1. Preterm premature rupture of membranes
Dr Movahed

2. INTRODUCTION
This term defines spontaneous rupture of the fetal membranes before 37 completed weeks and before labor onset (American College of Obstetricians and Gynecologists, 2013d).
Such rupture likely has various causes, but intrauterine infection is believed by many to be a major predisposing event.
There are associated risk factors that include low socioeconomic status, body mass index < 19.8, nutritional deficiencies, and cigarette smoking.

3. INTRODUCTION
Women with prior preterm premature rupture of membranes (PPROM) are at increased risk for recurrence during a subsequent pregnancy.
Despite these known risk factors, none is identified in most cases of preterm rupture.

4. INCIDENCE
PPROM occurs in 3 percent of pregnancies and is responsible for, or associated with, approximately one-third of preterm births.

5. PATHOGENESIS 
The pathogenesis of spontaneous membrane rupture is not completely understood.
The strength and integrity of fetal membranes derive from extracellular membrane proteins, including collagens, fibronectin, and laminins.
Matrix metalloproteases (MMPs) decrease membrane strength by increasing collagen degradation.
Tissue inhibitors of MMPs (TIMMPs) bind to MMPs and shut down proteolysis, thereby helping to maintain membrane integrity.

6. A variety of pathologic events can disrupt this homeostasis and initiate a cascade of biochemical changes that culminate in PROM.
The MMP-1, MMP-2, MMP-3, and MMP-9 members of this family are found in higher concentrations in amnionic fluid from pregnancies with preterm prematurely ruptured membranes.
Studies of amniochorion explants have demonstrated that the expression of MMPs can be increased by treatment with IL-1,TNF-α, and IL-6.
Recent studies by Mogami (2013) provide a mechanism by which bacterial endotoxin or TNF-α elicits release of fetal fibronectin (fFN) by amnion epithelial cells.

7. The fFN then binds Toll-like receptor 4 in the amnion mesenchymal cells to activate signaling cascades.
These result in increased PGE2 synthesis and elevated activity of MMP-1, MMP-2, and MMP-9.
Increased prostaglandin levels promote cervical ripening and uterine contractions.
Increased MMPs allow collagen breakdown in the fetal membranes resulting in premature rupture.

8. ANTECEDENTS AND CONTRIBUTING FACTORS

9. Threatened Abortion
Vaginal bleeding in early pregnancy is associated with increased adverse outcomes later.
Weiss (2004) reported outcomes with vaginal bleeding at 6 to 13 weeks in nearly 14,000 women.
Both light and heavy bleeding were associated with subsequent preterm labor, placental abruption, and subsequent pregnancy loss before 24 weeks.

10. Lifestyle Factors
Cigarette smoking, inadequate maternal weight gain, and illicit drug use have important roles in both the incidence and outcome of low-birth weight neonates.
Overweight and obese mothers have an elevated risk of preterm birth.
Other maternal factors implicated include young or advanced maternal age, poverty, short stature, and vitamin C deficiency.
Psychological factors such as depression, anxiety, and chronic stress have been reported in association with preterm birth.

11. Lifestyle Factors
Neggers and coworkers (2004) found a significant link between low birth weight and preterm birth in women injured by physical abuse.
Studies of work and physical activity related to preterm birth have produced conflicting results.
There is some evidence, however, that working long hours and hard physical labor are probably associated with increased risk of preterm birth.

12. Genetic Factors
The recurrent, familial, and racial nature of preterm birth has led to the suggestion that genetics may play a causal role.
Several studies have also implicated immunoregulatory genes in potentiating chorioamnionitis in cases of preterm delivery due to infection.

13. Birth Defects
In a secondary analysis of data from the First- and Second-Trimester Evaluation of Risk (FASTER) Trial, it was found that birth defects were associated with preterm birth and low birth weight.

14. Periodontal Disease
Gum inflammation is a chronic anaerobic inflammation that affects as many as 50 percent of pregnant women in the United States.
Vergnes and Sixou (2007) performed a meta analysis of 17 studies and concluded that periodontal disease was significantly associated with preterm birth.
The researchers concluded, however, that the data were not robust enough to recommend screening and treatment of pregnant women.

15. Periodontal Disease
Michalowicz (2006) randomly assigned 813 pregnant women between 13 and 17 weeks’ gestation who had periodontal disease to treatment during pregnancy or postpartum.
They found that treatment during pregnancy improved periodontal disease and that it is safe. However, treatment failed to significantly alter preterm birth rates.

16. Interval between Pregnancies
Short intervals between pregnancies have been known for some time to be associated with adverse perinatal outcomes.
In a meta analysis reported that intervals < 18 months and > 59 months were associated with increased risks for both preterm birth and small for gestational age newborns.

