cervical insufficiency preterm labor continuum · 8/3/2007 cervical insufficiency-preterm labor...

8/3/20071

Cervical insufficiency preterm labor continuum

Cervical insufficiency Cervical insufficiency preterm labor continuum preterm labor continuum

Time to change the way we thinkTime to change the way we thinkTime to change the way we think

Alexander Kofinas, M.D.

8/3/2007 Cervical Insufficiency-Preterm Labor Continuum 2

• Preterm births are an Obstetrical Nemesis– In US 13.5% of all pregnancies are delivered <37 weeks– Preterm births account for 80% of neonatal morbidity &

mortality {Lancet 2002; 360: 1489-97, Obstet Gynecol Survey 2002;57:S9-S34}

• Rising prevalence despite our efforts– Prevalence has increased from 8% 13.5% in 20 years

• Very costly- we spend $26 billion annually• Multiple factors are contributing to this paradox of

modern perinatal care


Epidemiology: survival ratesEpidemiology: survival ratesEpidemiology: survival rates

Lancet 2002;360:1489


Epidemiology: causes of Preterm DeliveryEpidemiology: causes of Preterm DeliveryEpidemiology: causes of Preterm Delivery

Lancet 2002;360:1489


Preterm Labor ManagementPreterm Labor ManagementPreterm Labor Management

• Presence of true labor• Role of expectant management• Gestational age effect• Etiology of labor and choice of

tocolytic agent


True Labor?True Labor?True Labor?

Sonographically documented progressive cervical shortening

• With or without perceived uterine contractions • With or without uterine contractility by sonography

• Presence of uterine contractions with progressive cervical effacement and ultimately dilation



• Presence of true labor• Role of expectant management

– Fetal safety • Infection• Ischaemia• amniocentesis

• Gestational age effect• Etiology of labor and choice of tocolytic

agent



• Presence of true labor• Role of expectant management• Gestational age effect

– Singleton after 35 weeks– Twins after 34 weeks

• Etiology of labor and choice of tocolytic agent


Choice of TocolyticChoice of TocolyticChoice of Tocolytic

• IV Magnesium Sulfate• β2-agonists (Ritodrine, Terbutaline• Calcium channel blockers

(Nifedipine)• Indomethacin


Administration and Mechanism of Magnesium Sulfate

Administration and Mechanism of Administration and Mechanism of Magnesium SulfateMagnesium Sulfate

• IV continuous infusion– 4-6 gm bolus with 2-6 gm/hour continuos– Therapeutic level 6.5-7.5 mg/dl

• Oral– Gluconate, Oxalate (no clinical effect)

• Mechanism of action– Calcium antagonist (not a Ca++ channel blocker)

Competes with Ca++ for entry in the calcium channels of the myocytes


Efficacy of Magnesium SulfateEfficacy of Efficacy of Magnesium SulfateMagnesium Sulfate

• Magnesium as a single agent is not very successful in reducing preterm delivery

• Macones et al identified 8 randomized trials– Mg++ vs.placebo: positive trend but statistically not significant (OR

1.66, 95% CI 0.88-3.15)– Mg++ vs. Ritodrine: fewer preterm deliveries but not statistically

significant (RR 95% CI, 0.47-2.25) {Obstet Gynecol Surv. 1997 Oct;52(10):652-8}

• A systematic review revealed that Mg is not effective and has noeffect on prolonging gestation {Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD001060}


Maternal Side effects of Magnesium SulfateMaternal Side effects of Magnesium SulfateMaternal Side effects of Magnesium Sulfate

• Flushing and Headache• Dry mouth and nasopharyngeal passages• Nausea and other GI symptoms• Shortness of breath• Pulmonary edema (in combination with β2-

agonists) • Maternal Death


Neonatal Side effects of Magnesium SulfateNeonatal Side effects of Magnesium SulfateNeonatal Side effects of Magnesium Sulfate

• Self limited Lethargy• Self limited Hypotonia• Magnesium used as tocolytic is associated

with excess pediatric mortality (OR 3.7%)

Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD001060, Am J Obstet Gynecol 2002;186:1111-18, Obstet Gynecol 2000;96:178



• Magnesium Sulfate (parenteral)• β2-agonists (Ritodrine, Terbutaline)• Calcium channel blockers



Efficacy of β2-agonists EfficacyEfficacy of of ββ22--agonists agonists • Canadian preterm labor investigators group trial

– Better than placebo in 24h, 7 days, and a trend towards less deliveries prior to 32 weeks.

