"The Road Not Taken..."

Recently, I was asked to see a very interesting patient in consultation. Although a favorable outcome of her pregnancy is by no means guaranteed at this time, I am fairly sure that the timely request from her physician for a “curbside” consult averted what most certainly would have been a disastrous outcome for both mother and baby. It is worth relating the story, because it points to the fact that sometimes things aren’t what they seem and the eyes of an objective observer can often provide valuable insight into how complicated medical conditions can be further complicated by the normal physiologic changes of pregnancy.

The patient is a 28 year old woman who is carrying her first pregnancy. In 2000, she was developed kidney failure and was found to have a condition called Goodpasteur’s syndrome. This is a disease wherein the individual develops autoantibodies against the glomerular basement membrane. Both her kidneys were removed and after awhile on dialysis, she became a candidate for a kidney transplant. A donor was found and she had this procedure performed at a university medical center. With immunosuppressive therapy, the transplant held and remained in excellent functioning condition, and other than periodic checks with the transplant team, her routine care was assumed by a group of nephrologists who practiced at her local hospital.

After consultation with her transplant doctors, she and her husband decided to risk a pregnancy. Her immunosuppressive therapy was reduced to "maintenance levels to minimize risks to the baby” and she conceived earlier this year without difficulty. Other than for the mild hypertension with which she entered the pregnancy, probably the consequence of her immunosuppressive drugs, and modest therapy for the same, the pregnancy had progressed without significant complications until recently. Baseline studies early in pregnancy revealed good renal function, a normal serum creatinine and creatinine clearance, and a 24 hour urine protein of only about 100 mg.

At 24 2/7 weeks, she presented to her physicians with a severe headache, the acute onset of swelling (diffuse edema) and weight gain, and “4+ proteinuria.” Her blood pressure was elevated over what it had been. She was admitted to the hospital with the presumptive diagnosis of severe preeclampsia. A 24 hour urine collection revealed that she now was spilling1600 mg of protein. Her liver function tests, LDH, and coagulation studies were all normal. Her serum albumin had drifted down to 2.4 mg/dL reflecting the loss in her urine and possibly reduced production by her liver.

Assuming that an extremely premature delivery was going to be necessary soon, her physicians gave her betamethasone to help accelerate fetal lung maturation and arranged for consultation with her local nephrologists and the neonatal intensive care unit. To help assess fetal status in this equation, she was sent to our office for an ultrasound. This showed normal fetal growth, normal amniotic fluid, and normal Doppler flow studies. In other words, the baby was well-grown, was having no trouble pushing blood through the placenta ,and did not appear to be starving as the result of poor placental function. Indeed, the fetal heart rate tracing was even very reassuring for this early gestational age. Her nephrologist came to see her and his only terrifying comment to her was that “your pregnancy is going to have to be terminated early for severe preeclampsia.” No other management plan was offered.

Less than satisfied with the nephrologist’s input, and even more chagrined by the comments made directly to the patient, her obstetrician corralled me in the hall for my “curbside consult.” He filled me in on her past medical history, pregnancy course, the events leading to her hospitalization, and results of her evaluation to date in the hospital. The patient certainly was at high risk for preeclampsia because of her history of an autoimmune kidney disease, renal transplant, and baseline hypertension and for all intents and purposes, she met the criteria for this diagnosis. But, two plus two did not entirely equal four at this point in her case. Usually severe preeclampsia at this early gestational age is accompanied by poor placentation resulting in fetal growth restriction, abnormal Doppler flow studies (increased resistance to fetal placental perfusion and fetal blood flow redistribution, otherwise known as “cranial sparing”), and decreased amniotic fluid as a consequence of the former. The baby had none of these problems. It appeared that her “preeclampsia” was being driven from the maternal side, not as the result of fetal compromise as is typically the case. In my past experience with renal transplant patients, I had seen similar consequences as the result of transplant rejection during the pregnancy.

It was at this point that we went to talk with the patient. She was as advertised. She complained of a headache but had no visual disturbances. She had no epigastric or right upper quadrant pain. She had diffuse edema of the face, hands, and especially the lower extremities, but reflexes were completely normal. When questioned about her immunosuppressive therapy, she confirmed that this was still at the maintenance levels of cyclosporin and prednisone at which she started the pregnancy. We suspected that between her pregnancy weight gain, normal plasma volume expansion, and the normal increases in metabolic rate during pregnancy, her cyclosporin levels were now subtherapeutic and she probably was undergoing renal allograft rejection.

While waiting for the cyclosporin levels to return from the lab, a quick phone call to her transplant doctors resulted in permission to raise the dose in the interim. The levels came back within 24 hours and were found to be undetectable despite the fact she had conscientiously been taking the prescribed amount of the drug. Within days after raising the dose of cyclosporin, her swelling began to resolve, her weight dropped, her blood pressure improved, and her serum albumin started to rise. Indeed, now two weeks later, she appears stable, the baby remains ’happy’, and more importantly, is now at a gestational age where morbidity and mortality related to prematurity improve with every passing day of gestation.

Is she out of the woods? Probably not. As I told her at the outset, I will be very surprised if she gets past 30 weeks in the pregnancy. But, miracles happen and we are now hopeful that she might. She is still at high risk for developing preeclampsia and differentiating that from transplant rejection remains a challenge. Indeed, she might succeed in the pregnancy, but still lose her kidney as a result of complications. However, I often wonder at times such as these if more than chance is at play because it was another one of those situations when the right person just happened to be in the right place at the right time and “the road not taken” might make “all of the difference.”

Labels: Kidney transplant and pregnancy; preeclampsia; allograft rejection and pregnancy

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Anogenital Warts (Condylomata acuminata) and Pregnancy

I recently completed a seven-part series on cervical dysplasia and cancer in pregnancy. The incentive to begin that series came from a young patient who had a mildy abnormal Pap test and extensive involvement of her vagina, vulva, and perianal areas with anogenital warts (Condylomata acuminata). In my comments related to her care, I mentioned that we had discussed options for treatment of her warts. Subsequently, one of our readers contacted me and wanted to know specific details about my approach to the treatment of anogenital warts during pregnancy "because the problem seems to be getting worse rather than better." I used that query as an opportunity to complete a set of 'guidelines for managment of anogenital warts' that our residents could use in their clinics. It's rather long and rather 'clinical' but it also contains some useful information and a few 'pearls' so it is presented in its entirety below...

Background

• Anogenital warts are caused by infection with human papillomaviruses (HPV) of which more than 120 different types have been identified
• 80-90% anogenital warts are caused by HPV types 6 and 11 (nononcogenic types)
• It is estimated 15 to 38% of sexually active adolescents have genital warts
• Women are at increased risk for larger warts and more diffuse anogenital effectively prior to delivery, even if there is extensive involvement of the vagina, vulva, and perianal areas, unless the woman has an underlying involvement than men, but they are often more responsive to any form of therapy
• Conditions under which there is down-regulation of the cell-mediated immune response, such as pregnancy, are associated with more severe disease
• Many women will have spontaneous improvement in their condition within months following delivery
• Genital warts are unsightly, uncomfortable, and psychologically traumatic, and they can be a nidus for superimposed bacterial infection (a source of risk for premature rupture of membranes and premature labor), increase the risk for neonatal HPV infection (anogenital, oral, and laryngeal), and complicate the repair of obstetrical lacerations
• Anogenital warts found during pregnancy can often can be treated immunodeficiency condition or requires immunosuppressive therapy (e.g., HIV, SLE, pregestational diabetes, renal transplantation, tobacco abuse)

Therapeutic Options

• Trichloroacetic acid (80%)
• Imiquimod 5% cream
• Cryotherapy
• Surgical excision
• Laser ablation
• Podofilox 0.5%, podophyllin 25-50% in benzoin, and 5-fluorouracil are not recommended for use during pregnancy

Approaches to Therapy

• Trichloroacetic acid (TCA) and/or Imiquimod 5% cream (Aldara 5%) are my preferred choices of topical therapy during pregnancy
• TCA can be applied both externally and internally, but is extremely painful applied to any surface area external to the hymenal ring
• Imiquimod cream should only be applied externally. Unpredictable, severe, painful, erosive reactions can occur when this drug is applied intravaginally . (Furthermore, because of the Th-1 augmenting effects of Imiquimod, the increased vascularity of the vagina during pregnancy, and the undocumented extent of systemic absorption under these circumstances, intravaginal application is not advised as it may pose an unrecognized risk to the baby, although I am not aware of any such complications actually occuring).

