Hans Van Der Slikke, MD

Prepregnancy weight and the risk of adverse pregnancy outcome


 Sven Cnattingius, M.D., Ph.D., Reinhold Bergstrom, Ph.D., Loren Lipworth, Sc.D., and Michael S. Kramer, M.D.


Karolinska Institute, Stockholm Sweden, Upsala University, Upsala Sweden, and McGill University, Montreal Canada


Statistical analysis of Birth Registry Data


Obesity before pregnancy is associated with an increased risk of several adverse outcomes of pregnancy. The risk profiles among lean, normal, or mildly overweight women are not, however, well established.

We studied the associations between prepregnancy body-mass index (defined as the weight in kilograms divided by the square of the height in meters) and the frequency of late fetal death, early neonatal death, preterm delivery, and delivery of a small-for-gestational-age infant in a population based cohort of 167,750 women in Sweden in 1992 and 1993. The women were categorized as follows, according to body-mass index: lean, less than 20.0; normal, 20 through 24.9; overweight, 25 through 29.9; and obese, 30 or more. The estimates were adjusted for maternal age, parity, smoking, education, whether the mother was living with the father, and maternal height.

Among nulliparous women, the odds ratio for late fetal death were increased among women with higher body-mass indexes as compared with lean women, as follows: normal women, 2.2 (95 percent confidence interval, 1.2 to 4.1); overweight women, 3.2 (95 percent confidence interval, 1.6 to 6.2); and obese women, 4.3 (95 percent confidence interval, 2.0 to 9.3). Among parous women, only obese women had a significant increase in the rate of late fetal death (odds ratio, 2.0; 95 percent confidence interval, 1.2 to 3.3). Among nulliparous women, the risk of very preterm delivery (at <32.9 weeks' gestation) was significantly increased among obese as compared with lean women (odds ratio, 1.6 95 percent confidence interval, 1.1 to 2.3), whereas among parous women, the risk was highest among those who were lean. The risk of delivering a small-for-gestational-age infant decreased more with increasing body-mass index among parous than among nulliparous women.

Higher maternal weight before pregnancy increases the risk of late fetal death, although it protects against the delivery of a small-for-gestational-age infant.

While it is not news that obese women have increased risk of poor outcome with their pregnancies, it is news that their fetuses have an increased risk of late fetal death. But, hold on, maybe not. In the paper, the authors do mention that there was a higher incidence of diabetes and gestational diabetes among the obese women. They did not look at the increased late fetal death rate in relationship to diabetes however. This is the only mechanism by which I can explain an increase in the late fetal death rate among obese women.

Now that I have said that, onwards to look at the rest of the paper. This study suffers from the same ills as all studies based on large data bases. The investigator is at the mercy of a large number of people who have no interest whatsoever in the study. Over the two year interval in which data were collected, there were 204,555 singleton births. However, prepregnancy body-mass index could only be calculated on 167,750 or 82%. Actually this is probably better than most large data bases. It still excluded nearly 40,000 deliveries and depending on the demographics and outcomes of those pregnancies, might have altered the results.

The author's classification of weight groups based on BMI (Body-Mass Index) is slightly different from the one I am familiar with. They classified "Lean" as BMI <20, "Normal" as BMI = 20 through 24.9, "Overweight" as BMI = 25 through 29.9, and "Obese" as BMI > 29.9. I was taught that "Lean" was < 24, "Normal" was 24 through 26.9, "Overweight" was 27 through 29.9, "Obese" was 30 through 34.9, and "Morbidly Obese" was > 34.9. This probably makes little difference except that we have to be aware of the definitions being used in the study. Other definitions of interest are as follows: "Late Fetal Death" = Stillbirth occurring at 28 or more completed weeks of gestation' [The authors do not state whether this was the fetus dying at > 28 weeks or the fetus being delivered at > 28 weeks]; "Early Neonatal Death" = death occurring during the first week after birth; "Preterm Delivery" = Delivery at < 37 weeks; "Moderately Preterm" = 33 through 36 weeks; and "Very Preterm" as Delivery at < 33 weeks.

