Diseases, Disorders information

Major congenital anomalies are observed in about 3% of all births. Maternal exposure to drugs or environmental chemicals may be responsible for 4-6% of these anomalies, or approximately 1 in 400 liveborn infants.

Whether birth defects occur in a conceptus exposed to a potentially teratogenic agent depends in large part on two factors: 1) gestational timing of the exposure and 2) the genetic makeup of the conceptus and the mother. Morphogenetic stage of the organism’s development is a key factor in susceptibility to a potential teratogen. Exposure to a teratogenic agent during organogenesis may result in a gross defect involving the organ undergoing formation at that time. Conversely, exposure to such an agent during histogenesis may produce finer structural defects within the target organ system. Substantial evidence suggests that, second only to the gestational timing of exposure, the most important variable is difference in the genetically determined activity of the enzymes involved in the metabolism of drugs and chemicals. This difference is termed pharmacogenetic variation. An important determinant of teratogenic potential is mode of exposure. The teratogenic agent may reach the developing embryo or fetus either by direct passage through maternal tissues (eg, ionizing radiation) or by placental transfer (eg, drugs or chemicals).

Drugs and Chemicals

Epidemiologic studies have determined that most drugs commonly used during pregnancy (eg, aspirin, acetaminophen, metronidazole, caffeine, phenothiazines) are not associated with an increased risk of congenital anomalies. However, based on anecdotal evidence, maternal hyper-thermia seems to be associated with congenital anomalies when the fever persists for a protracted period of time (>24 hours) and is high (at least 101 o F). Numerous other agents have been implicated as teratogens, including chemotherapeutic agents. However, approximately 95% of the 200 most frequently prescribed drugs appear safe for use during pregnancy.

This shows fecal incontinence over a ten-year period of time, and importantly, in the same 300 patients. In other words, patients surveyed – same group – at 1,5 and 10 years. Not different patients at different years. So daytime perfect fecal incontinence is shown here at about 75%. Imperfect, meaning once or twice a week – or perhaps slightly more frequently – shown here at about 5%. Frequent fecal incontinence is very low. The night time success rate is lower than the daytime, for obvious reasons. This reaches about a 55%-60% chance of having perfect fecal control at night.

The mortality – for this usually, completely elective procedure – is very low. Morbidity is also not bad. Pelvic sepsis being a particularly difficult problem in 5% of patients. Wound infections are good at Mayo in general, but in this group it’s about 3%. Small bowel obstructions occur with a frequency no higher than the literature frequency of Brooke ileostomy.

The problem of pouchitis. About 40%-50% of our patients will experience an episode of pouchitis in the postoperative period. What does that mean? Well, let’s take a flow diagram of pouchitis in our patients. So of 100 patients after ileoanal anastomosis, 50 will never have the problem. So let’s go to the 50 that do. Twenty-five of the 50 will have one episode leaving 25 with more than one episode. Of that 25 patients, only four will have something called chronic, unremitting, long term problems with pouchitis, of whom three of the four will be managed. We can talk about the management perhaps later. And one will fail. So about half will have one episode. Among all the others with a rate of 15% have chronic pouchitis or 4% of all patients after ileoanal anastomosis, and most of those are managed medically. Among the patients that failed this operation, only 4% – if you have 100 patients who failed the operation – only four will fail because of pouchitis. They mainly fail for septic problems, mechanical problems with the operation. Perhaps something akin to Crohn’s disease occurring in the pouch or in the anal canal. But again, here’s that four patients with pouchitis as a cause of failure. So there’s no doubt that there are implications for patients with pouchitis, if there is increased incontinence, there are systemic manifestations of the disease at times, there is a need to take canadian medications and a whole host of different things have come along, and there are some workplace and social inconveniences. But there is no permanent increase in stool frequency in these patients and there is little chance of outright failure.

Ulcerative colitis. As everyone pretty much knows, ileoanal anastomosis has replaced Brooke ileostomy as the operation of choice in most institutions for ulcerative colitis, because of the following factors: the disease is removed, the malignant potential largely eliminated, fecal continence is preserved, there is no stoma and we have fairly good data that the quality of life is improved.

