Flushing
• Nausea
• Loss of deep tendon reflexes (9.6-12 mg/dl)
• Respiratory paralysis (12-18 mg/dl)
Magnesium Sulphate • Cardiac arrest (24-30 mg/dl)

Inactivates myosin light chain

 Intracellular free Ca kinase

Myometrial relaxation
 COX Inhibitor

Arachidonic acid
Side Effects:
• Nausea
COX • Esophageal reflux
• Gastritis
• Platelet dysfunction

Prostaglandin H2

Activates myosin light chain

Enhance myometrial gap junction kinase
Intracellular Ca

Myometrial Contraction
 Conclusion
• Treatment Focus prevention of preterm
birth
• Accurate estimation of fetal festational age
and pathologic cause  plan for tocolysis
• Reasonable choice for initial tocolysis 
Nifedipine
Post term
 Definition
• A pregnancy reaching 42 completed weeks (294 days)

• Kehamilan yang mencapai atau melebihi 42 minggu

(294 hari atau taksiran partus + 14 hari)ACOG

• Kehamilan yang mencapai 42 mingguAAFP

• Kehamilan 42 minggu lengkap atau 294 hari dari

periode haid terakhir (280 hari dari konsepsi)RSCM
 Prevalence and etiology

• The prevalence of PT is commonly reported as

4–10%. In Europe, the prevalence estimates
range from 0.8% to 8.1%
• The etiology of PT is largely unknown, but both
fetal abnormality (e.g., anenceph-aly) and
placental sulphatase deficiency can be
associated with prolongation of pregnancy.
• It has also been suggested that some genetic
factors , fetal gender and a high pre-pregnancy
body mass index (BMI) can contribute to an
increased risk for PT
 Prevalence and etiology

• Insiden 7% dari seluruh

kehamilan(ACOG),5-10% dari
seluruh kehamilan(AAFP),
• *41 minggu lengkap: 27%,
• *42 minggu lengkap: 4–14%,
• *43 minggu lengkap: 2–7%(RSCM)
 Diagnosis

• The diagnosis is overtly simple: pregnancy

duration beyond 42 weeks from the LMP.
• Unfortunately, even in the presence of
regular menstrual cycles, the true GA is
different from the estimated GA in a
significant number of cases.
• The most accurate method for assessing GA
is fetal biometry per- formed by US in early
pregnancy.
 Risk Factor
• Primipara
• Riwayat kehamilan postterm
 Complications of postterm
pregnancy Fetal
• Mortalitas perinatal meningkat 2x
lipat pada gestasi 42 minggu dan 6x
lipat lebih pada gestasi 43 minggu ke
atas(ACOG) 4-6x lipat pada gestasi 44
minggu(AAFP)
• Kematian perinatal berkaitan dengan
aspirasi mekonium dan
asfiksia(RSCM)
 Maternal

• Distosia
• Laserasi perineum(ACOG)
• SC 2x lebih banyak
• SC emergensi
• CPD
• Ruptur serviks
• Kematian janin inpartu
• Bayi besar
• Perdarahan postpartum
• Infeksi puerperium(AAFP)
• Distosia(RSCM)
 Neonatal

• Mortality A higher rate of NM is reported.

Where evaluated, both small for gestational age
(SGA) and major congenital malformations
appear to increase this risk
• Neonatal complications Neonatal complications
include low Apgar scores, acidemia, admission to
neonatal intensive care unit (NICU), meconium
aspiration syndrome (MAS), clavicular fracture
and Erb’s palsy.
 Management
• Two management strategies are
recommended. The first is to prevent
the prolongation of pregnancy by
inducing labor and the second is
expectant treatment under close
surveil- lance, with active
management by induction of labor or
CS only when specifically indicated.
 Subjek ACOG (2004)
Evaluasi Evaluasi antenatal
antenatal pada gestasi 40-42
minggu memperbaiki
luaran perinatal
NST, BPP, atau MBPP
Manajemen Secara rutin, dilakukan induksi
kehamilan jika sudah mencapai gestasi 41
postterm minggu
*bila serviks matang,
disarankan induksi
*bila serviks belum matang,
lakukan pematangan serviks
dan induksi
Pematangnan serviks dapat
menggunakan:
*PGE2 (dinoproston)
*PGE1 (misoprostol)
AAFP (2005) RSCM
Jika dilakukan
manajemen
ekspektatif, harus
dilakukan monitor
2x/minggu
NST, AFI, BPP (C)
Induksi persalinan lebih Induksi persalinan
disarankan daripada pada gestasi 41
manejemen ekspektatif (A) minggu
*Induksi dilakukan pada gestasi
41 minggu (B)
*menurunkan mortalitas
perinatal
Jika ditemukan oligohidramnion,
bayi harus segera dilahirkan (C)
Briscoe D, Nguyen H, Mencer M, et. al. Management of pregnancy beyond 40 weeks’
gestation. Am Fam Physician 2005;71:1935-42
PROM &
PPROM
 Definition
 Preterm premature rupture of membranes
(PPROM) refers to chorioamniotic
membrane rupture before the onset of
labor in pregnancies at less than 37 weeks
of gestation.

