SSRIs and Persistent Pulmonary Hypertension

Freshly oxygenated blood from the placenta enters the baby through the umbilical vein. Some of this blood is diverted into the liver before traveling to the heart and the rest goes directly to the heart through a blood vessel, called the ductus venosus. The ductus venosus is oriented in such a way that the highly oxygenated blood carried in this vessel, preferentially, shoots through a hole (the foramen ovale) between the upper chambers of the heart (the atria), is pumped into the left ventricle and then into the ascending aorta through which it is distributed, largely, to the organs above the diaphragm, especially the brain.

The less oxygenated blood that enters the fetal heart, preferentially, ends up in the right ventricle and is pumped out through the pulmonary artery. However, instead of going into the lungs, as will be the case after the baby is born, most of this blood bypasses the lungs through an extension of the pulmonary artery, called the ductus arteriosus, that plugs directly into the descending aorta, providing oxygen to organs below the diaphragm and returning blood back to the placenta through the umbilical arteries so that it can get more oxygen.

The ductus venosus, the foramen ovale, and the ductus arteriosus, comprise what is known as the ‘fetal circulation’ that helps distribute the most oxygen to the most important organs while conserving oxygen by diverting blood flow away from the lungs while the baby is in the womb. When the baby is born and takes its first breath, the lungs fill with air, resistance to blood flow through the lungs goes down, and all of these ‘shunts’ begin to close, generally, completing that process within minutes to hours after birth. When conversion to the normal extrauterine circulation is complete, poorly oxygenated blood enters only the right side of the heart, is pumped from the right ventricle into the pulmonary artery, then into the lungs where it picks up oxygen, and returns to the left side of the heart and into the circulation.

So, now what does all of this have to do with SSRI antidepressant drugs like paroxetine (Paxil), fluoxitene (Prozac), sertraline (Zoloft), fluvoxamine (Luvox), citalopram (Celexa), and escitalopram (Lexapro)? Dr. SW Wen and colleagues at the University of Ottawa reported last year (Am J Obstet Gynecol 2006;194:161-6)that women on SSRIs later in pregnancy were at increased risk for preterm delivery (19.3% vs. 12.0%), low birth weight babies (9.0% vs. 5.3%), unexplained fetal death (1.1% vs. 0.4%), and babies who had seizures in the neonatal period (0.4% vs. 0.1%). Babies exposed to SSRIs late in pregnancy also may be at risk for withdrawal symptoms such as jitteriness, irritability, high-pitched crying, increased muscle tone, and difficulties eating and sleeping. Indeed, one study reported that as many as one-third of babies exposed to SSRIs late in pregnancy will suffer some degree of withdrawal symptoms (Levinson-Castiel R, et al., Arch Pediatr Adolesc Med 2006;160:173-6)

However, a far greater problem was reported by Dr. Christina Chambers and colleagues in the New England Journal of Medicine (2006;354:579-87) and relates to our discussion on fetal circulation. These investigators found a six-fold greater risk for persistent pulmonary hypertension (PPHN) in babies whose mothers took an SSRI drug after 20 weeks’ gestation compared to babies whose mothers did not. PPHN is a serious problem that can result in respiratory failure with short- and long-term morbidity and mortality of 10-20%. PPHN is accompanied by increased resistance to blood flowing through the lungs and, if present, can result in persistence of the fetal circulation described above where blood continues to bypass the lungs through the foramen ovale and the ductus arteriosus. That may be hunky-dory for a fetus, but it is very bad news for a newborn baby who has no other source of oxygen than its own lungs. The mechanism by which SSRIs contribute to PPHN is currently unknown, but the seriousness of this complication warrants honest assessment of the risks and benefits of continuing these drugs during pregnancy.

To put this into perspective, PPHN was found in about 1% of babies exposed to SSRIs late in pregnancy and this risk must always be weighed against the maternal risks of complications related to discontinuing SSRI antidepressant therapy. Indeed, LS Cohen and colleagues reported in the Journal of the American Medical Association (JAMA. 2006;295:499-507) last year that women who discontinued their antidepressant therapy during pregnancy were five times more likely to suffer a relapse of depression than those who did not. If a woman suffers from a serious depressive condition, and is either pregnant or considering a pregnancy, she should not discontinue her therapy on her own without consultation with her physician.