The next two slides are my surgical experience with this problem over a five week period in January. Here are four patients who underwent this operation and look at the interesting mix of patients; polyposis, refractory, bad bleeding. This patient was stage II of a III stage disease. He had toxic megacolon. This patient was refractory to medical management and another four – again, this is only a five week period – this one had cancer. He’s a little older. We did a Brooke ileostomy, so that’s seven out of eight patients presenting had this ileoanal anastomosis. Here are two DALM lesions and another refractory to medical management. So the operation is being performed very frequently at our institution and interestingly for me, different indications. It’s an operation in evolution. There are problems with the operation if there are problems connecting the pouch to the anus, you can get a stricture, fistula and sepsis. And this can lead to fecal incontinence. You can have multiple stools. More about pouchitis in a minute. Not all patients are candidates because they are either too tall, too short, or overweight and older patients may not do as well as younger patients.

As I said, the operation has evolved from a simple, straight connection of the ileum to the anus with all sorts of problems, all they way down to a double-stapled ileoanal anastomosis. A small data set, which I’ll share with you in a minute, is based on 1,847 patients undergoing the operation, until 2006. Almost all of which had two stages of the procedure done, and I can perhaps talk to that later. Most of these were for ulcerative colitis and the follow-up was six years on mean. The operation we perform is shown here. It’s usually two stages, as I say. The colon is removed, the pouch is made and connected to the anus and the diverting ileostomy is constructed, because almost every one of these patients is ill and they are almost all on steroids. The average age is about 33. The male to female ratio is even. The stools per day, again – and this is in this group of 1,800 patients – was 10 a day so they were actively sick. Seventy percent of them had a sexual dysfunction preoperatively and most of them had two stages. This graph shows over a ten-year period of time the probability of a successful outcome. We tell our patients that there is a 91% to 92% chance of having a functioning pouch at the end of ten years. Interestingly, the number of stools per day at dismissal doesn’t change over a six-year period of time, so that stool frequency is fairly well fixed at about 5-8 in the 24 hour period fairly early in the postoperative course.

Ileorectostomy is an operation we perform often for patients with colonic Crohn’s disease but in whom the rectum must be normal, or very minimally involved, and you can tell that by inflating air into the rectum and seeing if it blows up normally. If it doesn’t, then the surgeon would be anastomosing the small bowel to a rigid pipe of rectum, which is totally unacceptable for long term control of continence. There can be really no anal pathology either, and they can’t already have short bowel.

Here is our general experience with ileorectostomy for Crohn’s disease, in 80 patients and with a reasonable mortality, but in our thought process we figure a third, a third, a third. A third of the patients will go from a ileorectostomy to Brooke ileostomy at some point in their postoperative course. Another third will have their ileorectostomy in place but doing poorly; poor control, lots of stools and so forth. But only a third have a fully satisfactory, long term outcome with ileorectostomy for Crohn’s disease.

What about this change in intrarectal Crohn’s? Well in Crohn’s disease of the anus it is surprising how often this is misdiagnosed when patients come to us. It’s really pretty simple. If the patients have huge skin tags, fissures, big ulcers in the anal canal -often not uncomfortable – there is a blue discoloration, cyanotic hue to the perianal area. That they are stricturing, that as you do a digital you can barely get your finger in, it’s a circumferential stricture at the top of the anal canal, or they have fistulas in funny locations. I mean, it’s obvious that this patient … and they have the symptoms of internal inflammatory bowel disease, it’s obvious that they have Crohn’s disease of the anus. But it is not so obvious if the patients are completely symptom free, no obvious evidence of proximal involvement, but they do indeed have anal Crohn’s.

What are we doing today? Well, thanks to – at least at our institution – our gastroenterologists are aggressively treating patients with anal Crohn’s disease, and the role of the surgeon has changed a little bit. We are still draining abscesses, placing setons as drains through complex fistulas to keep them drained so that they don’t form abscesses, and we medicate – in this era of anti-TNF alpha – we medicate these people aggressively. We will take them back to the operating room as necessary and the goal is to dry up the perianum. I think if you watch the literature for the next several months and years, that I think this is a rational approach in patients – particularly in younger patients – before we even think about having to excise the perianum and the anus for perianal Crohn’s disease.