 Premature rupture of membranes (PROM)

prior to the onset of labor (as defined by
uterine contractions causing cervical
change) at term (≥ 37 weeks).
DIAGNOSIS
Nitrazine paper testing
• Vaginal pH (3.5-4.5)
• Turns blue in
presence of alkaline
Amniotic fluid
• 93.3% sensitivity
• False positive (1-
17%) for urine,
blood, semen, BV,
Trichomonas
Fern slide

Must allow slide to dry

thoroughly prior to
examination under
microscope. Assess for
arborization of fluid.
Cervical mucous has
broad, ferning pattern
that is different than the
fern of amniotic fluid.
 Fetal Fibronectin
• fFn present in cervical
secretions <22 wks, >34
wks
• Used for assessment of
potential PTB
• Positive result (>50
ng/dl) may be indicative
of PROM and represents
disruption of decidua-
chorionic interface

In PPROM, Sensitivity-98.2%, Specificity-26.8%.

 AmniSure
• Newer test
• Point of Care test
• Sensitivity-98.7-98.9%
• Specificity-87.5-100%
• Awaiting further testing prior to
recommendations
 AmniSure
Remove swab
and rotate in
solvent x 1 min.

Read
results
after 5-
10 mins
have
passed.

Place Swab 2-3 in.

into vaginal canal
x 1 min. Discard swab and place
test stick into solvent.
 Ultrasonography
• 50-70% of women with
PPROM have low AFV on
US
• Mild reduction requires
further investigation
• Rule out other causes
(Renal agenesis, utero-
placental insufficiency,
obstructive uropathy)
• Measure for pockets of
fluid and quantitate AFV
into AFI
Ultrasound showing 7 cm pocket of fluid
Transabdominal Injection of
Dye
• Amniocentesis
• Collect Fluid samples
• Inject dye (Indigo
Carmine)
• Tampon placed in
vagina and checked
for blue staining 30-
60 mins after
procedure
 Symptoms

• Over 90% of women with PROM and

PPROM report a history of ‘gush of
fluid’.
 Incidence
• Approximately 80% of PROM at term begin labor
within 24 hours and 95% within 72 hours. In case of
PROM in preterm gestation, labor generally sets in
within 24 hours in 35–50% patients, and within 72
hours in 70% patients. Whereas in women with
preterm PPROM, almost 90% deliver within the next
two weeks

• PPROM occurs < 1% at < 24 weeks, about 2–5% at 24–

33 weeks, 3–8% at 34–36 weeks, compared with about
8–10% for PROM at term. PPROM is responsible for
25–30% of all preterm births (PTB).
 Potential Routes of Infection Rute Infeksi
Retrograde from
abdominal cavity

Hematogenously Amniocentesis
through placenta

Ascending from
vagina
INFECTION
 Classification
• PPROM can be classified:
 PPROM < 24 weeks (usually 16–23
6/7 weeks, and called
also previable or midtrimester or very
early PPROM)
 PPROM 24–33 6/7 weeks (early
PPROM)
 PPROM 34–36 6/7 weeks (near-term
PPROM)
 Risk factors
• Transvaginal ultrasound cervical length <
25 mm is associated with a high rate of
PPROM– compared with preterm labor (
PTL)–related PTB.

• Some factors that may be associated

with PROM include infection, smoking,
vaginal bleeding, uterine distention, and
lower socioeconomic status.
 Complications
 Premature labor/delivery: in 50% of PPROM, labor occurs within 24 hours,
and in 80–90% within 7 days.
 Distress syndrome (RDS), intraventricular hemorrhage (IVH), and
periventricular leukomalacia (PVL), infection and necrotizing enterocolitis
(NEC).
 Infections: mother is at risk of chorioamnionitis, endometritis, and sepsis
(Mean incidence of chorioamnionitis is about 3–15%. Major neonatal
infections occur in 5% of PPROM, and 15–20% of cases develop
chorioamnionitis. Fetal infection can precede clinically evident
chorioamnionitis, resulting in neonatal pulmonary and cerebral morbidities.
 abruptio placentae, cord prolapse, perinatal death, pulmonary hypoplasia,
compression syndrome, long-term infant morbidities, Increased need for
cesarean delivery, and retained placenta are most common with early and
very early PPROM

• The most important and common complication PROM is intrauterine

infection.
MANAGEMENT
 Work up

• Speculum examination is necessary

to confirm the diagnosis

• Avoid manual/digital examination of

the cervix once

• Ultrasound should evaluate

 Maternal surveillance
All women with PPROM/PROM should
be monitored for signs and symptoms
of infection by assessment of clinical
parameters e.g. fever, maternal/fetal
tachycardia, uterine tenderness,
purulent vaginal discharge).
 Fetal surveillance
• The two most common types of fetal surveillance are NST
and biophysical profile (BPP).