A recommended approach to therapy of both internal and external disease using these compounds is as follows:

Internal disease

• Use a speculum for visualization
• Cleanse the vagina with 5% acetic acid (be careful you do NOT use the TCA by mistake)
• Dry the vagina
• Apply TCA using a Q-tip to all visible intravaginal disease (trying to stay inside the hymenal ring), including visible cervical disease, starting at the apex of each wart and ending just around the base
• Allow to dry before removing the speculum
• Inform the patient she may feel a warm sensation.

External disease (minimal)

• Isolated external lesions may be treated with TCA as well
• First cleanse with 5% acetic acid, then dry
• Apply TCA quickly to as many lesions as tolerated (you must work quickly because it will hurt)
• Allow to dry thoroughly after application
• CAUTION: Externally, TCA may cause scarring (internally it does not), particularly if reapplied to incompletely healed skin

External disease (extensive)

Imiquimod 5% cream can be used externally in conjunction with intravaginal TCA. The patient should be given a prescription for Imiquimod 5% cream and the following instructions:

• At bedtime, wash, thoroughly rinse, and dry the vulvar and perianal areas that need to be treated (you may need to point out the warts to the patient in the clinic using a mirror)
• Using a very small amount of the cream on a finger tip, rub the cream into each wart and just around the base until the cream vanishes
• Suggest use of absorbent (cotton) underwear
• Do not wash the areas until the next morning
• Initially, prescribe three times per week application
• If redness and irritation develops, discontinue therapy until it begins to resolve, then resume treatment (If the reaction is poorly tolerated, reduce to a twice weekly dosing schedule)
• If the patient has no significant skin reaction within two weeks (and her warts have also not improved), increase the application frequency to daily until a reaction develops
• Inform the patient at the outset that even if she develops a severe reaction, she will heal completely and without scarring
• Imiquimod can be used for up to 16 weeks if necessary

Adjuncts to Therapy

• If extensive intravaginal disease is treated, place the patient on metronidazole 500mg BID 7-14 days
• Advise to discontinue smoking
• Advise to refrain from intercourse during treatment
• Suggest partner evaluation and treatment
• Identify and control underlying medical conditions
• Minimize doses of concurrent immunosuppressive therapy if possible

Follow-up

• Schedule return visit in no less than 2-3 weeks; resolution of disease, regardless of therapeutic approach, depends on the inducement of a sufficient immune response and this can take time
• Repeat evaluation and treatment as detailed above
• Continue treatment up to 37 weeks
• If the patient has no response to therapy, local excision or laser ablation can be offered, but this is not recommended beyond 34 weeks. (Combinations of Imiquimod and ablative therapy of external disease are safe and can be effective in recalcitrant cases

Management of Delivery

• There is no indication for cesarean delivery if there is minimal disease
• Indeed, even extensive disease presents only a relative contraindication to vaginal delivery
• Cesarean can be discussed with the patient as an option, although this may not prevent the baby from acquiring HPV
• If a baby is delivered through a birth canal with condylomata, try to avoid vigorous oropharyngeal suction to reduce the risk of inoculation of the respiratory tree

Genital Warts and Recurrent Respiratory Papillomatosis (RRP)

• 7 of every 1000 children born to mothers with vaginal condylomata develop RRP, also referred to as ‘juvenile laryngeal papillomatosis (JLP) or ‘juvenile-onset recurrent respiratory papillomatosis (JORRP)
• The risk is 231-fold higher than that of births in women without a history of genital warts
  RRP is the most common benign neoplastic disease of the larynx in children and adolescents
• The mean age of onset in children is 4 years, so it is easy for us not to recognize the association between RRP and maternal genital warts
• Labor > 10 hours in women with genital warts is accompanied by a two-fold greater risk of RRP in their children than those laboring <>
• Cesarean delivery does not appear to be protective against RRP
• Birth by cesarean section may be associated with increased risk for more severe disease among those who develop RRP, but the reasons for this are unclear
• RRP can be a source of lifetime morbidity and mortality for the child, and incurs enormous costs to the health care system, estimated to range from $60,000 to $470,000 or more per patient
• Although spontaneous remission is possible, pulmonary spread and malignant transformation have been reported.

References

Reeves WC, Ruparelia SS, Swanson KI, et al. National registry for juvenile-onset recurrent respiratory papillomatosis. Arch Otolaryngol Head Neck Surg. 2003;129:976-82.

Silverberg MJ, Thorsen P, Lindeberg H, et al. Condyloma in pregnancy is strongly predictive of juvenile-onset recurrent respiratory papillomatosis. Obstet Gynecol. 2003;101:645-52.

Stamataki S, Nikolpoulos TP, Korres S, Felekis D, et al. Juvenile recurrent respiratory papillomatosis: still a mystery disease with difficult management. Head Neck 2007;29:155-62.

Wiatrak BJ, Overview of recurrent respiratory papillomatosis. Curr Opin Otolaryngol Head Neck Surg. 2003;11:433-41.

Wiatrak BJ, Wiatrak DW, Broker TR, Lewis L. Recurrent respiratory papillomatosis: a longitudinal study comparing severity associated with human papilloma viral types 6 and 11 and other risk factors in a large pediatric population. Laryngoscope. 2004;114:1-23.

Labels: anogenital warts, condylomata acuminata

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Grand Rounds 3.44 at A Chronic Dose

Thanks to Laurie Edwards at A Chronic Dose for including a link to my recent post in which we address common questions related to the evaluation of HSIL in pregnancy, the risk and benefits of diagnostic procedures, and its natural history, in this week's Grand Rounds 3.44, It's All in a Days News. For those of you who might be interested, that post is part of a seven part series on Cervical Dysplasia and Cancer in Pregnancy. Great job, Laurie, on on your first effort as a GR host! Sign up more often! By the way, I have a yellow lab mix as well - half lab and half husky. She's a mess and ALL dog, although I don't know if that is such a good thing!

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Cervical Dysplasia and Cancer in Pregnancy - 7

In our fifth post in this series, we discussed a case of a woman who had a high-grade intraepithelial abnormality (HSIL) found on her intake Pap test and was subsequently diagnosed with minimally invasive cervical cancer (stage 1A1) during her pregnancy and the successful outcome of management for both her and her baby. Her case illustrates the importance of early detection and the value of routine screening by the Pap test during pregnancy, thorough evaluation by trained providers regarding the extent of the disease once an abnormality is detected, and participation of the patient with proper counseling in the management decisions that were ‘right’ for her.

In many ways, this woman was quite fortunate to have become pregnant. She was in her early 30’s and had been in a stable relationship with a single partner for many years. She had stopped having annual Pap tests because she had "never had an abnormal one" and was not aware of any time in her life that she might have contracted HPV, although she had had other sexual partners in the years before she was married. If she had not gotten pregnant, she may well have become one of the unnecessary tragedies of her cancer being diagnosed at a stage when the outcome would probably have not been so favorable.