For gastroduodenal Crohn’s disease, which is indeed quite rare, the symptoms of pain, nausea, vomiting and weight loss with studies to confirm upper GI Crohn’s disease with complications, as you see here, in obstruction, fistula and hemorrhage. The surgery for gastroduodenal Crohn’s disease is fortunately rare but consists really of only bypass and strictureplasty. Resection is reserved for only the worst situations.

What about disease-free margins in small-bowel Crohn’s disease? Just briefly, there are studies that show with normal and disease margins no difference in the rate of cumulative recurrence rate over an eight year period of time. This was published many years ago now, in 1983. In work from our own institution we would say that gross residual disease, in the orange line, has a much higher rate of recurrence than in the overall group of patients without gross residual disease. So what our practice is – at least mine is – is to approach the patient with small-bowel Crohn’s disease, resect that to non-diseased margins and do the anastomosis. If indeed the pathologist tells us that the margin is involved, I’ll go back slightly again – maybe 2 or 3 more centimeters – and do the anastomosis at that level. But I will not resect and resect apparently normal bowel if the disease margin is … if the margin is microscopically diseased only. Perhaps I can answer questions about that in a few minutes.

What about strictureplasty? I think all of you have surgeons who are interested in doing strictureplasty on patients. The rationale for strictureplasty, at least in their minds, is shown here. That indeed the disease involves the whole intestine. It is obviously impossible to cure Crohn’s disease by mere excision alone, and all diseased bowel does not need excision. So if the main problems the patients are having are stenotic in nature, then these can be relieved usually without excising the bowel. In this slide I will show you pretty much the originators or the popularizers of this operation. He was Alexander Williams in a 1985 publication showing a complication rate of about 14% and a symptom recurrence rate of 40% in patients who underwent strictureplasty. The Fazio group published a large group of patients, and our group here at the bottom showing the same preoperative complication rate and only 20% of the patients having recurrent symptoms. So strictureplasty is a definite option for patients with stenotic complications of small-bowel Crohn’s disease.

Methenamine is Mandelamine. This has been around forever. It liberates formaldehyde in an acid urine.

Anthelmintics. Pyrantel pamoate and mebendazole, Anamenth and Vermox all are useful in most of the common infestations that we have. I would point out that that the pyrantel pamoate is available over the counter. You don’t have to write a prescription for that if you don’t want to.

Albendazole is a newer antiparasitic drug that has been marketed. This is Albenda. Again, it is useful in pinworm and most of the common infections. It is suggested that it be given with a fatty meal to enhance absorption. In animal studies, though, it has been hepatotoxic and it’s also suggested that it may be teratogenic. So I think probably most clinicians are sticking with the old standbys that we’ve had around forever.

Metronidazole is Flagyl. We’ve mentioned the use of this particular product in pseudomembranous colitis. It’s useful in intestinal amebiasis, vaginal infections. It is the drug of choice for Giardiasis. It also can be used for GI strains of bacteroides or anaerobes. In fact, Flagyl or metronidazole, in many circles, is considered the drug of choice for anaerobe prophylaxis and treatment because it is fairly nontoxic and it is less expensive than things like cefoxitin or clindamycin.

Its toxicities include nausea, headache, a metallic taste in the mouth and a disulfiram or Antabuse-like reaction with alcohol. There have been claims in the past that this drug is carcinogenic. It is not. There is no proven history of any tumor formation in humans with this product. It probably should be avoided during the first trimester of pregnancy but after that it is probably a safe drug to use.
Canadian Pharmacy Antibiotics
Pediculicides and scabicides, again, are a controversial area. Lindane or Kwell is being roundly criticized as it well should be. This was used for many years as the routine pediculicide of choice. People tended to think that you drowned it with Kwell rather than just using it sparingly. It’s now been shown that this fairly readily absorbed, can get into the brain and may have neurotoxic effects if it’s overused.