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Premature Labor

Preterm labor is the greatest cause of perinatal mortality and morbidity. In the last 10 years, there has been no change in the incidence of preterm labor. Mortality rates have decreased. For the infants above 1000 grams, the mortality rates have shown the greatest improvement. Fifty percent of patient’s with spontaneous preterm labor have no risk factors, the multiple clinical causes are the result of the release of hormones and cytokines.

There are several new tests available to identify patients at risk for preterm labor, attempts to delay preterm delivery for more than 48 hours have not been successful. Ancillary measures such as maternal transport, cortical steroid and antibiotic administration have been helpful to lower morbidity. There are new modalities of therapy such as COX-2 inhibitors and oxytocin antagonists, these may hold some promise, and finally, probably the most important thing that I am going to talk about, not necessarily just relating to preterm labor is the field of genomics and proteomics, that in the next decade is going to touch everybody’s lives in this room.

Fortunately, because of the institution of ultrasound for dating, the use of tocolytics to delay delivery, use of antenatal corticosteroids and antibiotics, paying great attention to fetal well being during labor and on the neonatal side, the use of Surfactant and also new modes of ventilation, and also the use of continuous airway pressure, we have seen a decrease in perinatal mortality from 31 per thousand to 18 per thousand over this five year period. Even though mortality rates have decreased markedly, morbidity rates remain high and mortality and morbidity rates are the highest among the lowest birth weight groups. This is the latest statistic from our intensive care unit and it’s a illustrative of what else is going on in the country.

Morbidity continues to be high among this group of infants. This data is from 1992, so that I am sure when we get some redata which should be available soon, and there are some preliminary data, the incidents of respiratory distress syndrome will have decreased in this group to somewhere of the order to 30 to 40%, but it still is a significant problem.

Long term morbidity is significant at will. This data was published in 2006, and illustrates that major neurologic deficit has decreased significantly so that almost 70% of infants at 24 weeks go on to not have major neurologic problems, however, they do have minor problems and only about 25 to 30% have complete absence of any learning disability or disorder.

Looking at the epidemiology, we can divide preterm labor into spontaneous, and indicated or induced. Seventy five percent of preterm labor is spontaneous and 25% is indicated or induced because of these conditions, preeclampsia being the most common. I mentioned before that 50% of these patient’s who have spontaneous premature labor have absolutely no risk factors when they enter the pregnancy, which is why all our screening programs have shown very low sensitivity and specificity.

Let’s talk about the pathophysiology of preterm labor. In searching for a common cause of preterm labor, researchers looked at labor at term, and I am sure you realize that there has been a great deal of interest in the physiology of labor at term and great strides have been made and most remarkably they show that in various species, it seems to be the same, and it’s related to an increase in estrogen which changes the estrogen progesterone ratio. In some species there is a dramatic decrease of progesterone in all species, there is an increase in estrogen. For sheep and baboon, that estrogen is estradiol 17 beta.

The hormone that appears to stimulate the production DHEA is corticotropin releasing hormone, that comes from both the fetal pituitary and also, from the placenta, it stimulates the production of cortisol from the cortex and as I mentioned before, DHEA from the fetal adrenal zone. What’s very interesting about this system is that it’s a positive reinforced system, unlike it is in the adult, that is cortisol stimulates production of CRH rather than inhibiting it as it does in the adult.

Regarding the pathophysiology of preterm labor, he has kind of synthesized the thinking about cytokines and his thinking is that infection, inflammation, ischemia or fetal stress provoke the outpouring of interleukin I and tumor necrosis factor alpha, that these cause an increase in the production of interleukin 6, also interleukin 8, interleukin 6 is responsible for stimulation of amnion to produce prostaglandin, we talked about prostaglandin stimulating the myometrium and also the cervix, and IL8 which recruits neutrophils to produce matrix metallo proteases which change the nature of collagen in the cervix to cause cervical effacement. This was offered primarily to explain how infection causes preterm labor, lately, other researchers have offered other cytokines.

Regarding abruption of the placenta, Dr. Felipe published some elegant work about thrombin, showing that it’s a very potent uterotonic agent and induces uterine contractions through the phosphatidal inositol pathway which is also involved with cytokines. So it appears that cytokines are involved in all of these pathways to induce preterm labor. I mentioned risk scoring and why it has such low sensitivity and positive predictive value, I am not going to talk too much about risk such as the risk of habits during pregnancy, smoking, cocaine, the risks of socioeconomic groups, the risk of race we talked about.

The flora changes when membranes are ruptured and we consider that 20 to 40% of preterm delivery is probably related to infection, we can see that bacterial vaginosis is probably very important. Intrauterine infection is described as a chronic infection, that is, fetal fibronectin is found to be positive about seven weeks before infection is demonstrated. Amniotic fluid culture is positive long before preterm labor begins. Actually, the current thinking is that it’s quite possible that intrauterine infection may begin even before conception. It’s been shown that patient’s who carry bacterial vaginosis have a plasma cell endometritis and that may be the reason why they develop premature labor later on in the pregnancy.

Goldberg showed that infections more often cause early rather than late midtrimester preterm birth and fetal infections can result from intrauterine infections and cause an entity called the fetal inflammatory response syndrome. This occurs when the fetus actually gets infected and has been diagnosed with cardicentesis primarily by Romero’s group and results in shock in the fetus. There is great interest in this particular syndrome. There are other predicting factors besides risk scoring that have come to play over the years, home uterine activity monitoring, how many of you have been involved in tha.

Here we see a positive predictive value of 50% and most important, a negative predictive value of 89% and here is the relationship of the cervix to low uterine segment and how it changes as labor begins to evolve. First it is a T with the cervix in the low uterine segment, then as the cervix effaces it becomes like a Y, then with further shortening and with further widening of the internal os, like a V and finally like a U, and you can very clearly see this on ultrasound and vaginal ultrasound is the tool you would use. Cervical length and funneling like infection is associated with early preterm delivery, not only can you use it at 24 to 28 weeks but it has been shown lately that you can use it at 15 weeks, it’s as equally useful in twins and triplets.

Lately, at the more recent meetings, they have shown that there is not only a qualitative relationship but a quantitative relationship as well, that is the more fetal fibronectin, the greater the likelihood of preterm delivery. Also, fetal fibronectin 30% of the time may go from positive to negative which shows that the uterus is capable of repairing injury, probably immunomodulatory cytokines. If one combines these two tests, particularly in a high risk group, that is, patient’s who have had a previous preterm delivery between 18 and 36 weeks. A cervical length less than 2.5 will give a probability of delivery of 0.31, a positive fibronectin of 0.48, and combining 2.63, so these can be very powerful predictors of preterm labor.