Volume 27, Issue 1

Clinical and experimental evidence indicate that PTD results from four primary pathogenic mechanisms: activation of the maternal or fetal HPA axis; amniochorionic-decidual or systemic inflammation; decidual hemorrhage; and, pathologic distention of the myometrium . Each of these four pathways has a distinct epidemiological and clinical profile, and unique biochemical and biophysical pathways initiating parturition, but shares a common final biochemical pathway involving myometrial activation and stimulation, and enhanced genital tract protease activity promoting PPROM and cervical change. Traditional methods of predicting women at risk relying on obstetrical history or symptoms and epidemiological risk factors are neither sensitive nor specific. Recent approaches to predicting PTD, including sonographic measurement of cervical length and biochemical assays for hCG, cytokines, fFN, MMPs, estrogens, and CRH, are more sensitive than traditional methods. Moreover, given the heterogeneous, interactive etiopathogeneses of PTD, multiple biochemical markers should not only increase sensitivity and specificity, but also permit the detection of the relative contribution of each pathogenesis to the overall risk of PTD.

This paper reviews data that support the effectiveness of the French approach of using risk scoring for evaluating the risk of preterm delivery. This approach, which was developed in 1969 and spread to obstetricians and midwives throughout France in the early 1970s, includes systematic information about the recognition of uterine contractions, advice about reduction of physical exercise, and the prescription of work-leave for women with heavy or physically demanding work loads. The effectiveness of this prevention strategy is assessed using three different data sets: an evaluation of a pre-term prevention program in the Alsace Region of France, five successive French national sample surveys which collected data on pregnant women, and a study of the effectiveness of a prevention program for twins in the district of Haut de Seine near Paris. The authors show that the rate of preterm birth in France declined substantially, but that the decline was concentrated among singleton spontaneous births. Since the 1970s induced preterm births have increased, and, interventions have not reduced the high rates of preterm birth among twins.

In summary, these studies have suggested that prostaglandin dehydrogenase may have a central role to play in the mechanisms which determine biologically active prostaglandin concentrations within human fetal membranes and placenta at the time of labor, at term or preterm. Moreover, our studies indicate that the regulation of PGDH may by multifactorial (figure 3). In certain regions of the membranes, we suggest that PGDH expression may be influenced by levels of anti-inflammatory and pro-inflammatory cytokines. In other regions of the membranes, we suggest that PGDH may be regulated at a transcriptional level by competing activities of progesterone and cortisol. The action of progesterone could be effected through systemically-derived steroid, or by locally synthesized steroid, acting in a paracrine and/or autocrine fashion. The effects of cortisol in placenta must be due to glucocorticoid derived from the maternal or fetal compartment, since the placenta lacks the hydroxylases required for endogenous cortisol production. However, metabolism of cortisol by 11β-HSD-2 reduces the potency of this glucocorticoid in placental tissue. In chorion however, cortisol may be formed locally, from cortisone, in addition to its being derived from the maternal circulation and/or from the amniotic fluid. Our current studies do not allow us to delineate whether the effects of progesterone and cortisol on PGDH are exerted through the glucocorticoid receptor (GR) or progesterone receptor (PR) or both. It is possible that through pregnancy, PGDH activity is maintained by progesterone acting either through low levels of PR in membranes, or, more likely, acting through GR. At term, elevated levels of cortisol compete with and displace progesterone from GR, resulting in inhibition of PGDH transcription and activity. In this way, local withdrawal of progesterone action would be effected within human intrauterine tissues, without requiring changes in systemic, circulating progesterone concentrations. Since glucocorticoids appear also to increase expression of prostaglandin synthesizing enzymes within the amnion and chorion, directly by upregulating PGHS-2, or indirectly through the intermediary action of a paracrine effector such as CRH, their role in coordinating processes of parturition remains central. Further understanding of the regulation of PGDH may be of therapeutic importance. For example, it is possible that PGDH activity in lower segment chorion may be reduced in those patients with premature cervical softening, or may be particularly high in those patients with an unfavorable cervix, presenting with a low Bishop score and poor progression at the time of labor. If the enzyme in this region crucially determines the passage and availability of biologically active prostaglandins from amnion and chorion to underlying cervix, then pharmacologic manipulation of PGDH activity may effectively regulate PG transfer in these clinical conditions. Glucocorticoids appear to have a central role in promoting production of agents that are uterotonic to myometrial activity. It is likely that these activities explain the transient increments in uterine contractility reported in patients receiving prenatal corticosteroids to promote fetal pulmonary maturity [11]. Recognition of this physiology suggests that careful monitoring of these patients is advised, and would argue further against repeated, indiscriminate, use of glucocorticoids in patients with an inappropriate diagnosis of threatened preterm labor.