Indeed, two cases in the past year of women who were not so fortunate were actually the impetus for this series on cervical cancer in pregnancy. One is an acquaintance of a woman with whom I work and the other is a local television personality in the Charlotte, NC area who has shared her story publicly. It is my understanding that both women have a very aggressive and somewhat unusual form of cervical cancer called ‘neuroendocrine small cell cervical carcinoma.’ These tumors look and behave more like ‘oat cell carcinomas’ of the lung in that they grow very rapidly, are often not detected until they have deeply invaded, and are poorly responsive to therapy. Indeed, in both cases their cancers were already stage II/III at the time of diagnosis. The five-year survival with these cancers under the best of circumstances is less than 15%. Aware of this poor chance of survival, even if they underwent early pregnancy termination and began the most aggressive treatment currently available, both women elected to carry on with their pregnancies, deferred treatment that might harm their babies, and planned early deliveries, but at a gestational age when it was unlikely their babies would have serious consequences of prematurity. The decisions all these women had to make epitomize the full range and complexity of the problems dealing with cancer in pregnancy.

Women in the age range of 30-50 years are at greatest risk for developing cervical cancer because once infected with an oncogenic HPV type earlier in life, it can take years for this to culminate in a malignancy. Even when high-grade intraepithelial lesions are present, they are rarely associated with any signs or symptoms to warn of a potential problem. Eighty percent or more of cervical cancers are squamous cell tumors, these are often are relatively slow-growing compared to other malignancies, and some women may not have any significant signs or symptoms of disease until an advanced stage is reached.

Many women will develop an abnormal malodorous watery or blood-tinged discharge from their vaginas as one of the first signs of invasive cervical cancer and this is often followed by intermittent, painless bleeding that at first might only occur after intercourse. In most cases, the bleeding will eventually increase in amount, frequency, and duration, often becoming continuous with time, but this might not happen until the tumor has become quite large and/or deeply invasive. Some women may not notice anything unusual at all until they develop persistent bladder or rectal pressure, pain in the flank or a leg, bloody urine or difficulty voiding, rectal bleeding or difficulty passing stool, or swelling in one or both legs. These latter symptoms are indicative of deeply invasive disease involving pelvic organs and are likely to be accompanied by lymph node involvement and a poorer prognosis.

Although, I do not have the expertise to discuss the current management of advanced cervical cancer in pregnancy, there are a few observations I have made over time in helping to care for these women with the GYN Oncologists. Women who are diagnosed in pregnancy with an advanced stage of cervical cancer have significant challenges before them and decisions that will have to be made. Nowhere in the practice of medicine is it more important to provide adequate counseling and support than it is under these circumstances and that can usually only be accomplished by a well-integrated multidisciplinary team that might include among others: specialists in oncology, maternal-fetal medicine, and neonatology; trained counselors; and at times, specialists in infertility, personal physicians, clergy, and even an institutional ethical review board.

The diagnosis of any malignancy during pregnancy immediately places the woman and her unsuspecting baby in an unwelcome state of unanticipated conflict. How she chooses to balance her innate feelings of altruism versus self-preservation may have a significant impact on her own survival and the outcome of the baby. Information with which she is provided must be accurate, explained in terms that she can comprehend, and must be presented in as unbiased and consistent a fashion as possible. In this regard, members of any ‘multidisciplinary team’ must be in agreement with regard to the information she is given. Providers must respect that the final interpretation and choices based on the information is, ultimately, the woman’s prerogative and will be made against the background of her own make-up, including her personal beliefs, faith, other family concerns, and even friends. Among the issues that need to be addressed are:

• What is the presumptive diagnosis?
• What other procedures need to be done to establish the clinical stage of the cancer?
• Which if any of these diagnostic procedures can be done in pregnancy and what deleterious affects might they have on the baby?
• Will pregnancy limit the interpretation of these studies?
• What is the natural history and prognosis of the cancer by stage of disease in women who are not pregnant?
• Does pregnancy increase the risk of disease progression apart from any delays in treatment?
• What are the treatment strategies and their comparative results in women who are not pregnant?
• Which of the treatment options can be started in pregnancy?
• What are the known or suspected affects of different forms of treatment on the baby and do these differ by developmental stage of the baby?
• Would prospects for survival be improved by ending the pregnancy early? How much?
• If no treatment is started during the pregnancy, what is the prognosis for delivering a live and healthy baby?
• Will treatment decrease the risk of complications during pregnancy and improve the prospects for delivering a healthy baby?
• What are survival and complication rates for babies at different gestational ages?
• Are there promising experimental treatments available and under what conditions could they be tried in pregnancy or in the post-partum period?
• What is the best route of delivery?
• What procedures can be done at the time of delivery to improve diagnosis or prognosis?
• Are there reasonable options available to spare/preserve fertility or to allow for the birth of another baby even if this requires a ‘surrogate’ carrier?

This concludes our series on cervical dysplasia and cancer during pregnancy. If readers would like to share their personal experiences in this regard, I know there are many other women out there who would appreciate your thoughts. Thanks for reading!

Labels: Cervical dysplasia and cancer in pregnancy, HPV

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How to Interpret a "Positive" First Trimester Screen

A reader left the following comment on a post I wrote regarding "Abnormal First Trimester Screening Results." I have gotten this question repeatedly since we have begun offering this procedure for early aneuploidy (chromosomal abnormalities) screening, so I thought both the question and the response might be of general interest to our readers...

"We learned yesterday from first-trimester screening results that we have a 1 in 110 risk of having a baby with Down Syndrome (decreased from my age-related risk at age 41 of 1 in 34). I was told this is still considered a "positive" result, because the standard is 1 in 240. Hearing the counselor call our results "positive" for Down Syndrome was frightening. I appreciate your description of what these results mean. This has helped me to put it in perspective and understand what the risks really are. I'm not sure that labels such as "positive" or "negative" are very helpful in these cases." Anonymous, July 17, 2007

To Anonymous July 17: The results are what they are. You have a 1 in 110 chance of having a baby with Down syndrome. That means you have a 109 out of 110 chance of having a baby that does NOT have Down syndrome. In other words, of 110 women with any combination of the variables (age, blood test results, nuchal translucency measurement, etc.) that produced your 'results' from the database, only 1 of those would be expected to have a baby with Down syndrome (trisomy 21).

Personally, I do not like the "screen positive and negative" way of presenting things to patients. That may suffuce for research purposes but it makes us sound like we're talking out of both sides of our mouths! This is not a black or white test result and it's not fair to present the information to patients in that way! Could you have a baby with Down syndrome? Sure, someone has to be the one; that's true even if you have a 1 in 10,000 result. There are shades of gray that contribute to the interpretation of the test result, and those are the factors you bring to the table. How you use the number to make further decisions regarding additional screening and/or diagnostic testing depends on your personal level of risk tolerance. Do you view the cup as half empty, or half full? Do you bet nickels in Vegas, or $100 dollar bills? How comfortable does the test result make you feel?...and, many other factors that make you who you are.

In the end, if you opt for a diagnostic test, I would suggest an amniocentesis at 16 weeks. The risk of that procedure in experienced hands is generally less than 1 in 1000. The other alternative is to simply consider having a "genetic sonogram" at 18-20 weeks. If the baby is growing well and there are no fetal abnormalities or significant "markers" for aneuploidy (e.g., thickened nuchal skin fold, hypoplastic nasal bone or middle phalanx of the fifth digit, etc.) at that point (again, by an experienced examiner), your a priori risk based on the first trimester screen result (not your age alone) is reduced by at least 60-80% (I usually quote people 90%). Do what is MOST COMFORTABLE for you. Thanks for reading and for your good question.

