R. Daniel Braun, MD


 	Any woman who is sexually active or is at least 18 years old should have a Pap smear. Cervical cancer is most commonly 	caused by HPV (Human Papilloma Virus). This is a virus that is most commonly spread by sexual contact. It is thought 	to be the most prevalent STD (Sexually Transmitted Disease) in the United States with about 85% of the adult population 	having had it. Once you get the HPV in your genital tract, it is difficult if not impossible to get rid of it. 	HPV is also the causative agent of Genital Warts. Some people with HPV infection will develop warts, some will 	develop precancerous and if ignored cancerous changes, some will develop both, and even a few will develop neither. 	These changes may occur relatively soon after infection or may not occur for many years.
 	
 	


 	All women, who are sexually active or over 18 years of age, should have a Pap smear every year for at least 3 years. 	If all three of those are reported as "No Pathologic Change" (see area below for description of Pap Smear 	reports), then that woman can got to getting a Pap smear every 3-5 years. Even so that woman should still have 	a pelvic exam and routine normal health maintenance visits every year.
 	
 	


 	A Pap smear is a screening test for pre-cancerous changes of the uterine cervix. The preceding sentence contains 	two key concepts that are frequently misunderstood by laypersons and in quite a few instances physicians. I will 	start by addressing those concepts.
 	
 	A Pap smear is looking for pre-cancerous changes of the uterine cervix. It is not designed to find cancer and it 	is not designed to find abnormalities of any other organs. (E.g. the ovaries or lungs) The cervix develops cancer 	in a slow prolonged manner; usually 10-20 years from the first changes until cancer develops. At any place along 	the way, something may happen to reverse the process and make things normal again. These changes are called dysplasia 	or sometimes Cervical Intraepithelial Neoplasia or even Squamous Intraepithelial     Lesion (different names for the 	same process).
 	
 	When a Pap smear is obtained, the cervix is scraped with a wooden stick and a tiny brush. The stick and brush are 	then moved across a glass slide causing the cells to become attached to the slide. The slide is then chemically 	treated and sent to a cytology laboratory where it is first stained with special dyes and then examined through 	the microscope by a cytotechnologist. If no abnormal cells are seen, it is reported as normal. A random sampling 	of these "normal" slides are reviewed by a pathologist. If abnormal cells are seen, the slide is then 	looked at by a pathologist. The pathologist then assigns a diagnosis to the smear. Under the "Bethesda" 	system (the system currently in use in the U.S.) for pap smear reporting, there are several possible diagnoses 	he can make. They are:
 	
 	1. No Pathologic Change. (Normal)
 	
 	2. Inflammation. (Signs consistent with an infection)
 	
 	3. Atypical Squamous Cells of Undetermined Significance (ASCUS)
 	Some squamous cells are present which aren't normal, but they may be due to inflammation [95-98%] or pre-malignant 	change[2-5%])
 	
 	4. Atypical Glandular Cells of Undetermined Significance(AGCUS)
 	Some glandular cells are present which aren't normal but they may be due to
 	inflammation [80-85%] or pre-malignant change[1O-15%1)
 	
 	5. Low Grade Squamous Intraepithelial Lesion (LGSIL) (Some squamous cells are present which may come from an early 	pre-malignant lesion)
 	
 	6. High Grade Squamous Intraepithelial Lesion(HGSIL) (Some squamous cells are present which may come from an advanced 	pre-malignant lesion)
 	
 	7. Malignant cells are present. (Malignant squamous or glandular cells are present which may come from a cancer)
 	
 	All of these, with the exception of numbers 1 and 2, require some kind of further evaluation. The kind of evaluation 	depends on which one it is.
 	
 	Usually ASCUS will be evaluated by repeating in 3 months. If that repeat is still abnormal, then a colposcopy with 	biopsy is indicated. If it is "No Pathologic Change", then the patient can resume normal annual Pap smears.
 	
 	Usually AGCUS requires, colposcopy, endometrial biopsy, and endocervical curettage. Further treatment depends on 	the results of those tests.
 	