17. Prior Preterm Birth
A major risk factor for preterm labor is prior preterm delivery.
The recurrent preterm delivery risk for women whose first delivery was preterm was increased threefold compared with that of women whose first neonate was born at term.
More than a third of women whose first two newborns were preterm subsequently delivered a third preterm newborn.
Most—70 percent—of the recurrent births occurred within 2 weeks of the gestational age of the prior preterm delivery.
Importantly, the causes of prior preterm delivery also recurred.

19. Infection
A link between preterm birth and infection seems irrefutable.
Intrauterine infections are believed to trigger preterm labor by activation of the innate immune system.
In this hypothesis, microorganisms elicit release of inflammatory cytokines such as interleukins and TNF-α, which in turn stimulate the production of prostaglandin and/or matrix-degrading enzymes.
Prostaglandins stimulate uterine contractions, whereas degradation of extracellular matrix in the fetal membranes leads to preterm rupture of membranes.

20. It is estimated that 25 to 40 percent of preterm births result from intrauterine infection.
In several studies, antimicrobial treatment has been given to prevent preterm labor due to microbial invasion.
Based on available data, these strategies especially targeted mycoplasma species.
Morency and colleagues (2007) performed a meta analysis of 61 articles and suggested that antimicrobials given in the second trimester may prevent subsequent preterm birth.

21. Andrews and associates (2006) reported results of a double-blind interconceptional trial in which they gave a course of azithromycin plus metronidazole every 4 months to 241 nonpregnant women whose last pregnancy resulted in spontaneous delivery before 34 weeks. Approximately 80 percent of the women with subsequent pregnancies had received study drug within 6 months of their subsequent conception. Such interconceptional antimicrobial treatment did not reduce the rate of recurrent preterm birth.
Tita and coworkers (2007) performed a subgroup analysis of these same data and concluded that such use of antimicrobials may be harmful.
In another study, Goldenberg and colleagues (2006) randomized 2661 women at four African sites to placebo or metronidazole plus erythromycin between 20 and 24 weeks’ gestation followed by ampicillin plus metronidazole during labor. This antimicrobial regimen did not reduce the rate of preterm birth or that of histological chorioamnionitis.

22. Bacterial Vaginosis
In this condition, normal, hydrogen peroxide-producing, lactobacillus-predominant vaginal flora is replaced with anaerobes that include Gardnerella vaginalis, Mycoplasma hominis.
Bacterial vaginosis has been associated with spontaneous abortion, preterm labor, PPROM, chorioamnionitis, and amnionic fluid infection.
Environmental factors appear to be important in bacterial vaginosis development. Exposure to chronic stress, ethnic differences, and frequent or recent douching have all been associated with increased rates of the condition.

23. From all of these studies, there seems no doubt that adverse vaginal flora is associated in some way with spontaneous preterm birth.
Unfortunately, to date, screening and treatment have not been shown to prevent preterm birth. Indeed, microbial resistance or antimicrobial-induced change in the vaginal flora has been reported as a result of regimens intended to eliminate bacterial vaginosis.
Okun and associates (2005) performed a systematic review of antibiotics given for bacterial vaginosis and for Trichomonas vaginalis. They found no evidence to support such use for the prevention of preterm birth in either low-risk or high-risk women.

24. Multifetal Gestation
multifetal births account for approximately 3 percent of infants born in the United States.
The majority—95 percent—of these births are twins.
The increased rate of multifetal births is due to the increased number of women having babies after the age of 30, at which time the risk to conceive multiples rises.
In addition, the use of fertility treatments has contributed to the elevated rates of multifetal pregnancies.
Preterm delivery continues to be the major cause of the excessive perinatal morbidity and mortality with multifetal pregnancies.

25. The effects of uterine stretch are obvious in these pregnancies, and this likely is related to the increased incidence of preterm cervical dilatation.
It is likely that early uterine distention acts to initiate expression of contraction-associated proteins (CAPs) in the myometrium.
Excessive uterine stretch also leads to early activation of the placental–fetal endocrine cascade
The resulting early rise in maternal corticotropin-releasing hormone and estrogen levels can further enhance the expression of myometrial CAP genes.

26. Summary of Preterm Labor Pathophysiology
Preterm labor is a pathological condition with multiple etiologies.
Most research in this field has been focused on the role of infection in mediating preterm birth. It is possible that intrauterine infection causes some cases currently categorized as idiopathic spontaneous preterm labor.

27. Infection does not explain all causes of preterm birth
Infection does not explain all causes of preterm birth. In recent years, our understanding of other influences on the parturition process, such as maternal nutrition before or during pregnancy, genetics, the vaginal microbiome, and dynamic regulation of the extracellular matrix, has led to new avenues of research.
The current and future application of genomic and bioinformatics as well as molecular and biochemical studies will shed light on pathways involved in term and preterm labor.