Labels: aneuploidy, first trimester screening

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Cervical Dysplasia and Cancer in Pregnancy - 6

Our last post detailed the management of a pregnant woman who was found to have multifocal carcinoma in situ and microinvasive squamous cell carcinoma of the cervix early in pregnancy. Although she had a successful outcome from the management approach used in her case, I thought of several questions after finishing the post that might come to the minds of our readers: Are there risks to a pregnancy from the diagnostic and surgical procedures (cervical biopsies, conization, and cerclage) that were performed on our patient? Are there long-term risks of these procedures to future pregnancies if invasive cancer is not found? What is the natural history of high-grade intraepithelial lesions during pregnancy and afterwards when microinvasive disease is NOT found during the evaluation? What is the best route of delivery in the face of high grade intraepithelial lesions (not invasive cancer)? To answer some of these questions, let’s turn to past experience and some reports in the recent literature.

First, there are risks to ANY surgical procedure during pregnancy and though relatively small under these circumstances, must be balanced against the benefits. Because of the normal increases in blood flow to the uterus and cervix that occur during pregnancy, significant hemorrhage may occur even when a simple cervical biopsy is performed. The risk of bleeding is proportional to the area biopsied and when a large ‘biopsy’ such as a ‘cold knife conization’ is performed the amount of bleeding can be considerable both during the procedure and the post-operative period. In our case, we chose to perform a cervical cerclage as a means of both minimizing the risk of bleeding and providing some protection from premature labor under these circumstances and controlled additional bleeding using electrocautery after the specimen was obtained.

Other providers may choose to perform the entire conization, or even simply a wider biopsy of the TZ, during pregnancy using a LEEP (loop electrosurgical excision procedure) as a means of minimizing bleeding. Still others prefer the use of the CO2 laser, but the downside of these latter approaches is the ‘surgical margins’ may be obscured due to heat damage (thermal injury) and that can complicate interpretation of the presence and the depth of invasion. All of these procedures have the potential to increase the risk of premature rupture of membranes, premature delivery, intrauterine infection, and even pregnancy loss during the pregnancy, but these are surprisingly uncommon occurrences, particularly if the surgical procedures are performed prior to 24 weeks.

There are some long-term risks to both fertility and pregnancy success when cervical conization has been performed. We have known for years that scarring after extensive conization, particularly if heavy cauterization of deeper tissues was required, or infectious complications followed the procedure, can lead to stenosis (narrowing) of the cervical canal and even complete occlusion in some cases. This could impair fertility by preventing the transit of sperm into the uterus or increase the risk for obstetrical complications (such as failure to dilate in labor, lacerations, or even cesarean sections).

These procedures also “shorten” and distort the normal configuration of the endocervical canal and destroy endocervical glands that produce the mucous that is involved in the ‘capacitation of sperm’ (important for efficient ‘fertilization’) and the protection of the uterine cavity from ascending infections. Pregnancy consequences of these results are summarized in a metaanalysis of 27 studies last year by Kyrgiou and colleagues (Lancet 2006;367:489-98) in which pregnancy outcomes following cervical conization procedures were evaluated. These investigators found that prior cervical conization was associated with increased risk (generally 2- to 3-fold) in subsequent pregnancies for premature rupture of membranes, preterm delivery, low birth weight, and cesarean delivery. High conizations can disrupt the internal cervical os and lead to cervical incompetence.

Of course, there are also risks of incomplete evaluation of high-grade intraepithelial disease and microinvasive cervical cancer, the greatest being that there might be more extensive disease present than previously thought. If you recall, the patient featured in our case report had “multifocal areas of carcinoma in situ and microinvasion.” Such high-grade disease may encompass a wide surface area and it is not uncommon, even in experienced hands, to find disease in the surgical margins of a conization specimen (indicating incomplete resection) when the final pathology report returns. A recent study by Phongnarisorn (Int J Gynecol Cancer 2006;16:655-9) actually reviewed 129 hysterectomy specimens from women who had cervical conizations with residual high-grade disease or microinvasive disease in the original surgical margins. Of these, 57 (44.2%) had residual high-grade intraepithelial lesions and 20 (15.5%) residual invasive carcinoma (18 were microinvasive and 2 were frankly invasive). Fortunately, with truly ‘microinvasive’ disease, there is only about a 1% chance of having positive lymph node involvement and no more than about 0.2% chance of actually dying from cervical cancer if appropriate therapy is instituted and the patient continues in regular follow-up.

If a high-grade intraepithelial lesion is found in pregnancy with no evidence of invasion based on a thorough evaluation (colposcopy, biopsies, and conization if deemed necessary) by an experienced provider, there is fairly low risk of progression to significant invasive disease during the course of the pregnancy. Robova and colleagues (Eur J Gynaecol Oncol 2005;26:611-4) assessed persistence, progression, and regression of both low-grade and high-grade intraepithelial disease diagnosed during pregnancy and 24 months of follow-up after delivery. Of the sixty-two women with HSIL, they observed complete regression in 14 (22.6%), regression to LSIL in 17 (27.4%), persistence in 25 (40%), and progression to microinvasive disease in 6 (9.7%). Obviously, with the high risk of persistence of HSIL and progression of HSIL to invasive disease, aggressive and ongoing follow-up after delivery is indicated and this should be accompanied by a low threshold for ‘definitive therapy.’

Women will frequently ask if a cesarean delivery is indicated for high-grade intraepithelial lesions. They are usually asking two questions contained within one: Does a vaginal delivery increase the risk of disease progression? And, could I possibly give my disease to my baby? Answering the last question first, I usually tell them that high-grade lesions are the end-result of an HPV infection, but usually by the time HSIL is present, the virus has gained the ability to control cell growth, but that control is at the expense of losing the capacity to produce intact and infectious viral particles that could be passed on to other individuals. With regard to the first question, there has actually been some evidence presented in years past that a vaginal delivery actually increases the chance of disease regression. Recently, Kaneshiro and colleagues (Am J Obstet Gynecol 2005;192:1452-4) reviewed retrospectively data on 201 pregnant women with abnormal Pap tests. Regression rates for vaginal and cesarean section groups for LSIL were 58% vs 42%, respectively, and for HSIL, 53% vs 25%. Although the latter did not reach statistical significance, we can safely say that vaginal delivery certainly does not increase the risk of progression in women with HSIL.

Labels: Cervical dysplasia and cancer in pregnancy, HSIL, LSIL, microinvasive cancer

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Cervical Dysplasia and Cancer in Pregnancy - 5 (A Case Report)

Within the past year, I helped the GYN Oncologist at our institution care for a pregnant woman who had cervical cancer. She was 33 years old and pregnant with her third child. At her intake OB visit she had a Pap test done that returned with a diagnosis of a high-grade lesion (HSIL). Her physician performed a colposcopic examination (looked at the cervix through a magnifying scope), and did multiple biopsies of the cervix in "the most abnormal appearing areas." He made a comment that, despite best efforts, the "upper limits of the transformation zone (TZ) could not be completely seen." This means that the junction of the TZ and the columnar epithelium up in the cervical canal could not be adequately visualized. This is a concern, because there could be disease lurking inside the cervix itself that could not be adequately assessed and there is no place for complacency under these circumstances.


The biopsies of the outer cervix (ectocervix) returned from the pathologist with the diagnosis of "squamous cell carcinoma in situ and microinvasive carcinoma." The patient was then referred to the GYN Oncologist for further evaluation. His recommendation was that she should have a ‘cold knife conization’ (wide wedge-shaped excision of the transformation zone and portion of the cervical canal) of the cervix performed to more thoroughly evaluate both the depth of invasion and the cervical canal that could not be visualized at the time of her original colposcopy. Further recommendations would be based on those results. She was sent to me at about 13 weeks for additional thoughts on management before the conization was performed.