 	LGSIL and HGSIL usually require colposcopy with biopsy. Further treatment depends on the results.
 	
 	Malignant cells present requires biopsy, colposcopy with biopsy, or whatever other tests are needed to find the 	source of the malignant cells.
 	
 	This seems easy. However this follows Braun's Law of Life: If it seems easy, you have missed something. Indeed 	we have missed something here. If one performs Pap smears on 100 patients who have cancer of the cervix, anywhere 	from 20-50 of them will be either no pathologic change or inflammation. Why is this? Because when cancer of the 	cervix is present, it causes a lot of inflammation which can obscure the cancer cells. It also may come about because: 	when the smear was taken, the brush or spatula did not scrape over the area containing the cancer, the cells may 	have gotten washed off the slide during the preparation and staining of the slide, the slide may have gotten mixed 	up with somebody else's slide, or the cytotechnologist reading the slide didn't see them.
 	
 	If one does Pap smears on 100 patients with pre-cancerous changes, approximately 85 will have a report of either 	HGSIL or LGSIL. This is because it is easier to get these cells off the cervix and onto the slide and because there 	is usually much less inflammation.
 	
 	Why do we use this test if it misses 50% of cancers and 15 % of precancers?? Because it takes from 10-20 years 	for a precancer to develop into a cancer. So if we screen all women every year for 3 years, we will miss 15% of 	15% of 15% or 3/1000 precancers over the course of three years. Since only 20% of women will have a precancer, 	that means we will miss 3 precancers in every 5000 women, who have "Normal" Pap smears 3 years in a row. 	If we pick up most precancers and treat them, we should have very few women developing cervical cancer. This is 	what has happened. Notice, I did not say "NO" women, I said very few women.
 	
 	In that light, Pap smears are a very effective "screening" test for cervical precancer. That means it 	picks up most cases of what it is screening for without calling too many normal patients abnormal and it does it 	at a relatively low cost.
 	
 	The concept of screening is to cut the incidence of the disease screened for to a low level. This is what has happened 	in the United States since the introduction of the Pap test. In 1941, there were 26000 deaths per year due to cervical 	cancer. It was noted that the rate had not changed in 25 years. Then in 1941, Papanicolau and Traut introduced 	the Pap smear. In 1996 there were 4900 deaths from cervical cancer(most of them in women who had never had a Pap 	smear). If there were no change in the rate one would expect 52000 since the population had doubled. Hence there 	was a 90% reduction in the death rate due to cervical cancer. This is what the Papanicolau smear was designed to 	do and it has done its job.
 	
 	The smear does not and was not designed to tell an individual woman; "You do not have cancer." This is 	how the test has been perceived by a large number of people. Now, we are in the process of developing newer (read 	more expensive) advancements on the Pap smear to overcome these misperceptions. All of these newer advancements 	will help to pick up those 3/5000 women with pre-cancerous changes missed by the Pap smear at an extra cost of 	$40-$50 per patient per year. That works out to $250,000 per 5000 women in the U.S. or about $25 million extra 	per year. Is this really worth it? Especially since none of these refinements in technique are perfect. They will 	still miss some patients. Do we then go on to more refinements which cost 4-10 times more and will still miss a 	few cases? What degree of accuracy are we willing to pay for? 

Articles

Who should have a Pap Smear?Any woman who is sexually active or is at least 18 years old should have a Pap smear. Cervical cancer is most commonly caused by HPV (Human Papilloma Virus).

What a Normal Pap Smear Means!

Principles of Weight Management

This patient is a 23 year old Gravida 1 who presents for prenatal care at 8 weeks gestation. She has a completely normal history and physical exam is compatible with an 8 week gestation. The pelvis is of normal configuration and size. Lab work reveals Rh positivity, Rubella immunity, and no abnormalities. She is provided with the usual information and given an appointment to return in 4 weeks.

