Pathophysiology of preterm labor

Pathophysiology of preterm labor

1. Dr Majaz Ahmed Khan Fellow Neonatology Pathophysiology of Preterm Birth

2. INTRODUCTION Accounts for 6% to 10% of all births. Two thirds of all perinatal deaths > 34 weeks + minor morbidities = 37 weeks. < 34 weeks accounts for 3-7 % of all preterm births( 75% of neonatal death and 50% of long term neurologic impairment.)

3. Risk factors for preterm labor- Race Age- low maternal age Socioeconomic status-inadequate nutrition, substance abuse, psychological factors Body mass index (BMI)-low BMI, poor weight gain, excess weight gain, obesity. Alcohol consumption Smoking Cocaine exposure Maternal stress— Activates–- maternal, placental ,fetal endocrine system --- promote parturition by way of an immune or inflammatory pathway.

4. Endocrinology and Biochemistry of Labor- During pregnancy- PROPREGNANCY -progesterone and PGI2 –inhibit myometrial contraction. At end of pregnancy- PROLABOR - Remodeling of cervix / uterus is stimulated to begin coordinated contractions. Labor occurs due to activation of cassette of contraction-associated proteins (CAPs) / labor associated proteins — Gap junction proteins Oxytocin Prostanoid receptors Enzymes for prostaglandin synthesis Cell signaling proteins.

5. Inflammation/Infection- Up-regulation of proinflammatory genes in fetal membranes/ myometrium / cervix. Transcription factor nuclear factor kappa B (NF-кB) is activated in uterus. Promotes IL-6 and IL-8 and COX-2 cervical ripening Prostglandin synthesis

6. Transcription factor nuclear factor kappa B (NF-кB) Down regulates progesterone receptors leading to functional progesterone withdrawal.

7. Corticotropin-Releasing Hormone- produced by- Hypothalamus/ placenta / maternal serum. Rise in the second half of pregnancy Peak during labor Rapidly decline post partum. CRH raised as early as 18 weeks of gestation in PTL. CRH concentrations could help identify women at high risk for preterm delivery CRH antagonists may be useful in preventing preterm labor.

8. Progesterone- Inhibit labor associated gene expression and inhibit contractions. PR antagonist RU486 can be used to ripen the cervix and induce labor. PTL occurs if increased expression of PR-A relative to PR-B. Oxytocin- Increase in OTR mRNA concentrations in the myometrium are associated with up-regulation of OT-binding sites and causes onset of PTL.

9. CAUSES OF PRETERM LABOR Causes- Intrauterine infection(chorioamnionitis) Placental abruption Cervical incompetence Premature membrane rupture Multiple pregnancy Intrauterine death Fetal and uterine abnormalities Genetic factors Hypertensive disorders.

10. Infection- Activates biochemical pathways leading to cervical ripening and uterine contractions. After twin preterm delivery, chorioamnionitis is more common and severe in the presenting twin than in the second twin. Indicating ascending infection-organism identical to that in the maternal lower genital tract.

11. organism settles in decidua of the lower segment. leading to deciduitis, chorionitis extension through the amnion into the amniotic cavity To fetus from aspiration and swallowing Most common organisms- Ureaplasma urealyticum, Fusobacterium, Mycoplasma hominis, Bacterial vaginosis and Trichomonas vaginalis.

12. chronic periodontal disease reservoir for bacterial products or inflammatory mediators leading to infection. causative pathogens include Prevotella and Porphyromomas species.

13. 2.PLACENTAL ABRUPTION- Placental abruption Release thrombin Protease activated recptors stimulates myometrial contractions

14. 3.Cervical Incompetence- Normal uterus is composed of collagen arranged in fibers and embedded in proteoglycans. Other components include a small amount of smooth muscle (10%) and some fibroblast cells. A t onset of labor-Decrease in collagen associated with an increase in cervical prostaglandins, proinflammatory cytokines, leukocytes, cell adhesion molecules , and nitric oxide synthase production. Ascending infection- increased inflammatory response leading to cervical shortening and dilation.

15. 4.Multiple Pregnancies/ polyhydramnios- Over distention of the uterus up-regulation of contraction-associated proteins Increase the expression of COX-2 and PGE2 synthesis. Multiple pregnancy-multiple placenta increased CRH earlier higher rates of preterm birth.