We reviewed her medical history and performed an ultrasound examination of the baby and the cervix. Her previous two pregnancies had delivered vaginally at term and had been uncomplicated. She had no ongoing medical problems. The current baby was normally grown and no gross physical abnormalities were seen within the limits of an anatomical survey for this early gestational age. The cervix measured 40 mm in length; no obvious adnexal abnormalities were seen. We offered her "combined first trimester screening for aneuploidy" to which she readily agreed. She had made it quite clear that if this baby was at increased risk for a chromosomal abnormality, she would want that diagnosis ascertained before making any decisions regarding therapy for her cervical cancer.


The oncologist had also asked that we discuss with her the option of placing a ‘cervical cerclage’ at the time the conization was performed. A cerclage is a stitch placed around the cervix that is usually reserved for women with cervical incompetence (a weak cervix that results in premature cervical effacement and early delivery). Women who have a past history of cervical conization (or conization during pregnancy) that has resulted in significant shortening of the cervical canal are at increased risk for premature rupture of membranes and premature labor and delivery. In her case, placement of the cerclage during the conization procedure would have the added benefit of helping to reduce the risk of bleeding. Remember, during pregnancy, blood flow to the cervix goes up dramatically.


She was scheduled for the conization with cerclage two weeks later. A week after I saw her, the first trimester aneuploidy screening test result had returned very reassuring (less than 1 in 4000 risks for trisomies 21, 18, and 13), so the patient elected not to proceed with an invasive diagnostic study (genetic amniocentesis) before the conization. On the day of her surgery, I placed the cerclage around her cervix as high as we could get transvaginally (about 30 mm up the cervix) but did not tie the suture until the oncologist had performed the conization. Once that was done, the cerclage was tied snugly and this immediately controlled the bulk of the bleeding from the conization. The patient was discharged from the hospital the same day.


She returned to our office at about 18 weeks for another ultrasound. The pathology report had confirmed "extensive carcinoma in situ and multifocal microinvasive squamous cell carcinoma with a depth of invasion less than 3 mm. The margins were clear, but there was some evidence of lymph vascular space invasion." Technically, these findings classified her as a stage 1A1 (lowest grade) cancer of the cervix. The baby looked fine by ultrasound and the cervical cerclage was in good position with no loss of integrity at the internal cervical os (opening) to suggest incompetence.


During the pregnancy, her own obstetrician continued to follow her for routine care, she was seen every 4-6 weeks by the GYN Oncologist and had periodic colposcopic exams performed, and we followed the growth of the baby and maternal cervical length. She was presented with the pros and cons of several options for delivery, ranging from a vaginal delivery with evaluation and management by the oncologist following delivery to a cesarean delivery with coincident hysterectomy and lymph node dissection. Because of her desire for no future pregnancies and because we could not guarantee that she didn’t have a higher grade cancer and lymph node involvement, even with the diagnosis of a stage 1A1 cancer, she elected to proceed with the latter. At 38 weeks, we performed an amniocentesis to confirm fetal lung maturity. The next day, her obstetrician delivered her baby by cesarean and the oncologist completed his part of the procedure.


The final pathology report on the surgical specimen showed only a few areas of carcinoma in situ on the cervix, no evidence of residual invasive disease, all surgical margins free of disease, and most importantly, no evidence of lymph node involvement. Mother and baby have both done well. This is one of those cases of cervical cancer during pregnancy that epitomizes the value of a medical care ‘team’ and that had a very happy ending…

Labels: microinvasive cancer, Pregnancy and cervical cancer

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Cervical Dysplasia and Cancer in Pregnancy - 4

Since our last post, a reader asked the simple question, “if the patient has an abnormal Pap smear and it is not cancer, then what is it?” Although my specialty is Maternal-Fetal Medicine, and I have no delusions (or desire) to be a cancer specialist, I have had a long interest in HPV problems and have been asked this question on many occasions. So today, let’s digress to briefly elaborate on the sort of information I will discuss with patients when questions such as this one arise…

Although almost all cervical cancer (as well as more than 50% of vaginal, vulvar, and anal cancer) are associated with HPV infections, infection by itself does not appear sufficient (in most instances) to cause cancer. Indeed, cancer occurs in only a small percentage of the women who have been infected with HPV. The time to development of cancer is usually many years and usually preceded by abnormalities of the cervical cells that are confined to the epithelium (intraepithelial neoplasia or dysplasia) and do not invade the underlying tissues. Risk factors mentioned previously (e.g., persistence of a ‘high risk’ HPV type, smoking, immunosuppression, early age of exposure to HPV, HIV infection) may increase the likelihood and accelerate the rate of developing invasive cervical cancer.

The full spectrum of cervical abnormalities can readily be detected with the Pap test. It is true that the Pap test may not detect these abnormalities if the surface of the cervix and the cervical canal are not adequately sampled, the areas of cervical abnormalities are not readily accessible (e.g., high in the cervical canal) or just missed, or the test is either misread or cannot be read due to other factors. The advantage of routine screening is that regular sampling (on a schedule recommended by your provider and appropriate to your circumstances) reduces the contribution of these factors to a ‘false negative’ result and usually some abnormality will be detected long before a serious problem has developed. The recent introduction of liquid-based cytology has increased the likelihood of detecting these abnormalities and offers the additional advantage of being able to be used for ‘reflex’ HPV-typing to check for the presence of a ‘high risk’ HPV type if a cytologic (cellular) abnormality is discovered.

The epithelium (‘skin’ surface) that lines the cervical canal and covers a good portion of the cervix that sits in the vagina starts out early in life as a protective barrier that is only one cell layer thick (columnar epithelium). The vaginal epithelium, on the other hand, is many cell layers thick (squamous epithelium) and there is a progressive transition in this type of epithelium from the plump, actively dividing cells at the base of the epithelium to the most superficial layers where the cells are flattened, relatively inactive, and eventually detach and fall off the surface. (The vaginal epithelium is much like the skin that covers our body, but it does not contain certain substances (keratins) that make the outer skin ‘tougher’ and more of a barrier to fluid loss). Whether columnar or squamous, both epithelia sit on a structure called the ‘basal membrane’ that separates the epithelium from deeper tissue layers.

Around the time of puberty, the outer cervical epithelium begins to undergo a transition from the original columnar epithelium to a squamous epithelium under the influence of normal hormonal and pH changes within the vagina. This transition is called squamous metaplasia and the area that undergoes these changes is called the transformation zone (TZ). The TZ, especially, during the time of transition, is very sensitive to environmental influences such as HPV and ‘cofactors’ that can eventually lead to the loss of usual cell control mechanisms (proliferation, DNA replication, and contact inhibition). Indeed, most cervical intraepithelial neoplasia or ‘lesions’ (for lack of a better term, “precancer”) and cancer arise in the TZ. This is probably also why women who become sexually active earlier in life before the normal TZ changes are complete are at greater risk for cervical precancerous lesions and even cancer if exposed to HPV at this time. The difference between the intraepithelial precancerous lesions and cancer is that cancer cells not only begin to proliferate uncontrollably, but they are also able to breech the basal membrane on which the epithelium sits and invade the underlying tissues. Intraepithelial lesions are confined to the epithelium and while they are there, they are NOT cancer, regardless of how nasty they may look.

