Preterm premature rupture of the fetal membranes: Current concepts

Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA.
Minerva ginecologica 09/2005; 57(4):389-96.
Source: PubMed


Preterm birth and preterm premature rupture of membranes (PPROM) are common causes of perinatal morbidity and mortality. Fetal membrane integrity is regulated partially by collagenases and inhibitors. A number of genetic polymorphisms with genes related to infection, inflammation and collagen degradation have been identified and studies as risk factors for PPROM. This manuscript reviews the state of the science on the pathophysiology of PPROM and possible genetic influences.

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    • "About one-third of PTBs result from the preterm premature rupture of membranes (PPROM) [2]. Although PPROM is usually caused by reproductive genital infections and inflammatory reactions of cytokine and chemokine pathways, and involves the extracellular matrix (ECM) [3]–[5], the pathogenic mechanisms underlying the remaining PTB are not yet well understood. Infections have been associated with and well characterized in PPROM [6], [7]. "
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    ABSTRACT: Preterm birth (PTB) is a live birth delivered before 37 weeks of gestation (GW). About one-third of PTBs result from the preterm premature rupture of membranes (PPROM). Up to the present, the pathogenic mechanisms underlying PPROM are not clearly understood. Here, we investigated the differential expression of long chain non-coding RNAs (lncRNAs) in placentas of PTBs with PPROM, and their possible involvement in the pathogenic pathways leading to PPROM. A total number of 1954, 776, and 1050 lncRNAs were identified with a microarray from placentas of PPROM (group A), which were compared to full-term birth (FTB) (group B), PTB (group C), and premature rupture of membrane (PROM) (group D) at full-term, respectively. Instead of investigating the individual pathogenic role of each lncRNA involved in the molecular mechanism underlying PPROM, we have focused on investigating the metabolic pathways and their functions to explore what is the likely association and how they are possibly involved in the development of PPROM. Six groups, including up-regulation and down-regulation in the comparisons of A vs. B, A vs. C, and A vs. D, of pathways were analyzed. Our results showed that 22 pathways were characterized as up-regulated 7 down-regulated in A vs. C, 18 up-regulated and 15 down-regulated in A vs. D, and 33 up-regulated and 7 down-regulated in A vs. B. Functional analysis showed pathways of infection and inflammatory response, ECM-receptor interactions, apoptosis, actin cytoskeleton, and smooth muscle contraction are the major pathogenic mechanisms involved in the development of PPROM. Characterization of these pathways through identification of lncRNAs opened new avenues for further investigating the epigenomic mechanisms of lncRNAs in PPROM as well as PTB.
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    ABSTRACT: Premature delivery is a major cause of neonatal morbidity and mortality. The incidence of premature deliveries has increased around the world. In Finland 5.3%, or about 3,000 children per year are born prematurely, before 37 weeks of gestation. The corresponding figure in the United States is about 13%. The morbidity and mortality are highest among infants delivered before 32 weeks of gestation - about 600 children each year in Finland. Approximately 70% of premature deliveries are unexplained. Preterm delivery can be caused by an asympto-matic infection between uterus and the fetal membranes, such can begin already in early pregnancy. It is difficult to predict preterm delivery, and many patients are therefore unnecessarily admitted to hospital for observation and exposed to medical treatments. On the other hand, the high risk women should be identified early for the best treatment of the mother and preterm infant. --- In the prospective study conducted at the Department of Obstetric and Gynecology, Helsinki University Central Hospital two biochemical inflammation related markers were measured in the lower genital tract fluids of asymp-tomatic women in early and mid pregnancy in an order to see whether these markers could identify women with an increased risk of preterm