– This study was criticized for being poorly blinded, underpowered, and including patients with PROM

• A meta-analysis of 16 randomized trials achieved enough power {King et al, BJOG 1988;95:211}– Better than placebo in 24h, 48h, and birth < 37 weeks.– No difference in perinatal morbidity and mortality

• Common criticism of above: no consistent use of steroids which may have affected morbidity/mortality figures


Administration of β2-agonists Administration ofAdministration of ββ22--agonists agonists

• IV infusion– Ritodrine only– Terbutaline has been associated with serious liver

damage• Subcutaneous infusion

– Terbutaline• Steady infusion with intermittent boluses

• Oral – Every 4 hours (very poor compliance)


Maternal Side-effects of β2-agonists Maternal SideMaternal Side--effectseffects of of ββ22--agonists agonists

• β2-agonists are widely distributed– Nausea and headache in 20-30%– Tachycardia, palpitations, and shortness of

breath in 50%– Pulmonary edema

• 69 % inflammation, steroids not responsible– Subendocardial ischemia– Cardiac failure (intracellular potassium

levels)


Neonatal Side-effects of β2-agonistsNeonatal SideNeonatal Side--effectseffects of of ββ22--agonistsagonists

• Significant adverse fetal effects are infrequent• Transient fetal tachycardia and arrhythmia• Neonatal hypoglycemia• Transient ventricular septal hypertrophy and EKG c/w ischaemia• 2-fold increase in periventricular and intraventricular

hemorrhage• Neuropsychiatric, cognitive, cardiovascular, and metabolic

abnormalities in the offspring of women treated with beta-agonist tocolytics. {Brain Res Bull 2003 Jan 15;59(4):319-29}



• Magnesium Sulfate (parenteral)• β2-agonists (Ritodrine, Terbutaline• Calcium channel blockers



Calcium channel blockers: efficacyCalcium channel blockers: efficacyCalcium channel blockers: efficacy• There are no randomized placebo-controlled trials to

evaluate efficacy• Several randomized trials comparing nifedipine with

ritodrine and other β2-agonists exist– Small numbers but with consistent superiority of nifedipine

• Meta analysis of available data revealed– More effective than beta-agonists in delaying labor– Improved neonatal outcomes

{The Cochrane Library 2006, Issue 4}


Calcium channel blockers: DosageCalcium channel blockers: DosageCalcium channel blockers: Dosage

• Oral administration• Short acting formulations• Sustained release formulations (XL)• 30-60 mg every 12 hours• Maximum dosage: 160-200 mg/day


Calcium channel blockers: Maternal side effects

Calcium channel blockers: Calcium channel blockers: Maternal side effectsMaternal side effects

• Flushing/redness in the lower extremities when standing

• Headache and lightheadedness• Nausea• Mild decrease of blood pressure• Clinically insignificant, self-limited increase in the

maternal heart rate• Mild serum glucose elevation (always <120 mg/dl)


Calcium channel blockers: Neonatal side effects

Calcium channel blockers: Calcium channel blockers: Neonatal side effectsNeonatal side effects

• Animal studies: diminished placental flow• In human fetuses no such side effects were noted

ever• Fetal and placental Doppler studies before and after

nifedipine failed to reveal any uteroplacental and fetal flow changes

• Nifedipine reduced neonatal morbidity and mortality– (large multicenter randomized investigation-Obstet Gynecol

1997;90:230)



• Magnesium Sulfate (parenteral)• β2-agonists (Ritodrine, Terbutaline• Indomethacin• Calcium channel blockers

(Nifedipine)


Indomethacin: efficacyIndomethacin: efficacyIndomethacin: efficacy

• Several studies showed indomethacin to be superior to placebo and other tocolytics– In prolonging gestation past 48 hours (94 % vs. 22%

over placebo)– Undelivered at 7 days (83 % vs. 16% over placebo)– Reduced incidence of delivery prior to 37 weeks vs.

placebo• Indomethacin was superior to other tocolytics in

all counts


Indomethacin:dosage and administrationIndomethacin:dosage and administrationIndomethacin:dosage and administration• Oral (up to 200 mg qd)

– Various schemes• We prefer a circadian pattern

– GI side effects• Rectal (initial load with 100 mg)

– No GI effects• Vaginal (initial load or continuous treatment)