Although the nomenclature has changed through the years, today, we basically divide abnormalities of the cervical squamous epithelium into low-grade intraepithelial lesions (LSIL, previously termed mild dysplasia or CIN 1), high grade intraepithelial lesions (HSIL, which includes the previously termed categories of moderate and severe dysplasia, or CIN 2/3, and carcinoma in situ (CIS)), and invasive cancer. There are other categories including atypical squamous cells of undetermined significance (ASCUS) (sounds like the ‘rodents of unusual size’ in "The Princess Bride," doesn’t it?!?) and a small percentage of cervical cancers arise from the glandular cells of the columnar epithelium (adenocarcinomas), and many of these are also associated with HPV infection, but for the sake of clarity, brevity, and my own sanity, these abnormalities will not be discussed by me herein.

There are now numerous studies in the literature that have tracked the natural history of HPV infections and cervical dysplasia, but I have selected two that are representative and present a spectrum of the information currently available. Moscicki and colleagues (Lancet 2004;364:1678-83) followed prospectively 899 women age 13-22 years of age who tested positive for HPV DNA. Of these, 260 (29%) were diagnosed with LSIL by cytology and of those who were, 61% had regressed by 12 months’ follow-up and 91% by 36 months’. Only 3% progressed to an HSIL lesion (and none developed cervical cancer) over that same period of time. In another study presented at the recent meeting of the North American Society for Pediatric and Adolescent Gynecology, Dr. Michelle Vichnin reported the results of follow-up on 195 women age 21 or less who were referred to their colposcopy clinic for an abnormal Pap test. Among these women, the average age of first intercourse was 14.9 years and the average age of the first ‘abnormal’ Pap test was 18 years. Thirty-four (17.4%) had biopsy proven HSIL and 13 developed their high-grade disease in 3 years or less after becoming sexually active. HSIL is invariably associated with infection with high risk HPV types and persistence and amount of HPV DNA that is found in the tissues is directly correlated with progression to invasive cervical cancer over time if the woman is not treated.

Labels: Cervical dysplasia and cancer in pregnancy, HSIL, LSIL

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Thanks Dr. Smith for Grand Rounds 3.42!

Thanks to Dr. Tara C. Smith at ScienceBlogs.com Aetiology for including my recent post in this week's Grand Rounds 3.42 regarding a conversation I had with a young teen who was pregnant, had an abnormal Pap test, and thought she had cervical cancer. This is not an infrequent misconception that can easily arise from both poor or hurried explanation and poor patient comprehension. Great job Dr. Smith - many interesting posts to feast upon for this week!

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Cervical Dysplasia and Cancer in Pregnancy - 3

It the last two posts we reviewed a discussion I had with a young woman who had misconceptions about the significance of an “abnormal Pap test” result early in her pregnancy. The point that was emphasized to her was the she did have genital warts and she did not have cancer. When she left, I think she had a better understanding of her condition, although I am also not sure she was completely convinced by my reassurances. Both anogenital warts and the most common forms of cervical cancer are clearly associated with human papillomavirus (HPV) infections, but the viruses that generally cause warts and the viruses that may lead to cancer are fundamentally (and biologically) very different beasts. Today, let’s digress with a brief overview of the HPV epidemic and mention the basic differences between HPV types.

To describe infection with HPV as widespread is a gross understatement – a better term would be ubiquitous. HPV is readily spread by intimate contact and most efficiently by sexual intercourse, although nonsexual routes of transmission (e.g., between mothers and newborns) and, rarely, fomite transmission (e.g., shared underwear) have also been documented. Condom use may reduce the risk but it is clearly not reliably protective. Among sexually active men and women, more than 50% will acquire an infection with one or more HPV types during their lifetimes. Risk for acquisition is directly related to lifetime number of sexual partners and early age of first intercourse. The CDC (Centers for Disease Control and Prevention) estimates that 80% of sexually active women will have evidence of a genital HPV infection by the time they are 50 years old.

Annually, in the U.S., 6-7 million individuals will acquire a genital HPV infection and more than 20 million will be dealing with active infections or complications related to the viruses. Three-quarters of all new HPV infections occur in sexually active individuals between 15-24 years of age among which there are more than 9 million currently infected. At any one time, about 1% of the sexually active adult population will have genital warts. In various studies, prevalence rates in women less than 25 years of age range from 28-46%. Fortunately, HPV infection in this group of women tends to be transient and is correlated with the development of a specific cell-mediated immune response to the virus (Schiffman, et al., J Natl Cancer Inst Monogr 2003;31:14-19). In one study of newly acquired HPV infections in college women, 70% of new HPV infections cleared within a year and 91% within 2 years with a median duration of infection of 8 months (Ho, et al. NEJM 1998;338:423-28). Persistent HPV infections are more likely to occur with oncogenic HPV types (see below), smokers, and in individuals who are immunosuppressed, such as those with diabetes, autoimmune disorders, organ transplants, and HIV infections.

Of the more than 120 different types of HPV, 25-30% are implicated in anogenital infections. Individuals may be infected with more than one HPV type and, indeed, there seems to be very little ‘cross-reactive’ immunity between different types. These viruses are divided by their innate biological properties into nononcogenic (noncancer-causing) types, such as HPV 6 and 11, the types which commonly cause more than 90% of anogenital warts, and the oncogenic types, such as HPV 16, 18, 31, 33, 45, the types associated with cervical intraepithelial neoplasia (or dysplasia) and cancer. HPV DNA can be found in 99.7% of invasive cervical cancer and the five oncogenic types listed here are associated with 63-97% of these malignancies worldwide. Unlike the nononcogenic types, the oncogenic HPV types are more likely to establish persistent infections and have the ability to integrate their DNA into the host genome. The production of two (at least) oncogenic proteins (E6 and E7) by these HPV types results in the inactivation of host cell factors (p53 and pRb) that usually limit cell proliferation. Although the pathway to cancer involves multiple steps, it is thought that the uncontrolled cell proliferation increases the risk of accumulating DNA damage that eventually leads to cancer.

With this information as an introduction, we will in our next post continue our discussion of cervical dysplasia and cancer in pregnancy and some of the special considerations to care that arise under these circumstances

Labels: cervical dysplasia and cancer, HPV disease

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Cervical Dysplasia and Cancer in Pregnancy - 2

By the time I got to the consultation room with the information from the clinic, the tears had stopped flowing (see yesterday's post). Her mother was with her and the first thing I asked was if she wanted her boyfriend there as well. Again, she shook her head no, so I asked her to “Look me in my eyes and hear me loud and clear – You do NOT have cervical cancer.” Then I went on to explain that she did indeed have genital warts and that they are caused by viruses called human papillomaviruses (HPV). Some HPV types can eventually lead to cancer, but the common types that are the most likely to cause the kind of warts that she has, do not.

The ‘abnormal’ cells found on her Pap test are the lowest grade of abnormality and are very typical of what is seen with genital warts alone and they are a NOT ‘cancer’ cells. I told her that these viruses are very common in young sexually active women and many of them do not even know they have the infection. Unfortunately, she probably contracted the virus from her boyfriend right around the time she got pregnant and her immune system was not as effective at controlling the infection because of the pregnancy. I told her that many women, if left untreated during the pregnancy, will often go on to clear their warts spontaneously within a few months after delivery, although they may never completely clear the virus that causes them.

I also explained to her that the presence of ‘warts’ reflects an active virus infection in which new viruses are being produced and can be passed along to other individuals and, sometimes, even to babies at delivery. But, in the same breath, I told her that the presence of genital warts is rarely an indication for a cesarean delivery unless they are so extensive that they might interfere with repair of lacerations that need to be fixed at the time. I did suggest that because she was still very early in the pregnancy, and had very severe involvement of the vagina, vulva, and perineal areas, that it was probably worth trying to reduce the amount of disease she had before the delivery to minimize any risks of complications. Then I outlined a possible treatment plan that would be ‘safe’ for her and the baby.