16. 5.Genetics- SNP of Matrix metalloproteinases (MMPs ) causes extracellular matrix degradation leading to rupture of membranes and cervical ripening and dilatation. 3 fold increase if 1 st delivery is a preterm birth 1/3 rd increase if two previous deliveries are preterm births Risk transmission to off springs.

17. Management of Preterm Labor The key aspects in management are- Establishment of diagnosis Need to inhibit/deliver Investigation about causes of labor Assessment of gestational age, expected fetal weight and associated fetal complications Tocolysis/steroids in selected cases Choosing of mode of delivery and place of delivery Provision of necessary neonatal back up.

18. Diagnosis of Preterm Labor- For documenting true preterm labor the following criteria should be met– Regular uterine contractions after 20 weeks and before 37 weeks which are 5-8 minutes apart or less and accompanied by one or more of the following: progressive change in cervix cervical dilatation of 2 cm or more cervical effacement 80 percent or more .

19. PREDICTION OF PRETERM LABOR Fetal fibronectin- Location- deciduas basalis next to the placental intervillous space. Function- fetal membranes to the uterine decidua. Mechanical/inflammatory changes- leaked into the cervicovaginal fluid. Strong negative predictive value:0.5 % deliver within 7 to 10 days after a negative test result. If > 50 ng/ml greatest odds ratio for preterm delivery before 35 weeks gestation.

20. 2.Cervical Length Measurement- Cervical Length-30 mm risk < 1% Cervical Length-5 mm risk > 80%. Inhibition of Preterm Labor The commonly used drugs are beta- mimetics , calcium channel blockers, prostaglandin synthetase inhibitors and magnesium sulfate .

21. Contraindications to Inhibition of Preterm Labor Absolute Congenital fetal malformation incompatible with life Intrauterine fetal death Chorioamnionitis Abruptio placentae Fetal distress Uncontrolled diabetes and thyrotoxicosis Relative Placenta praevia Intrauterine growth retardation Maternal hypertension

22. PREVENTION OF PRETERM LABOR Cerclage- NNT is 25, so indication is > 3 2 nd trimister losses(halved the incidence of PTL before 33 weeks) TRANSVAGINAL TRANSABDOMINAL McDonald Shirodkar failed vaginal cerclage. Suture at junction of vagina and cervix Suture at cervico isthmic junction Suture placed above cardinal and uterosacral ligament. Suture removed at 37-38 weeks to allow NVD -

23. 2. Progesterone- 100 mg of progesterone as a vaginal suppository between 24 and 34 weeks. Significant reduction in preterm delivery rates before 37 weeks and before 34 weeks in high-risk populations. Reduction in the incidence of birth weight less than 2500 g, necrotizing enterocolitis, intraventricular hemorrhage, and the need for supplemental oxygen. No reduction in perinatal death or respiratory distress syndrome . NNT is 7.

24. 3.Role of Antibiotics in Preterm Labor- In meta-analysis of 13 randomized studies about efficacy of antibiotics benefit was found with regards to chorioamnionitis, neonatal sepsis and prolongation of pregnancy by 7 days. But severe neonatal morbidity in the form of necrotizing enterocolitis, respiratory distress and intracranial hemorrhage and neonatal survival were not improved.

25. 4. Measures to Prevent Intraventricular Hemorrhage- Corticosteroids are beneficial in reducing Periventricular hemorrhage. The other interventions that are considered are Antenatal Vit K: Periventricular hemorrhages are shown to be reduced by Antenatally administered Vit K. Antenatal phenobarbitone: Phenobarbitone when given to mothers Antenatally is shown to reduce postnatal intraventricular hemorrhages in the infant . However, in a recent report the combination of vitamin K and phenobarbitone was found to cause a small and insignificant reduction in intraventricular hemorrhage .

26. Exact mechanism and cause of idiopathic preterm labor is still largely unknown. However, the role of antenatal steroids and antibiotics is largely established in improving perinatal outcome Provided when such deliveries are conducted at a well appointed maternal unit of a institution with appropriate neonatal units equipped and trained for such eventualities.

27. Thank You