Keeping these definitions in mind, their significant results for
association with Late Fetal Death are as follows:

The association with Late Fetal Death when broken down by parity follows:

The association with delivery at < 33 weeks and at 33-36 weeks follow:

The association with delivery of a Small for Gestational Age infant follows:

I interpret these data to show that there is a statistically significant increase in the Late Fetal Death Rate as the BMI increases. This is particularly true in the nulliparous population. In the parous women, this did not become significant until after the BMI was > 29.9. How can we utilize this clinically? Well, I don't think we can go out and get all women to lower their BMI to < 20 prior to achieving pregnancy for the first time, nor do we necessarily want to because this increased BMI was also associated with a decreased risk of delivery of a small for gestational age infant. The 4.3 fold increase in LFD was from 1.4/1000 to 5.7/1000. This is from less than 1% to less than 1 %. This comes about from the fact that there were so many patients in the study. The higher the "N", the more likely that any diference found will be significant statistically.

The protective effect of an increased BMI in parous women is about 2.5 fold and actually decreases the rate of SGA from 2.7% to 1.4%. This could be clinically significant. But again how can we use it? Can we have all of our parous patients go out and increase their BMI prior to getting pregnant. I doubt it.

The other finding of interest to me was the fact that there was a slight decrease in the incidence of very preterm and moderately preterm deliveries in those parous patients whose BMI resided in the middle range. Those women who were on the extremes. Lean and obese, had a higher incidence of preterm delivery than did those who were normal and overweight.

Another item to consider when evaluating this paper is the population that was studied. There was a 4.5% incidence of preterm delivery. As I write this, I sit in a hospital which has a 15.9% incidence of preterm delivery. In other words what is a small clinically insignificant change in this group of patients could be a clinically significant change in a group that has a higher incidence of the problem. Looking at this same data on another population might be well worth the effort.

I frequently catch students and residents with a trick question. I ask them what is the number one strongest association with birth weight. They usually respond with smoking. Then I get to smile and say no it is not. It is maternal prepregnant weight. 1 The reference listed below is one of many that can be found in the literature which will attest to this.

One of the soap boxes, that I like to stand on is about the complications of pregnancy that occur as a result of obesity. I find it interesting that the authors called a BMI of 30, obese. In the population I deal with, approximately 10% have a BMI >35. This leads to a higher cesarean rate, anywhere from 1.5 to 4 times higher in the obese, depending on which study you read and what definition of obese was used. Most papers looking at this used definition of a weight greater than 250 pounds at any time during the pregnancy. With this definition, the cesarean section rate, the rate of hypertensive disease of pregnancy, the incidence of gestational diabetes, and the incidence of fetal macrosomia are all increased. Yet very few laypeople and only a few more physicians consider obesity to be a serious complication of pregnancy. In fact, I am aware of patient with a weight of greater than 300 pounds who have had ovulation induction.

In summation, I find this to be a well done study, that raises some interesting issues that should be studied further.

:

Eastman,NJ and Jackson, E; Weight relationships in pregnancy. I. The bearing of maternal weight gain and prepregnancy weight on birth weight in full term pregnancies. Obstet Gynecol Surv 1968;23:1003-25.

NEJM 1998;338:147-52

Articles

Prepregnancy weight and the risk of adverse pregnancy outcome

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:  "Good morning, we're here in Geneva at the 6th  Analogue Conference and next to me is Professor Bartsch from Innsbruck.   He's the Head of the Department of Urology and he's talking about  antagonists and analogues in prostate cancer.  Professor Bartsch, could  you explain to us what exactly is the advantage of the antagonist these  days in prostate cancer?"
       
       

:  "If you give  an analogue of GnRH then you give a substance which is very similar to  GnRH and, therefore, what you're doing first of all is you're going to  stimulate GnRH and, therefore, you get a surge of LH and you get a surge  of testosterone.  If you give a GnRH antagonist, which is competitive  to GnRH receptor signs, you get no surge so you get a total depression  of LH and testosterone.  What's even more interesting is if you look at  the       FSH levels.  The FSH levels cannot be suppressed by GnRH analogues  but they can be suppressed by GnRH antagonists.  At the time we don't  know the input of       FSH but we have realized in the last couple of years that it's not  only androgens which influence prostate growth and benign prostatic       hyperplasia as well as in prostate cancer but it is a  multi-hormonal disease.  At this time there are very good studies going  on in the United States showing       FSH and FSH receptors in prostate carcinoma specimens, in radical  prostatectomy specimens, and in the high-grade PIN lesions as well."
       