She seemed satisfied with what she had been told, but was still concerned about the ‘cancer’ issue. “They told me I would have to have the cancer cells treated” she said, and her mother shook her head in agreement and told me she “was right there when they told her that.” I wasn’t about to argue with either of them about what they had been or thought they were told. There have been too many instances I have been aware of in the past when physicians, trying to insure that follow-up appointments for monitoring cervical dysplasia are kept, have used the “C” word to strike fear into the heart of the unwary rather than spending time on a more prolonged explanation. But, I did use this as an opportunity to provide some more information.

With the low-grade abnormalities she had on the Pap test, if these were only caused by one of the noncancer-causing types, 9 out of 10 women with one of these types will have a normal Pap test within 3 years without any treatment. Indeed, sometimes the treatment is worse than the disease under these circumstances. However, I also told her that some people will be infected by more than one HPV type and if she was, it would increase the chance she also had a type that might some day lead to cancer. “After you deliver, we will check you out on all that, but even then, you should have annual examinations until we recommend otherwise. It usually takes many years to develop cervical cancer and, if we follow you carefully, there is no reason you should ever get to that point.”

As she was getting ready to leave, I saw one other notation in her record that was worthy of comment under this situation. “By the way, I see you are a smoker. Smoking is not only associated with more difficulty getting rid of warts, it probably also increases your risk of cervical cancer from HPV. That’s something you could quit right now that will help both you and your baby. Why don’t you put the money you would spend on cigarettes into a college fund for your daughter, after all, you’ll probably be around now to see her finish high school.” She laughed nervously, but I think she got the message!

Labels: HPV; cervical dysplasia and pregnancy

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Thanks to Over!My!Med!Body! - Grand Rounds 3.41

Thanks to the folks at Over!My!Med!Body! for including the final post in my series on Hypertensive Disorders in Pregnancy - 8 (9 and 10!) in this week's Independence Day Grand Rounds 3.41. I know it didn't quite meet with the theme, but for those who wade through it, the take home message points to exciting advances in the potential early diagnosis and management of preeclampsia - still one of the leading causes of perinatal morbidity and mortality here and throughout the world. A GREAT Grand Rounds guys and gals!

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Cervical Dysplasia and Cancer in Pregnancy - 1

Awhile back, a reader asked me to discuss cervical cancer in pregnancy. I had put the topic on the back burner, waiting for a good segue into the subject from a patient care perspective. When it comes right down to it, cervical cancer during pregnancy in the U.S. is not very common. Although estimates vary, it is expected there will be about 11,150 new cases and 3,670 deaths related to cervical cancer here in 2007 at a treatment cost of about $2 billion. However, of these, only about 1-3% (100-300 cases annually) will occur coincident with a pregnancy. Fifty years ago, cervical cancer was the leading cause of cancer-related death in women in the U.S., but with the introduction and widespread adoption of the Papanicalaou (Pap) smear (and now liquid-based cytology), and the subsequent early detection of preinvasive cervical abnormalities amenable to relatively conservative therapy, the incidence and mortality have dropped significantly, a trend that has continued in the U.S. among all ethnic groups. To put the U.S. statistics in perspective, worldwide, it is estimated that this year there will be about 493,000 cases and 273,500 cervical cancer deaths, with 85-90% of these occurring in developing countries.

So, what compelled me to bring up this subject now? Recently, I saw a young woman (16 years old) early in pregnancy for an ultrasound to confirm her ‘dates’ and evaluate the baby’s anatomy. The baby looked just fine, but after I told her the baby was a girl, she got very upset. This was not the kind of upset that women typically get when they would have preferred a baby of different gender, but I did ask her if she had been hoping for a boy. She shook her head no, but continued to sob uncontrollably. So, I asked if there was something else she wanted to talk about. At that point she asked her boyfriend to leave the room and as soon as the door was shut, she told me that “he gave me warts, and the one’s inside turned into cancer, and the doctor told me they can’t do anything for me.” At that point (I was very relieved), I told her that I bet there was some misunderstanding, that she probably is going to be just fine, and that I would look into it for her before she left. This is a scenario I have seen too many times before, so I was fairly confident in what I had told her.

While she was being moved to a consultation room, I called to our clinic to get the ‘real story.’ As it turned out, this was her first pregnancy, she had conceived very shortly after becoming sexually active (her boyfriend was much older), she did have anogenital warts with heavy vaginal involvement, her Pap test had returned with low-grade squamous intraepithelial neoplasia, and she had been told that she probably wasn’t going to be treated during the pregnancy. This was a little different from what she had actually thought she heard which was that she had cancer and there was nothing we could do to help her and that she wasn’t going to be around to see her baby girl graduate from day care! So, I went back to the consultation room to talk with her and the conversation we had will be the subject of our next post….

Labels: anogenital warts, Cervical dysplasia and cancer in pregnancy, HPV disease

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Hypertensive Disorders of Pregnancy - 8 (9 and 10!)

I started this article 3-4 days ago and was about to post it to the site last night and realized it looked more like a scientific review article for the New England Journal of Medicine than anything most of you would care to read. So, I have pared it down (although it’s still a bit long), hopefully, simplifying enough that the points will come through without compromising the scientific integrity of the work being done in this area. The general concepts are what is important here and not the scientific jargon. I want you to know where the current research is taking us and offer some thoughts of my own regarding risks and opportunities of therapeutic advances in this area.

I really could go on for many more posts related to hypertensive disorders in pregnancy, but I think I will call it quits (for awhile) after this one, lest I run the risk of boring to tears all of you who are not interested in the subject. If you haven’t figured it out by now, I am VERY interested in it; and, if you haven’t noticed already, much of what we have discussed related to preeclampsia overlaps with the subject of recurrent early pregnancy loss upon which we have spent lots of time! Indeed, I often look, rather simplistically, at the issues related to abnormalities of placentation that comprise the most common source of preeclampsia as pregnancies that almost miscarried, but didn’t quite; and, the ones that came closest to being lost are also the ones most likely to result in the more severe forms of preeclampsia.

I think the greatest advances that will be made in the management of preeclampsia over the next decade will be the early identification of the biological ‘markers/mediators’ involved in its pathogenesis, applying this knowledge to identifying patients truly at risk, and implementing specific interventions designed to counteract their effects as a means of preventing, reducing the risk of developing, or decreasing the severity of preeclampsia that eventually develops. It just makes sense, if most preeclampsia is the end result of abnormalities of placentation that occur in early pregnancy, then there MUST be factors that can be detectable during the first and early second trimester of pregnancy that reliably reflect the pathologic processes in progress.

Indeed, many studies are now being conducted around the world to identify and characterize just such factors. One group of factors, under intense investigation, is antiangiogenic substances. If you recall in our 4th post on this subject, we pointed out that angiogenic (blood vessel growth promoting) and other growth factors are probably critical to the success of early placentation in terms of trophoblast invasion, migration to, and remodeling of, the spiral arterioles, and arborization and vascularization of the placental villi. Two ANTIangiogenic substances currently in the news are soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). Bear with me while I give you an overview of this fascinating area of research…

In 2003, Maynard and colleagues (J Clin Invest 2003;111:649-58) reported that the soluble (circulating) placental substance sFlt-1 is produced in greater amounts in women with preeclampsia. We now know this upregulation, or increase in sFlt-1 production, are the consequence, at least in part, of a placental environment with suboptimal levels of oxygen. sFlt-1 is an antagonist of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). Indeed, sFlt-1 actually binds to these growth factors (and is now sometimes referred to as soluble VEGF receptor-1, or sVEGFR-1), thereby, preventing them from interacting with endothelial cells. In a series of elegant experiments, Maynard and colleagues demonstrated that serum from preeclamptic women with increased levels of sFlt-1 caused endothelial cell (cells on the inner lining of blood vessels) dysfunction and arteriolar constriction in vitro and that these deleterious effects could be overcome with addition of exogenous VEGF and PlGF. Furthermore, they showed that the “administration of sFlt-1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia” found in the kidneys.