• There is insufficient evidence to assess the optimal type or

frequency of testing. The NST or BPP performed daily have
poor sensitivity (39 and 25%, respectively) and similar
predictive values for predicting infection

• Given lower cost, the NST is usually suggested for daily to

twice a week fetal surveillance. Monitoring may be more
frequent with oligohydramnios, with a preference for BPP as
a back-up if the NST is non-reassuring.
 Corticosteroids
• Reduces the risk of death, RDS, and
intraventricular hemorrhage

Betamethasone is the drug of choice and is

the only medication shown in clinical trials to be effective
Betamethasone : 12 mg IM, 2 doses at 24 hour interval
At the presence time, many practitioners still use
Dexamethasone 6 mg IM (widely available and cheaper)

Preterm Labour
 Tocolytic
• At the presence time, tocolytic
therapy can only delay delivery for
- Acquiring time for better neonatal
care
- Lung maturation by corticosteroid
- Antibiotic administration for
preventing neonatal infection.
Preterm Labour
Tocolytic ACOG

Preterm Labour
Type of drugs Mechanism of action Dosage

Magnesium Antagonis Ca intrasel Dosis loading 4-6 g, dilanjutkan 2-4

sulfate g IV per jam

Terbutaline Reseptor Beta2 adrenergik 0.25-0.5 mg SK setiap 3-4 jam

(Bricanyl) agonis (simpatomimetik) Atau
mengurangi ion Ca bebas - 2,5 -10 µg/menit IV, maksimal
intrasel 80µg/menit IV

Ritodrine Sama dengan terbutaline 0.05-0.35 mg per menit IV

(Yutopar)

Nifedipine Calcium channel blocker 5-10 mg SL tiap 15-20 menit

(Procardia) (sampai 4 kali), dilanjutkan 10-20
mg oral tiap 4-6 jam

Indomethacin Inhibitor prostaglandin 50-100 mg suppositoria, dilanjutkan

(Indocin) 25-50 mg oral tiap 6 jam

Preterm Labour
 Recommendations based on the
evidence
• In patients with PPROM at term, induction of
labor is recommended. Induction should
probably occur at least within 6–12 hours of
PPROM, or earlier if feasible.

• Oxytocin is a safe and effective (as well as cost-

effective) means of induction with PROM at
term.

• In the study in which it was evaluated, most

women with PROM at term, if given a choice,
prefer induction
 Cont’t..

• In one small trial, compared with

placebo, vitamin C 500 mg and vitamin
E 400 IU daily in women with PPROM at
26–34 weeks was associated with 7-day
prolongation in latency, but no other
effects on maternal or neonatal
morbidity and mortality.
TERIMA KASIH
 Corticosteroids for fetal/neonatal
maturation and benefit
• Antenatal steroid therapy should be
administered in women with PPROM at
24–32 weeks, as this intervention is
associated with lower neonatal
complications: 44% less RDS, 53% less
IVH, 79% less NEC, and a trend for a
32% lower incidence in neonatal death,
without any increase in maternal or
neonatal infection
 Antibiotics for prolongation of
latency and fetal/neonatal benefit
• Benefits of maternal antibiotic therapy when there is PPROM
are:
• Maternal: 43% less chorioamnionitis.
• Fetal/neonatal: prolongation of pregnancy; 29% reduction
in PTB within 48 hours; 20% reduction in PTB within 7 days;
32% reduction in neonatal infection, 17% in use of
surfactant, 12% in oxygen therapy, and 18% in abnormal
cerebral ultrasound scan (including IVH) prior to discharge
from hospital. There is a trend for a 10% decrease in
perinatal mortality (RR = 0.90, 95% CI 0.74–1.10).
RDS and NEC are also decreased with ampicillin and
erythromycin treatment
• Ampicillin and erythromycin or erythromycin are associated with
significant benefits in neonatal outcomes, and should be used
routinely in women with PPROM 24–34 weeks.

• A combination of ampicillin and erythromycin – e.g. ampicillin 2 g

and erythromycin 250 mg both intravenously (IV) every 6 hours for 48
hours, followed by amoxicillin 250 mg and erythromycin base 333 mg
both orally (po) every 8 hours
for 5 days, for a total of 7 days – in women with PPROM

• In a large trial, amoxicillin/clavulanate was associated with an

increased risk of neonatal NEC, although there is no consistent trend
towards a positive or negative effect of broad-spectrum antibiotics for
NEC in the literature
• Clinical chorioamnionitis requires
therapeutic antibiotics,
for example ampicillin (2 g IV every 6
hours) plus gentamicin (1.5 mg/kg IV
every 8 hours or 7 mg/kg ideal body
weight every 24 hours).
 Tocolysis for prolongation of latency and
fetal/neonatal benefit
• Tocolysis may be used for ≤ 48 hours with concurrent
administration of antibiotic and corticosteroids for
prolongation of pregnancy and achieving fetal maturity
before 32 weeks in the presence of contractions and in the
absence of contraindications to expectant management.
• Compared with short-term tocolysis to allow steroid effect,
long-term tocolysis > 48 hours is associated with a non-
significant prolongation of pregnancy, no differences in
neonatal complications, but increases in chorioamnionitis
and postpartum endometritis. It should therefore be avoided.