       

:  "That means it's not only dependent of the androgen receptor?"
       
       

:  "This is the  task of the symposium to show the biology of this disease.  If you don't  have androgens you still have the androgen receptor and the androgen  receptor is just synthesized by non sterile activation life by growth  factors and you have a cross-talk with growth factors like IGF or EGF or  KGF and the androgen receptor doesn't use androgens to pre-synthesize,  it just uses growth factors."
       
       

:  "Are there many antagonists on the market already?"
       
       

:  "No, actually  not.  It's very limited, we have a Phase II and a Phase III study with a  very good GnRH antagonist, and we're looking forward to new studies.   The most interesting point, however, is to look and get more insight to  the mechanism of       FSH to tumor growths of prostate cancer."
       
       

:  "Do you think more insight could also lead to more, let's say, prevention of prostate cancer?"
       
       

:  "The problem  of prostate cancer is that it's the most common cancer in males; it's  the second leading cause of death in men after lung cancer.  If you  look, since 1930, we have not improved mortality and as a clinician you  have three options to reduce mortality.  One is prevention, one is to  screen, and one is to find a better treatment for the metastatic lesion.   This substance should be on the third way to find a better treatment  for the metastatic lesion."
       
       

:  "I  see, and so the best way is to do screening on prostate cancer.  If you  can do a good screening, perhaps, you can do an area intervention?"
       
       

:  "You know  screening is highly controversial but when you ask me I'm very pro for  screening.  In the country where I'm living, we have done a big  screening study and for three years we have decreased mortality of 38%,  42%, and 39% of the patients."
       
       

:  "What kind of screening do you do?"
       
       

: "PSA  screening, and it's very simple.  Screening must be very simple because  otherwise the population does not accept it.  The population isn't going  to urologists; they are just going to a general practitioner or to a  nurse or just taking blood and PSA.  You do your total PSA and you do  your free PSA and then you decide if you will do a biopsy or not.  Then  when you have small tumors, you can do a radical prostatectomy and you  can do this without harming potency.  Patients are potent after the  operation and patients are continent, this means with the type of  operation we have today the patients are continent to 97% and they are  potent to 84%."
       
       

:   "That's a lot, so despite the progress, mortality is not so far.  There  is a good hope that in the near future the results will be a lot  better."
       
       

:  "We have to  because we're all becoming older and as we're becoming older prostate  cancer will increase.  Prostate cancer today - and you can see this in  all types of literature, which is written in northern Europe and the  United States - is the number one killer, it's a so-called silent  killer.  We as physicians have to face the community, we have to help  the community, and we have to help find out how to cure cancer."
       
       

:  "Professor Bartsch, thank you very much."
       
       

OBGYN.net Conference CoverageFrom 6th GnRH Analogue ConferenceGeneva, Switzerland February 2001

Antagonists and Analogues in Prostate Cancer

:  "Good morning, we're here at the Analogues  Conference in Geneva, and next to me is Dr. Henk Franke who presented  about analogues in endometriosis.  What special topic about analogues  did you address, Henk?"
       
       

:  "We  performed a prospective randomized control trial in the Netherlands for a  couple of years, and in forty-one patients we performed a laparoscopy  before treatment, and we did not remove the endometriotic implants if we  found them intraperitoneally.  We then started treatment with Zoladex, a  GnRH agonist depot formulation, once a month for six months.  It's a  placebo-controlled trial so after six months we performed a laparoscopy  again, and if implants were found, we then removed them.  However, in  both groups we found a significant reduction of endometriosis."
       
       

:  "Why did you give this add-back therapy with it?"
       
       

:  "Firstly, if  you use a GnRH agonist depot, a lot of patients complain of climacteric  complaints and, secondly, you can see a decrease in the bone mineral  density.  In the group of patients using a placebo, we saw a decrease in  the bone mineral density of 5%.  In the patients using an add-back that  was a continuous combined estrogen-progestin combination, we saw an  increase of the bone mineral density of 0.18%."
       
       

:  "So this means analogues can be given for a longer period and remain effective?"
       