Our intention is to review recent data and provide recommendations for the use of antibiotics in cases of preterm labor or preterm premature rupture of the membranes (pPROM). Various studies assessing antibiotics as treatment for preterm labor demonstrate neonatal or maternal benefits only in certain circumstances. Antibiotic treatment should be given to patients with bacterial vaginosis and Trichomonas vaginalis . Currently, antibiotics should not be applied routinely to prolong pregnancy in women with preterm labor and intact membranes. However, antibiotic therapy should be given to patients with pPROM to prolong pregnancies at 24 to 32 weeks' gestation. Our management of pPROM up to 32 weeks' gestation includes use of corticosteroids, antibiotic (extended spectrum penicillins) and tocolytic treatment for preterm labor and pregnancy prolongation. We consider expectant management previous to evidence of intrauterine infection. In women with pPROM at 32 to 34 weeks we found it beneficial to deliver 24 hours after administration of corticosteroids or, in cases of intrauterine infection, immediately. Finally, we report on our research work regarding fetal brain development in preterm birth. Further studies will be necessary to clarify the role of the interleukin-6/interleukin-6 receptor pathway in the development of intracerebral hemorrhage frequently occuring in premature infants.

We are now in the era of Evidence-based Medicine and many people involved in purchasing and supporting health care together with the general public are demanding that clinical practice be based upon sound scientific evidence of efficacy and safety. It is now possible to evaluate many interventions in perinatal medicine by examining the results of systematic reviews. For example, interventions that are effective for neonatal respiratory failure have recently been published. The practice of neonatal intensive care is approximately 90% evidence based but there is still room for improvement. Much more work needs to be done in preparing systematic reviews for the Cochrane Library. European reviewers in perinatal medicine, comprising pregnancy and childbirth and neonatology, would be welcomed. Perhaps for the new millennium we will be able to boast that the practice of perinatal medicine is totally evidence-based.

The key function of the uterine cervix to maintain pregnancy is biochemically characterized by an increased synthesis of proteins (e. g., collagen), proteoglycans, and glycoproteins (e. g., fibronectin) as well as by defined interactions between these components of the extracellular matrix. In contrast to the slow phase of the cervical ripening process in late pregnancy, cervical dilatation during parturition requires the rapid production and action of catabolic enzymes leading mainly to collagen degradation and changes in its architecture but also to degradation of other fundamental matrix proteins. Evidence suggests that an increased production of TNF-α and IL-1β, e. g., induces a rise in the expression of endothelial adhesion molecules with subsequent extravasation of neutrophils into the cervical stroma and that the chemotaxis and degranulation of these cells is triggered by an increased concentration of IL-8. Rising concentrations of hyaluronan at this time have been considered as potent inducers of IL-1β and TNF-α synthesis by various leukocyte populations. The increase in IL-6 synthesis stimulates prostaglandin and leukotriene production causing dilatation of cervical vessels and further promoting the extravasation of leukocytes. The proteases released after degranulation of neutrophils encounter an already destabilized collagenous fiber network. Since a sustained action of proteases may lead to severe tissue damage, this process is strictly limited in time and is controlled by increasing concentrations of tissue inhibitors of protease in the lower uterine segment immediately after delivery. The clinical consequences of this basic research is to develop new concepts in a more causal treatment of cervical pathology during pregnancy and parturition.

Aims: We have performed fetoscopic laser occlusion of chorioangiopagous vessels (FLOC) in previable pregnancies affected by twin-twin transfusion syndrome (TTTS) since 1988. Treatment outcomes obtained after the procedure's learning curve are presented and compared to those from other centers performing FLOC or other treatment methods. Methods: A total of 100 cases of FLOC have been performed at our centers. The later 67 TTTS patients had a mean gestational age of 21.1 ± 1.7 weeks (range 18–24.5) with a mean fundal height of 33.1 ± 4.9 cm (range 27–44) when treated. Eighteen (27 %) had failed another treatment method before FLOC. Results: All 67 cases have delivered with 82% (55/67) having at least one surviving twin and 93/134 (69 %) of the twins surviving overall. Thirty-eight have surviving twins, 17 have one survivor (5 neonatal and 12 fetal deaths), and 12 have none. The mean duration of pregnancy following FLOC was 9.9 ± 5.5 weeks (range 1.0–19). Only 4 of 93 (4.3 %) survivors have significant handicaps at a mean follow-up of 14.3 ± 10.1 months (range 1.0–34). Conclusion: Fetoscopic laser occlusion of chorioangiopagous vessels within the vascular equator limits the duration of fetal pathophysiology in TTTS and results in neonatal outcomes superior to the modified procedure and other treatment methods.

Intrauterine death of one fetus in monochorionic twinning is associated with high rates of perinatal morbidity and mortality in the surviving fetus. Subsequent development of hydrops fetalis in the donor twin after fetal demise of the recipient twin has been described in only two case reports and pathophysiology remains unclear. We report on a monochorionic-diamniotic twin pregnancy complicated by severe twin-twin transfusion syndrome. Ultrasound examination at 20 weeks of gestation showed discrepant twins with oligohydramnios in the smaller twins' sac and polyhydramnios in that of the larger twin. Repeated amniocenteses permitted prolongation of the pregnancy. However, the recipient twin developed deteriorating hydrops fetalis and died at 28 weeks of gestation. After this event, subsequent development of hydrops fetalis in the surviving donor twin could be observed, as well as an increase of amniotic fluid. An elective cesarean section was performed at 29 weeks of gestation. Initial hypoxemia could be effectively treated by high frequency oscillatory ventilation, surfactant therapy and inotropic support. The infant was discharged in good condition at the age of 2 months. Although rare, antenatal demise of the recipient twin in a monochorionic pregnancy can be associated with the subsequent development of hydrops fetalis in the surviving donor twin. We speculate that this phenomenon is due to ischemia-reperfusion injury of the previously poorly perfused twin.