At her second visit at 12 weeks, she has gained 2 pounds, has no complaints, her uterus is palpable just above the pubic symphysis, and fetal heart sounds are heard with the doppler stethoscope. Everything continues to progress normally and she is instructed to return in 4 more weeks.

Now at 16 weeks, she still has no complaints. The uterine fundus is now half way between the pubic symphysis and the umbilicus. Fetal heart tones are again heard. At this visit, an ultrasound is ordered and she is offered a "Triple Screen". "What's a triple screen, Doc?" she says. I have already sat down and made myself real comfortable, since if she hadn't asked, I was going to tell her all about it anyway.

"A triple screen," I say, "is a blood test that is done to look at the risk for a pregnancy having a fetus with either Down syndrome or a spina bifida. This is not a test that tells us the baby does or does not have either one of these defects. This is a test that tells us the baby is at high risk or low risk for one of these problems. The triple screen measures the levels of three (hence triple) hormones in the pregnant woman's blood stream. These are alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol. The fetus and/or the placenta plays at least a major role in the production of each of these, so they reflect the fetal condition to a certain extent. e.g. alpha-fetoprotein is elevated in fetuses with spina bifida and certain other brain and spinal cord conditions and it is low in may cases of Trisomy 21(Down Syndrome)."

"So, if we do this test the report will come back and say that in a 23 y/o African-American at 16 weeks who has these levels of these three hormones, the risk of her having a baby with Trisomy 21 is 1 in 10,000. This means that you are at extremely low risk, not no risk but very low risk. On the other hand it could come back and say the risk is 1 in 10 that this baby has Trisomy 21. This would mean the risk is high, not absolute but high." She now says, "Why do the test if it doesn't give us an answer?" My response is that if it says low risk we accept that low risk and do nothing further. If the risk is high, then we would offer her the test that does give us a definitive answer; an amniocentesis with fetal karyotype.

"Then why not do an amniocentesis on everyone?" she asks. I respond that the amniocentesis is an invasive procedure with some risk to the fetus and even a little risk to the mother. In addition it costs a lot more to do.

She then asks me, "Why should I do this when I am going to have an ultrasound anyway?" "Because," I replied, "an ultrasound is not diagnostic of Trisomy 21. Sometimes, one can see things on ultrasound that make one suspicious of Trisomy 21. Even if some of these things are seen, the incidence of Trisomy 21 is around 5%. So if one does see them, an amniocentesis is then recommended. In other words, the ultrasound is also a screening test which will pick out pregnancies that are at high risk for Trisomy 21."

At this point, I also let her know that there are other things that can lead to false triple screen results. The most common of these is wrong dates. In her case we don't need to worry about that because of her early visits and the ultrasound. Also, other fetal abnormalities such as abdominal wall defects may cause the triple screen to be abnormal.

She now says, "Gee, you know I don't believe in abortion, even if the baby has Trisomy 21. So why do this test?"

"Many women who know they have a Trisomy 21 baby do not abort. It is very helpful to know ahead of time. If you know, then there are support groups to which the expectant parents can be referred to help them prepare ahead of time for the problems that they will be facing as they raise this "special" child," I explain.

She decides at this point that she would like to go ahead and get the procedure done. We draw the blood and send it off to the lab. Four days later the triple screen report is called back to my office and I am informed that her risk of having a trisomy is 1 in 50. This certainly is an increased risk. She is now a candidate for Counseling and amniocentesis. I call her and set up the appointment to come in the next day with her husband.

After they come in, we talk about the results of the test. I explain  that this means that there is a 1 in 50 chance of the child having a trisomy and a  49 in 50 chance of it not having a trisomy. I also explain about an amniocentesis and its risks and benefits. We  discuss that the risk of causing a loss of the pregnancy are less than the risk of a trisomy being present. We also  talk about how the procedure can not tell her that the child is normal, just whether or not it has a trisomy. At  this point, we repeat the ultrasound so that we can do the amniocentesis without going through the placenta.  After cleaning her abdomen, I then insert the needle into the amniotic cavity, while watching on the ultrasound.  This allows me to direct the needle to a place where there is a collection of fluid and away from the fetal head.  I withdraw about 20 cc's(2/3 of an ounce) of slightly yellow clear appearing fluid. I put this into a pre labeled  container which is then sent to the cytogenetics-genetics lab. Following the procedure, we watch the site where the needle entered  the uterus and there is no bleeding seen. After placement of a Band-Aid, she goes on home with an appointment to  return in 10 days for the results.