       

:  "Of course,  you can extend the boundaries of therapy and use it for more than six  months.  Also, you know it's effective and what is essential is the  add-back therapy does not interfere with the efficacy of the treatment  so you can give it, for instance, for a year or two years.  We are now  performing a study where we would give patients - not endometriotic  patients - but climacteric patients with dysfunctional bleeding from the  uterus two years of a GnRH agonist depot and also with add-back."
       
       

:  "I'm curious and I'm looking forward to the results of this study."
       
       

:  "Thank you very much."
       
       

Analogues in Endometriosis

:  "Good morning, we're here at the Analogue  Conference in Geneva and next to me is Zoran Culig, he is a research  worker and MD at the Department of Urology in Innsbruck.  You're doing a  lot of research on prostate cancer cells and prostate cells, tell me  what your main topic of research is today."
       
       

:  "Our main  topic is working on androgen receptor signaling in prostate cancer, and  we have been working on this study since 1991.  At that time it was  thought that the androgen receptor had a less important role in prostate  cancer and this hypothesis was based mainly on studies on various  animal models in which tumor cells derived from late stages do not  express androgen receptors.  We and others have shown that in human  tissue, and even in a metastatic lesion, there is androgen receptor  expression and even metastases from patients who failed endocrine  therapy still express androgen receptor.  This led us to studies on  structure and function of these receptors, and we have found that mutant  androgen receptors do exist in prostate cancer tissue.  They are not  very frequent in early stages of prostate cancer, but their percentage  increases especially in metastases of prostate cancers, and we know that  these mutants in prostate cancer shows a gain of function.  That means  that in contrast to mutations, which are detected in patients with, for  example, the sequel of immunizations and which show a loss of function,  mutants detected in prostate cancer patients show a gain of function.   That means that other steroids and even non-steroidal anti-androgens  such as hydroxy-flutamide, which are used in clinical therapy for  advanced prostate cancer, switch to agonists.  This was very important  for the understanding of tumor progression and also for understanding of  the so-called anti-androgen withdrawal syndrome, which will cure in sub  group of patients with prostate cancer.  That means if there is a  cessation of anti-androgen during therapy that some of these patients  show a paradoxical improvement in clinical symptoms and also a decline  in PSA levels.  Furthermore, we also work on non-steroidal activation of  the androgen receptor, and it clearly exhibits non-steroidal activation  and some growth factors analogues of cyclin and see-ma-tha (some other)  phosphate, LHRH hormone itself, and interleukin-6 are among substances  that induce function of the androgen receptor in a ligand-independent  manner.  This also may be important in patients with prostate cancer  because these patients have low androgen levels and these low androgen  doses in combination with, for example, GnRH or interleukin-6 reduce  maximal concentration of androgen that is needed for maximal activation  of the androgen receptor.  That means that the androgen receptor does  not need a high concentration of androgen to be fully activated in  prostate cancer."
       
       

:  "So  these are findings over the last few years that you and your group with  Professor Bartsch did.  Can you tell us what this will mean for the  therapy and treatment of prostate cancer?"
       
       

:  "We know  there are several problems with applications of anti-androgens  especially because of these mutations and generation of hypersensitivity  of the androgen receptor during long-term androgen ablation.   Therefore, we have to clearly distinguish between beneficial effects of  anti-androgens, which are short-term effects, and long-term effects,  which might be harmful.  We have initiated an experimental approach to  treat prostate cancer cells and en-cup with antisense oligonucleotides  which are directed against the androgen receptor and with this antisense  oligoes we have achieved down regulation of androgen receptor  expression.  So this might be a novel approach that should be perhaps  tested in patients with late prostate cancer, and perhaps in combination  with another experimental therapy, for example, application of BCL-2  antisense oligonucleotides or anti-androgenic treatment because I  believe that because of the multi-hormonal nature of prostate cancer  that the successful therapy must target not only one signaling pathway.   We need to target most signaling pathways and the androgen receptor is a  good target for these new therapies because the androgen receptor is  implicated in communication with some other signaling pathways."
       
       

:  "We  are now using GnRH analogues and you started the trial with GnRH  antagonists.  Could you tell us what in theory could be the advantages  of these antagonists?"
       