While these observations (and many others I will not mention today) suggested that an excess of sFlt-1 in preeclamptic women (now known to arise from both placental and maternal sources) might contribute to the final pathogenesis of the end-stage preeclamptic syndrome, it did not answer the questions related to the actual cause of the abnormalities of placentation in early pregnancy that set the stage for placental hypoxia and sFlt-1 upregulation. Subsequent studies by other investigators have suggested a role for sFlt-1 in the pathogenesis of abnormal placental growth and development. As examples of the work in this area, Ahmad and Ahmed (Circ Res 2004;95:884-91) have shown that serum from preeclamptic women inhibits endothelial cell migration and angiogenesis and that this could be restored by specific removal of sFlt-1 from the serum to levels comparable to that found in the serum of nonpreeclamptic women. Nagamatsu, et al. (Endocrinology 2004;145:4838-45) have shown in tissue culture experiments that the cytotrophoblasts (placental cells) involved in the uterine invasion and vascular remodeling of maternal vessels not only can make VEGF, but also produce sFlt-1 in response to a reduced oxygen environment, thereby, countering the ‘angiogenic’ properties of VEGF. This suggests that the cytotrophoblasts themselves have an innate mechanism for regulating the extent and limits of their invasion into maternal tissues and that this control depends in part on sFlt-1.

In other posts, we spoke in broad generalities regarding the presumptive importance of the maternal immune response in both normal and abnormal placental development. As an example of the mother’s role in the regulatory processes under discussion today, Matsubara and colleagues (Reprod Immunol 2004;68:27-37) reported that decidual mononuclear cells can be induced by the lymphokine interleukin-2 (IL-2) (produced by T-lymphocytes as part of the immune response) to become ‘killer’ cells (lymphokine-activated killer, or LAK, cells). The LAK cells were found by these investigators to reduce the angiogenic activity of placental cytotrophoblasts and appear to do so by upregulating the production of sFlt-1 since they did not actually affect the amount of VEGF or PlGF made by the trophoblasts. Recently, Lockwood and colleagues (Am J Pathol 2007;170:1398-405) have demonstrated that the maternal decidual cells themselves (and not just the fetal trophoblasts) express sFlt-1 messenger RNA (mRNA) suggesting that these cells also can produce sFlt-1. Thus, these articles suggest at least two maternal regulatory mechanisms for limiting trophoblast invasion that, when ‘over-expressed’, could prevent normal placentation and lead to preeclampsia. Indeed, as part of the Lockwood report, it was also shown that the presence of thrombin enhanced sFlt-1 production by first trimester (but not term) decidual cells. This might offer a mechanism by which abnormalities of the coagulation system that cause excessive clotting (thrombin generation) in both recurrent pregnancy loss and preeclampsia might mediate their deleterious first trimester effects!

Now, briefly let’s discuss another antiangiogenic factor currently under investigation – soluble endoglin (sEng). In 2006, Venkatesha, et al. (Nat Med 2006;12:642-9) reported that “a novel placenta-derived soluble TGF (transforming growth factor)-beta coreceptor, endoglin (sEng)…is elevated in the sera of preeclamptic individuals (and) correlates with disease severity...” sEng was also found in in vitro experiments to inhibit angiogenesis and in vivo, and significant with regard to end-stage preeclampsia pathogenesis, to increase vascular permeability (leakiness) and induce hypertension. In pregnant rats, its effects were found to be amplified by the coadministration of sFlt-1, “leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and restriction of fetal growth.” The suggested mechanism of action on the blood vessels is impairment of TGF-beta binding to its receptors that is required for activation of pathways normally resulting in vasodilation (blood vessel relaxation) and more recent studies have supported this hypothesis (Santibanez, et al., J Cell Physiol 2007;210:456-68).

So, we now have two ‘markers’ for preeclampsia that may directly participate not only in the pathogenesis of the placental abnormalities early in pregnancy, but also in the ‘end-stage’ changes that characterize preeclampsia syndromes. This does give us specific targets for medical intervention. The questions remain, however, can the detection of sFlt-1 and/or sEng help us to diagnose the patient who is going to develop preeclampsia early enough in the pregnancy that medical intervention can be started, what interventions may be possible based on the ‘science’ to date, and will such interventions be safe for BOTH mother and baby?

Several recent studies have shown that these antiangiogenic factors increase and can be detected significantly before the onset of the preeclamptic syndrome. Levine and colleagues (NEJM 2006;355:1056-8) showed that sEng levels increase 2-3 months before the onset of preeclampsia in women who developed either preterm preeclampsia or term preeclampsia. Similarly, Rana, et al. (Hypertension 2007;50:137-42) demonstrated that both sFlt-1 and sEng are elevated by 17-20 weeks in women destined to become preeclamptic. Unfortunately, most of the placental development (or lack thereof) of significance related to preeclampsia is completed by this point in the pregnancy. If these markers are to be truly useful in altering the course of preeclampsia, we are going to have to establish their reliability in predicting it at earlier gestational ages.

With regard to ‘treatment’, several of the investigations cited above have shown that the effects of sFlt-1 can be overcome by the addition of excess VEGF (or the removal of sFlt-1 or sEng). I may be wrong about this but, unless this is proven to work early in pregnancy to improve the placental growth and development, I am afraid that such therapy later in pregnancy may improve the maternal condition at the expense of the baby. Remember, the placenta appears to be driving maternal preeclampsia because it is ‘unhappy’, probably as the result of insufficient oxygen. It does not make the mother sick capriciously; it is trying to improve its own condition by the only mechanisms it has at its disposal. Any therapy that only improves the maternal side of the equation has to impact negatively on the fetal side!

In closing, I would like to mention one other recent study that opens up another possible avenue for therapy. Cudmore and colleagues (Circulation 2007;115:1789-87) pointed out that heme oxygenase-1 (HO-1) and its metabolite carbon monoxide (CO) exert protective effects under conditions of oxygen deprivation and hypothesized that this might be the result of downregulation of sFlt-1 and sEng production and release. In a series of experiments, they found that mice lacking HO-1 produced higher levels of sFlt-1 and sEng than normal mice; enhancement of HO-1 production (using an adenovirus vector) inhibited release of both sFlt-1 and sEng from endothelial cells under conditions that would normally increase their production; the CO-releasing molecule (CORM-2) or CO itself inhibit sFlt-1 release; and, treatment of endothelial cells with statins that upregulate HO-1 also inhibit the release of sFlt-1. To me these findings are very exciting, because they may offer an option for early medical therapy that may have the greater chance for success in the actual prevention of the placental changes that contribute to the pathogenesis of preeclampsia. These studies also may help to explain why cigarette smoking (increased CO) seems to reduce the risk of preeclampsia by 50% or more!?!

I have one other thought and then I promise to bring this series to a close. I firmly believe that to have the greatest impact on preventing preeclampsia (and early pregnancy loss unrelated to aneuploidy), we need to maximize a favorable maternal immune response to pregnancy. Perhaps, someday we will have a ‘pregnancy vaccine’ that will do just that! Thanks for sticking with me on this. Hope some of you had as much fun as I did!

Labels: endoglin, heme oxygenase-1, Preeclampsia treatment and prevention, sFlt-1. sEng

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