delivery. These biomarkers were phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) and matrix metalloproteinase-8 (MMP-8). The study involved 5180 asymptomatic pregnant women, examined during the first and second ultrasound screening visits. The study samples were taken from the vagina and cervicix. In addition, 246 symptomatic women were studied (pregnancy weeks 22 – 34). The study showed that increased phIGFBP-1 concentration in cervical canal fluid in early pregnancy increased the risk for preterm delivery. The risk for very premature birth (before 32 weeks of gestation) was nearly four-fold. Low MMP-8 concentration in mid pregnancy increased the risk of subsequent premature preterm rupture of fetal membranes (PPROM). Significantly high MMP-8 concentrations in the cervical fluid increased the risk for prema-ture delivery initiated by preterm labour with intact membranes. Among women with preterm contractions the shortened cervical length measured by ultrasound and elevated cervical fluid phIGFBP-1 both predicted premature delivery. In summary, because of the relatively low sensitivity of cervical fluid phIGFBP-1 this biomarker is not suitable for routine screening, but provides an additional tool in assessing the risk of preterm delivery. Cervical fluid MMP-8 is not useful in early or mid pregnancy in predicting premature delivery because of its dual role. Further studies on the role of MMP-8 are therefore needed. Our study confirms that phIGFBP-1 testing is useful in predicting pre-term delivery. Ennenaikainen synnytys on suurin vastasyntyneen sairastavuutta ja kuolleisuutta aiheuttava tekijä. Huolimatta lääketieteen kehittymisestä ennenaikaisten synnytysten määrä maailmalla on lisääntynyt. Suomessa 5,3 % eli noin 3000 lasta syntyy ennenaikaisesti ennen 37. raskausviikon päättymistä. Vastaava luku Yhdysvalloissa on n.13 %. Suurimmassa sairastumis- ja vammautumisvaarassa ovat ennen 32 raskausviikkoa syntyneet lapset, joita Suomessa syntyy vuosittain noin 600. Ennenaikaisista synnytyksistä noin 70 % tapahtuu ilman tiedossa olevaa syytä, mutta jopa puolessa syynä oletetaan olevan kohdun seinämän ja sikiökalvojen välissä oleva oireeton tulehdus, joka voi alkaa jo alkuraskaudessa. Koska nykyisillä menetelmillä emme pysty riittävän hyvin ennustamaan ennenaikaista synnytystä, joudutaan monia potilaita ottamaan tarpeettomasti sairaalaseurantaan ja lääkehoitoihin. Toisaalta todellisessa riskissä olevat äidit pitäisi tunnistaa ja ohjata oikeaan synnytyssairaalaan, missä ennenaikaisesti synytynyt lapsi saa parhaan hoidon. HYKS:in synnytyssairaaloissa (Kätilöopisto, Naistenklinikka ja Jorvi) tehdyssä tutkimuksessa selvitettiin voidaanko tulehdusta osoittavien merkkiaineiden määrityksellä tunnistaa jo alku- tai keskiraskaudessa ne naiset, joilla on suurentunut ennenaikaisen synnytyksen vaara. Merkkiaineina käytettiin insuliininkaltaisen kasvutekijän sitojaproteiinia (phIGFBP-1) ja matrix metalloproteinaasia 8 (MMP-8). Tutkimukseen osallistui 5180 oireetonta raskaana olevaa naista, joilta otettiin tutkimusnäytteet emättimestä ja kohdunkaulakanavasta alku- ja keskiraskauden ultraääniseulontojen yhteydessä. Lisäksi tutkittiin 246 oireilevaa supistelevaa naista raskausviikoilla 22 - 34. Tutkimus osoitti, että suurentunut phIGFBP-1 pitoisuus kohdunkaulanavassa jo alkuraskaudessa lisäsi ennenaikaisen synnytyksen vaaraa. Vaara synnyttää hyvin ennenaikaisesti (ennen 32 raskausviikkoa) oli lähes nelinkertainen. Matala MMP-8 pitoisuus keskiraskaudessa lisäsi sikiökalvojen puhkeamisen riskiä ja huomattavan korkeita MMP-8 pitoisuuksia synnytyskanavassa oli naisilla, joilla ennenaikainen synnytys alkoi ennenaikaisilla supistuksilla. Ennenaikaisesti supistelevilla naisilla kohdun kaulakanavan mittaus ultraäänellä ja phIGFBP-1 pitoisuuden määritys kohdunkaulakanavavasta yhdessä ennustivat parhaiten ennenaikaista synnytystä. Yhteenvetona voidaan todeta, että kohdunkaulakanavan phIGFBP-1 tarjoaa lisätyökalun arvioitaessa ennenaikaisen synnytyksen vaaraa. MMP-8 ei sovellu alku- ja keskiraskaudessa kliiniseen käyttöön ennenaikaisen synnytyksen ennustamiseen johtuen sen kaksijakoisuudesta. Lisätutkimuksia MMP-8 merkityksestä alemmissa synnytyselimissä siis tarvitaan. Tutkimuksemme vahvistaa phIGFBP-n käyttökelpoisuuden ennenaikaisen synnytyksen ennustamisessa.
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