From 23rd Annual Society for Maternal-Fetal Medicine (SMFM) Conference held in San Francisco, California - February 2003    

Genetics, Genomics, Proteomics and Prematurity

Roberto Romero, MD interviewed by Hans van der Slikke, MD, PhD

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Hans van der Slikke, MD, PhD: “It February 7th and we are in San Francisco at the meeting of the Society for Maternal Fetal Medicine and next to me is Roberto Romero. Welcome, Roberto.”

Roberto Romero, MD: “Thank you very much, Hans.”

Hans van der Slikke, MD, PhD: “For those who don’t know you, please introduce yourself.”

Roberto Romero, MD: “I am Roberto Romero, I am Chief of the Perinatology Research Branch of the National Institute of Child Health and Human Development of the NIH in the United States.”

Hans van der Slikke, MD, PhD: “We are going to talk today about the diseases of prematurity. The question is how to diagnose the different kinds of prematurity and how the science of today can help us with that.”

Roberto Romero, MD: “I would say that we are experiencing a major change in our understanding of premature labour and delivery. The traditional view has been that premature labour and delivery is a condition that occurs because the uterus woke up a few weeks before its time and resulted in uterine contractions, cervical dilatation, membrane rupture and the delivery of premature babies, and the increasing paradigm that has governed the clinical management and the research in this field is that term labour and premature labour are fundamentally the same conditions, except for the gestational age at which they occur. 

We are coming to an understanding that being born before term is not the result of an extemporaneous activation of this mechanism, but rather it’s a disease process and, not only that, but premature labour is a syndrome that is caused by multiple aetiologies. So the fundamental breakthrough is that, rather than considering premature labour one condition, it is a syndrome characterised by uterine contractions, cervical dilatation, and membrane rupture caused by multiple disease processes.”

Hans van der Slikke, MD, PhD: “So there are several causes.”

Roberto Romero, MD: “Right.”

Hans van der Slikke, MD, PhD: “And how can we certify these several causes?”

Roberto Romero, MD: “Well, from the clinical point of view, we have proposed that the main causes of premature labour are infection, vascular diseases, uterine over-distension in the patient, who has polyhydramnios, or multiple gestation and there are other potential mechanisms, such as, for example, immune mechanisms or cervical disease. So, from a clinical point of view, those are the components of the ideological aspects of the syndrome.”

Hans van der Slikke, MD, PhD: “Which are not always the sole reason but could be found in combination together?”

Roberto Romero, MD: “Of course. Indeed, placental examination of patients who deliver after spontaneous premature labour indicates that the most common lesion is acute chorioamnionitis, followed by vascular lesions that are present in 20% of the cases. But in a sub-group of patients, there are approximately 20% there is coexistence of vascular and acute inflammatory lesions of the placenta, so you are quite correct in indicating that there maybe discrete causes or there may be a combination of factors.”

Hans van der Slikke, MD, PhD: “So these are the different definitions and, until now, we treat them all in the same way because we don’t have the real diagnosis which factor is the most important in this special woman. So how could you with your science help us in our daily practice?”

Roberto Romero, MD: “Well, the first step is we are going to try to identify, to classify the mechanisms of disease that are responsible for premature labour and the analogy that I often use is that when a patient presents with a cough to the emergency room, that patient with that sign may have pneumonia, a pulmonary oedema, cancer or may have asthma, and the clinical presentation is the same: a cough. But the aetiologies of the conditions are completely different and the treatment different. The patient with pneumonia will be appropriately treated with antibiotics, but it would be an inappropriate treatment, radiation or chemotherapy we will use with the cancer patient, and that, I believe, is where we are with premature labour. We have symptomatic treatment, which is tocolysis, that has started to reduce the rate of lung immaturity with steroids, but they are really palliative and symptomatic treatments. We don’t have ethiological treatment. So I think that the future of the investigation of basic and clinical premature labour is to develop a taxonomy of disease, just has been developed in the context of lung disease and we are trying to apply the tools of functional genomics, proteomics and the understanding of genetics of complex disease to dissect the causes of premature labour.”

Hans van der Slikke, MD, PhD: “So, first the genomics.”