       

:  "We now know  that there were some synergistic effects of GnRH agonists on the  androgen receptor activity.  How these agonistic effects are related to  proliferation of prostate cells is still not clear but we now test if  the LHRH receptor antagonist has an effect on androgen receptor  activity, and if not, there may be one additional improvement in therapy  where we use these new compounds.  So I think we are now in the initial  stage of these studies, and I hope that in a couple of months we shall  know more about the local effects of GnRH antagonists."
       
       

:  "You  told me before that there's also an advantage of the antagonists that  are working immediately and not having this initial surge in androgen  activity."
       
       

:  "Yes,  androgen receptor antagonists, their immediate effect is inhibitory but  the problem in prostate cancer is there is adaptation of cells and the  cells adapt to these conditions with low androgen involvement.  One of  these mechanisms includes adaptation of androgen receptors and because  of this we are now looking for new ways for inhibition of androgen  receptor expression and function."
       
       

Androgen Receptor Signaling In Prostate Cancer

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 "Here we are at the ISIS conference in       Stockholm in June, 1999, and here's Dr. Gary Dildy. We met Gary in San       Francisco last January, and now we want to talk to him more about fetal       pulse oximetry. Gary, please tell me how the status of the randomized       trial you told us about in January is at the moment."
       
       

 "The randomized       trial, which was initiated 2 to 3 years ago in the United States, was       concluded at the end of 1998 after enrolling approximately 1,000 women in       the trial. Five hundred women received standard heart rate monitoring, and       the other five hundred women received fetal heart rate monitoring plus       pulse oximetry. The data has been put together into a large database, and       was closed about one week ago. The data analysis was initiated earlier       this week in California, and currently the data analysis is being       continued because it's a rather complicated set of questions and       statistical issues. We hope to have the data analysis completed in       approximately one or two more weeks, so the results ought to be able to be       interpreted, I would say, by July of 1999. At the present time, with the       data being incomplete, it would be a little premature to try to give you       an interpretation of the outcome of the trial."
       
       

       "That's a pity. So when do you intend to have the results       there?"
       
       

 "We'll have the       results together, again, next month, in July. The results will then be       submitted to the U.S. Food & Drug Administration, and as I understand       it, the FDA will meet in October of this year and review the research       results. Pending the FDA's decision after the October meeting, we're going       to know soon whether or not this device is accepted for use and       distribution through the United States."
       
       

 "So,       it's too early to give us any results, but could you tell us about the       number of centers that participated, and the number of women       involved?"
       
       

 "Yes, there were       ultimately nine centers across the United States that were involved in       this clinical trial. There were centers that were university, academic       centers, and there were centers that were community referral hospitals. So       we have a pretty good mix of patients that were involved and who       volunteered to be subjects in the study. There were approximately 1,010       patients that were randomized, and we tried to get about 125 patients at       each of the nine centers. So the numbers roughly come out to be 100-125       patients per center."
       
       

"Do       you think 500 patients on each side of the trial is enough to prove what       you want to prove?"
       
       

 "Statistical       power analyses was performed before the study was actually begun because       we wanted to make sure that we had a realistic possibility of proving or       determining answers to the questions that were being asked. So we do think       that we have adequate power to answer those questions. There are some       questions that are important which might not be able to be addressed by       having a sample size of 1,000. Those are things that were considered prior       to the initiation of the trial, but we feel confident we can address the       majority of the questions with the number of patients that we enrolled in       the study."
       
       

 "You       told us in San Francisco, but could you repeat them? What are the major       questions in this trial?"
       
       

 "The primary       question or goal of the study was to determine if the addition of fetal       pulse oximetry in the management of women during their labor was safe and       efficacious, specifically with women who already have some abnormalities       identified in their electronic fetal heart rate monitoring. Thus, the       question is, can the addition of the pulse oximetry reduce the number of       caesarian sections for fetal distress by a factor of 50% at the same time,       while not compromising any of the outcome measures for either the mother       or the baby?"
       
       

 "So,       the answer on this question will be known within a few months. I thank you       very much, Gary."
       
       

 "Thank you very       much. I appreciate the chance to contribute to this program."

OBGYN.net Conference CoverageFrom ISIS - Stockholm, Sweden - June, 1999

The US Trials of Fetal Pulse Oximetry

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       "We're here at the Sheraton in Stockholm with Lennart Nordstrom and       Jason Gardosi at the ISIS Conference. You're the hosts of this conference       - Lennart, would you tell us something about how the conference is       going?"
       