– No GI effects– Offers local effect on the cervix


Indomethacin:Maternal side effectsIndomethacin:Maternal side effectsIndomethacin:Maternal side effects• Nausea and acid reflux• Prolongation of bleeding time COX1 inhibition in

platelets (clinically insignificant)• Renal effects

– Renal hypoperfusion– Sodium retention– Fluid retention

• Exacerbation of maternal hypertension• Avoid in conjunction with other nephrotoxic drugs• All above adverse effects are almost non existent due

to the typically short duration of treatment


Indomethacin: Neonatal side effectsIndomethacin: Neonatal side effectsIndomethacin: Neonatal side effects• Effect on fetal renal function – oligohydramnios

– Dosage and length of exposure related; reversible• Effect on ductus arteriosus

– Minimal to none prior to 32 weeks; dosage dependent, reversible• Necrotizing enterocolitis

– Parilla BV, et al Obstet Gynecol 2000;96:120-123: case control study: indomethacin as a single agent is not related to NEC

• Patent ductus arteriosus (neonatal)• Intraventricular hemorrhage

– Not a problem when used as a single agent– Indomethacin is protective against high-grade IVH


Prolonged use of Indomethacin

beyond 40 weeks!!!


SummarySummarySummary

• Indomethacin and Ca-channel blockers are better tocolytic agents

• Favorable and easily controlled adverse effects

• Ease of administration• No need for hospitalization

• Preterm labor related annual hospitalization expenses are in excess of $ 1 billion (Economic Burden of Hospitalization for Preterm Labor in the United States, Obstet Gynecol, 2000;96:95-101)


One of the most salient features of our culture is that there is so much bullshit.

Ένα από τα πιο έντονα χαρακτηριστικά τηςκοινωνίας µας είναι το ακατάσχετο

«παραµύθιασµα».

Harry G. Frankfurt Philosopher, Princeton University


Preterm Labor Versus Incompetent Cervix

Preterm Labor Versus Incompetent Cervix

Preterm Labor

Incompetent Cervix

Co-existing preterm labor and incompetent cervix


Cervical assessment:transvaginal ultrasound

Cervical assessment:transvaginal Cervical assessment:transvaginal ultrasoundultrasound


18mm

37 mm

39 mm

Indomethacin


Patients at high-risk for preterm birthPatients at highPatients at high--risk for preterm birthrisk for preterm birth

• Patients with history of infertility (RPL, OI-IUI and IVF) {J Obstet Gynaecol Can 2005 May;27(5):449-59},{BMJ 2004 Jan 31;328(7434):261},{Obstet Gynecol 2004 Mar; 103(3):551-63},{Obstet Gynecol 1995 Aug;86(2):188-92}

• Patients with previous preterm birth who have a risk as high as 30-60% for a subsequent preterm delivery. {N Engl J Med 2003;348:2379-85}

• Patients with placental Thrombosis, which is known to cause placental ischemia and subsequent preterm delivery and growth failure. {Kofinas A et al. Ultrasound Obstet Gynecol, in Press, J Matern Fetal Med. 2001 Oct;10(5):297-300, Am J Obstet Gynecol 2004;191:1996-2001, Am J Obstet Gynecol 2001; 185:1059-63.}

• Patients who experience one or all of the following symptoms (see next slide)


Vague preterm labor related symptoms

Vague preterm labor related Vague preterm labor related symptomssymptoms

• Pelvic pressure• A feeling of stretching and pulling in the pelvis• Low back pain (in the region of the tail-bone).• Pressure in the vagina• Excessive discharge (feeling wet in the vagina)• Having pelvic discomfort that they cannot define

clearly• A feeling of menstrual cramping• Intermittent deep pelvic discomfort• Gas pains• Rectal pressure and constipation