Roberto Romero, MD: “Genomics is a term that simply refers to the study of the genes that are up- or down-regulated in a particular condition and it has been used successfully in the context of cancer to classify different types of patients with breast cancer or with lymphomas and often conditions that cannot be separated by the pathologists looking at the tissues. Behaviour differences from a patient's response to chemotherapy, radiation therapy, but cannot be separated under the microscope. We are in a very similar situation with premature labour and what we intend to use, and several groups have already begun to use it, is to examine the foetuses of women who deliver premature babies and examine genes that are up- and down-regulated in that condition and we can already tell from the data that has been generated that there is, indeed, a number of this heterogeneity in the patients who have premature labour, confirming that this is a syndrome.”

Hans van der Slikke, MD, PhD: “Does this also relate to the fact that the mothers of women who deliver prematurely often, as well, had a premature delivery?”

Roberto Romero, MD: “Another application of genetic tools is to examine whether there are genetic factors that predispose to a pre-term delivery. These type of studies are conducting what we call genetic association studies and they consist of examining the relationship between a DNA variant that may be present in the mother or the foetus and the likelihood of pre-term delivery and there is now evidence that certain DNA variants, for example: polymorphisms in the genes that regulate the production of enzymes that degrade the matrix and, in particular, matrix is important because the membranes are fundamentally matrix tissues. We know that certain polymorphisms for the enzyme MMP9 and MMP1 are associated with excessive production of these enzymes and that there is an association between mothers with, between foetus carrying these polymorphisms and the likelihood of pre-term PROM. So the tools of genetics are helping us to understand the predisposition of certain individuals to pre-term delivery.”

Hans van der Slikke, MD, PhD: “So there’s a genetic factor and then we have the proteomics.”

Roberto Romero, MD: “Yes, the proteomics is a new name that really applies to the study of protein chemistry. Fundamentally, what it is, is a description of the protein composition of tissues or biological fluids and what we are aiming to do with proteomics is to identify in biological fluids, be that maternal blood, amniotic fluid or urine, changes in the protein composition that is associated with premature labour, or labour at term and, at this meeting, there were two abstracts presented indicating that there are, indeed, a protein fingerprint that is associated with labour and another group characterised the components of a protein profile that separates patients who have intra-amniotic inflammation and those who do not have intra-amniotic inflammation and the importance of these observations is that they provide a rapid mean to identify the patient who has inflammation and who will, potentially, can be used at the bedside.”

Hans van der Slikke, MD, PhD: “So this is a test that will give an answer within an hour?”

Roberto Romero, MD: “Within a half an hour to an hour.”

Hans van der Slikke, MD, PhD: “If there is information. So these three aspects: the genetics, genomics and proteomics are helping us more and more to see if there is genetic factor, if there is in genomics, it is an up or down regulation, and the other one, infection and the real question, because that’s the main question for the practicing obstetrician is, is she really in pre-term labour or not and is she to be treated and then in what way?”

Roberto Romero, MD: “Yes, and I believe that the tools of proteomics are going to help us a great deal with this because, as demonstrated by the work that was presented at the meeting this week in San Francisco, it is possible to identify a protein profile that identified the patient who is in labour. So, this has the promise of identifying the patient who may not need that treatment with tocolysis and perhaps steroids. Of course, this research needs to continue.”

Hans van der Slikke, MD, PhD: “I understand that several chips are already commercially available, so the step from science to practice could be short. Could you give any idea about when there will be this total change by this new research?”

Roberto Romero, MD: “In the field of cancer, the progress has occurred very quickly. Only a few years ago, two or three, there was research that demonstrated that different types of cancers have different prognoses and the Netherlands has been the first country in the world to develop chip micro-arrays to characterise a genetic profile of cancers as a clinical tool and that announcement was made last week. I believe that there is a lot more clinical testing that will be required and, in obstetrics, we are following the developments of other fields, but I think that probably proteomics will come first and genomics second in terms of application. In terms of genomics, in genetic association studies, there is much that needs to be done and the potential here is to help us identify the patient at risk and also to help us characterise the optimum means for therapy, just as we do in the patient with asthma.”

For further information, please see also this NICHD report:
Pathophysiology of Premature Labor and Complications of Prematurity