       

       "We've had the first day of the conference, which is a two-day       conference. So far, we've gotten a very good response from the audience.       It's invited speakers from all over the world, and we tried to cover most       of the issues on intrapartum monitoring and the new development, and so       far, I feel happy myself."
       
       

       "The symbol ISIS - what does it stand for, the name - ISIS?"
       
       

       "ISIS is an abbreviation for International Symposium on Intrapartum       Surveillance, which actually covers the field of fetus surveillance during       labor."
       
       

       "You told us you have a two-day symposium, but you had one day. I       think it was rather successful with the CTG course - master course - you       called it. Why did you call it a master course?"
       
       

       "This is the first master class on CTG, and when Jason and myself       discussed the program, we realized that we had availability to all the       experts in the world - the best experts in the world in the field of CTG.       So we thought it would be advisable to use them and to share their       knowledge when they were here; so we arranged the one-day course on CTG."
       
       

       "You're a master yourself, I may say so. Did you learn anything that       day?"
       
       

       "Yes, you always learn something when you meet colleagues with the       very best knowledge in the world, and I feel I'm lucky myself to be the       organizer to share their knowledge, and to have the possibility of them       speaking in all the informal meetings around here."
       
       

       "Can you imagine the most important things we've addressed       today?"
       
       

 "We       tried to cover different fields, both in knowledge of follow-up, as well       as technology, and updating the research frontiers. When looking into the       new methodologies, it's a long way from development to clinical practice,       but we're still getting more and more evidence where to go, which are the       possibilities, and which are the pitfalls in the research."
       
       

       "Thank you very much. It's already the fifth one - the fifth ISIS -       can you, Jason, tell us something about the history of ISIS?"
       
       

 "We       started on the first meeting in 1990, and this is the fifth one, as you       said, since then. Really the initial plan and the interest was to look at       the new technologies on monitoring during labor, and there were a whole       number of technologies, such as: ECG wave form analysis, fetoscopy,       pulsoximetry - which were being presented. There was excitement about the       potential of some of these technologies, and the meeting was put together       with putting these into the context of the possible future role for       intrapartum monitoring. Then the interesting things happened over the next       few meetings, more and more skeptical and critical approaches were taken       towards examining the promise and the current state of the technology,       much debate and discussion was had on whether or not they are ready to be       introduced into clinical practice. Then over the next, perhaps, meeting or       two - more and more we realized that there was also some short comings in       the interpretation of the current technology which we have, which is the       fetal heart rate monitoring and uterine pressure monitoring - or the       topogragh. This is why, as Lennart said earlier on, we have decided at       this meeting to put a special emphasis on the teaching and the discussion       of the merits of CTG monitoring - where we are today. This was a master       class because this was addressed to people who were really using this and       have had further information and experience, and we wanted to sort of see,       how we can even further improve the application of the technology that we       have today. The general standard of these meetings have always placed a       great emphasis on discussion, critical evaluation, and interaction from       the floor, from people who are essentially really quite interested in the       general area of monitoring during labor. That's why I think it's great fun       for everybody involved because it's very interactive, and I think as       medicine, we all learn a lot from this interaction."
       
       

       "Yes. Is it already decided where the next ISIS will be?"
       
       

 "Yes,       we are planning the next ISIS back where it started in England, and we're       not quite sure which particular city, but it will be organized by       Professor Arulkumaran and myself. We already have some ideas on which way       this is going and evolving, and I think the next year or two will see. I       think, us putting together this sort of program, that will continue the       logical progress of these meetings and exploring issues relating to       intrapartum care."
       
       

       "Thank you very much."
       
       

OBGYN.net Conference Coveragefrom International Symposium on Intrapartum Surveillance (ISIS)5th Meeting - Stockholm, Sweden - June, 1999

Hans Van Der Slikke, MD

Articles

Prepregnancy weight and the risk of adverse pregnancy outcome

Antagonists and Analogues in Prostate Cancer

Analogues in Endometriosis

Androgen Receptor Signaling In Prostate Cancer

The US Trials of Fetal Pulse Oximetry

The Conference Program and the role of Intrapartum Surveillance in Maternal/Fetal Health