Ten days later they return and I have to tell them that their fetus has Trisomy 21. They then immediately want to know; Does it have a heart defect? (I don't think so but it could), Will it have severe mental retardation? (I don't know how severe it will be), and Will it develop Leukemia? (I don't know.) These are all questions that the amniocentesis can't distinguish. They now ask what their options are. I explain that there are basically two options; termination or not. They want more information about both of these options. I explain that if they do not terminate, we will get them in touch with a support group of parents of children with Trisomy 21. Again they want to know how severely affected this fetus is and I have to again explain that we don't know. They want to hear about termination. I explain we would start by inserting a prostaglandin suppository into her vagina which would cause her to start having contractions which would lead into a labor like situation. We would relieve her pain with narcotics and or an epidural. Eventually, she would pass the fetus and the placenta. After observation for a while longer, she would be able to go home. They asked for time to think about this. I said that there was time to do that because she was only 18 weeks and we had up to 24 weeks to do this. However it would be better to do it sooner than later because the further along the pregnancy is the greater is the risk of complications.

Two days later, they called and told me that they want to terminate the pregnancy. I say OK, I will have to call the hospital and arrange it. At 7 AM three days later she comes to the hospital and after starting an IV, I insert a prostaglandin suppository. Within a half hour, she is contracting and by three hours, she is contracting quite strongly. She requests an epidural for pain relief and this is provided. About 9 PM, she passes the fetus vaginally. 25 minutes later, she passes the placenta. Examination reveal an intact placenta and that she has no lacerations. Once the epidural wears off and she is able to ambulate, she is released.

Two weeks later when she and her husband come back to the office, they have many questions regarding the risk of recurrence. I explain that it is thought that she might have a slight increased risk with future pregnancies and that either CVS or amniocentesis would be offered. I also explained that with the research going on now, there may be other techniques available by that time.

One year later, she presented at 7 weeks gestation, had a CVS done at 11 weeks gestation (which revealed no Trisomy), and delivered a healthy baby girl at 39 weeks.
 
 
 


 
 This patient is an excellent example of how the triple screen allows us to diagnose about 65% of Trisomies at a stage early enough to terminate the pregnancy if so desired. While the highest incidence of Trisomy is in women over the age of 34, the largest number of pregnancies with Trisomy occur in women under age 35. This is because the number of women having pregnancies under age 35 is so great. The triple screen offers a non invasive method of determining which of those women under 35 are at increased risk for a Trisomy pregnancy, so that we can offer them the more risky and invasive procedure of amniocentesis.

The alpha feto-protein portion of the triple screen also allows us to screen for Neural Tube Defects. If the AFP is elevated and a neural tube defect is ruled out, then other things such as abdominal wall defects and Congenital Finnish Nephrosis must be ruled out. Once they are ruled out, the pregnancy with an elevated AFP and none of these defects, still has an increased chance of poor outcome from such things as unexplained fetal death and intrauterine growth restriction. So this is valuable information that allows us to start testing these pregnancies and to intervene when indicated.

I offer triple screening to all of my patients. About 10-15% decline to have it done for various reasons, but the rest agree to it. I talk to them about what it is and what it does not do. I also explain to them the procedure that would be followed if they were to have an abnormal test. This is one reason that many of them decline. They say that if the test were abnormal, they would not want to have an amniocentesis. In other words since they don't want to know the answer, they don't ask the question.

This patient is a 23 year old Gravida 1 who presents for prenatal care at 8 weeks gestation. She has a completely normal history and physical exam is compatible with an 8 week gestation. The pelvis is of normal configuration and size.

Triple Screen

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