Kofinas Perinatal ProtocolKofinas Perinatal Protocol<24 Cervix <35 mm

Normal >34 mm Complete bed rest 15<Cervix<25 mm

One week later

>34 mm

Indomethacin 50 mg q6h one week

Cervix < 15 mm

Cervix < 25 mm Cervix >25 mmCerclage

Nifedipine

Indomethacin

Cervix>25 mm

Nifedipine Only

Cervix<25 mm

Cervix>35 mm

Bed rest Only

Cervix > 35 mm with bed rest

Normal CareRF

NRF

RF=Risk Factors, NRF=No Risk Factors


Kofinas Perinatal

Expected in High Risk Reduction from

Complications Incidence Patients High risk level

Chronic Hypertension 3% 3% 0%

Chronic Hypertension w/ PE 0.6% 1.50% -30%

Pregnancy Induced Hypertension. (PIH) 0.30% 15% -98%

Abruptio Placentae 1% 3% -66%

Oligohydramnios 3.7% 15% -74%

Preterm PROM 0.80% 10% -94%

Preterm Delivery 5.90% 30% -80%

Total Pregnancy loss 4% 29% -86%

Fetal death > 20 weeks 0% 4.40% -100%

Low birth weight (<2500) 5.30% 30% -82%

Antepartum Admissions 2% 30% -94%


Elements of SuccessElements of SuccessElements of Success• Find the mechanism of Preterm labor (ideally) and treat

specifically the underline pathology (needs a strong dose of optimism)

• Establish screening tools to identify patients at risk• Establish a reliable, consistent, objective and reproducible

method to diagnose preterm labor• Establish treatment methods for positive

– Patient education– Preventive treatment schemes– Early intervention when progressive cervical shortening is present

• Educate physicians to use above (get the horse to the spring and convince it to also drink water!!!!)


Neonatal Side-effects of β2-agonistsNeonatal SideNeonatal Side--effectseffects of of ββ22--agonistsagonists

Developmental toxicity of terbutaline: Critical periods for sex-selective effects on acromolecules and DNA synthesis in rat brain, heart, and liver.

These effects may contribute to neuropsychiatric, cognitive, cardiovascular, and metabolic abnormalities reported in the offspring of women treated with beta-agonist tocolytics.

Garofolo MC, Seidler FJ, Cousins MM, Tate CA, Qiao D, Slotkin TA.

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA

Brain Res Bull 2003 Jan 15;59(4):319-29


7.6 MILLION PERINATAL DEATHS OCCUR ANNUALLY WORLDWIDE7.6 MILLION PERINATAL DEATHS 7.6 MILLION PERINATAL DEATHS OCCUR ANNUALLY WORLDWIDEOCCUR ANNUALLY WORLDWIDE

Almost all (98%) perinatal deaths take place in developing countries, where out of every 1000 babies born, 57 are either born dead or die within the first week of life. This is five times the rate in developed countries where the perinatal mortality rate is estimated to be only 11 per 1000 births. The highest rates are found in western, central and eastern Africa (about 80 per 1000 births), with south-central Asia close behind (66 per 1000 births).High levels of perinatal mortality are found in the same places where maternal deaths are high and where many births are not attended by skilled personnel.

Family and Reproductive Health, WHO, Geneva, Switzerland, 1996.


Epidemiology: associated etiologic factorsEpidemiology: associated etiologic factorsEpidemiology: associated etiologic factors

• Socioeconomic status• Ethnic origin• Age and parity• Reproductive history (history of infertility)• Substance abuse• Inflammation

– Infectious (less than originally thought)– Non-infectious inflammatory processes

Lancet 2002;360:1489


Epidemiology: neonatal morbidityEpidemiology: neonatal morbidityEpidemiology: neonatal morbidity• Cerebral palsy/mental deficiencies• Blindness (retinopathy of prematurity)• Deficient physical development• Behavioral and social maladaptation• Chronic lung disease• Susceptibility to infection (infectious morbidity)• Necrotizing enterocolitis• Increased risk for such adulthood diseases as:

– Obesity/Diabetes– Cardiovascular disease– Cerebrovascular disease


Reasons of our failureReasons of our failureReasons of our failure• Complex etiology

– Unknown mechanism of labor – Multiple conditions may trigger labor

• Poor diagnostic accuracy– False labor– Early labor– Active labor

• Poor risk assignment– Complexity of various inter-related risk factors

• Poor therapeutic modalities or poor selection?– Smooth muscle relaxants

• Various tocolytics– Anti-inflammatory

• Indomethacin• 17-a-hydroxyprogesterone caproate

– Mechanical (cerclage)


Preterm Labor ManagementPreterm Labor ManagementPreterm Labor Management• Presence of true labor• Role of expectant management• Gestational age effect• Etiology of labor and tocolytic agent selection

– Inflammation/Infection– Ischaemia– Over-distention

cervical insufficiency preterm labor continuum · 8/3/2007 cervical insufficiency-preterm labor...

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