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More on Meds and Pregnancy: Adderall and Cymbalta

The following comment was received in response to one of my previous posts: “My friend has just discovered she was pregnant...at her yearly exam. The problem is she takes several meds…Adderall…(and) Cymbalta. She is around 13 weeks and is stressing due to meds. She has not had a complete ultrasound yet. What are her options? This child could have some serious issues correct?”

More and more women in the childbearing years are on combination drug therapies, often antidepressants and antianxiety agents, and sometimes additional medications to treat the side-effects of these other drugs. The questions above arise on a daily basis in my practice and the simple answer is “I don’t have an easy answer.” Adderall is an amphetamine (stimulant) that is used to treat ‘attention deficit hyperactivity disorders (ADHD)’ and ‘narcolepsy,’ a condition associated with frequently and uncontrollably falling asleep. Cymbalta is a drug that is used to treat major depressions and is classified as both a selective serotonin reuptake inhibitor (an SSRI, like paroxetine) and as a selective norepinephrine reuptake inhibitor (SNRI).

The dilemma I face when counseling patients in this situation is the following: BOTH are classified as FDA pregnancy category C drugs. This means that at sufficiently high doses (many times the highest recommended doses in humans), teratogenicity (birth defects) and/or embryotoxicity (fetal death) were demonstrated in certain (not necessarily all) animal experiments. Although the safety, effcicacy, and typical side-effects in nonpregnant humans have been defined in clinical trials before the drugs were marketed, as with most drugs, no controlled or even observational studies have been done (and probably never will be) in pregnant women with either of these drugs to look for deleterious effects similar to those found in the animal studies. Furthermore, even if each of these drugs turns out to be relatively safe by itself, the COMBINED effects are completely unknown. Herein lays my daily dilemma. Remember, as pointed out in my previous posts, it took years of human use before the problems associated with valproic acid and paroxetine were suggested by outcomes collected in voluntary pregnancy registries which are not the most efficient or scientifically rigorous means of gathering good data.

So, let’s get back to the patient query above. By 13 weeks, the baby has completed the embryonic period and almost all organ systems have formed their basic anatomic structures. If these drugs cause malformations of the heart, spine, kidneys, gastrointestinal tract, face, etc…there is nothing that can be done to prevent them at this point. In view of the patient’s concerns, I suggest counseling with a geneticist and a specialist in maternal-fetal medicine. Some fetal abnormalities can be seen by ultrasound even this early in the pregnancy. In addition, I would strongly recommend maternal serum screening at 16 weeks’ followed by a ‘targeted’ (sometimes referred to as a ‘level 2’) ultrasound at 18-20 weeks.’ If fetal malformations are identified during the pregnancy, or following delivery, these should be formally reported to the companies that distribute the drugs.

Even if no major fetal malformations are found, both of these drugs are in classes that are known to have potentially deleterious effects on the pregnancy and perhaps on both short- and long-term development of the baby's brain and nervous system. Whenever these circumstances arise, it is strongly suggested that the prescribing physician evaluate the need for continuing the drugs, the possibility of reducing doses to the least necessary to control the condition during the pregnancy, or perhaps suggesting alternative medications that may have a safer ‘track record’ during pregnancy. There are always risks and benefits that have to be weighed with regard to continuing and discontinuing therapy and these require individualization that cannot be addressed in the ‘blogosphere.’ Ideally, this discussion between patient and provider should be held preconceptionally, but even now, with regard to the inquiry above, this is definitely worth pursuing. And, to offer some reassurance, despite the unknowns and the general tone of my comments, the overwhelming odds are that the baby will suffer no serious consequences of this maternal medication use.

In my next post, I will discuss some of my pregnancy concerns related to both Adderall and, as promised previously, the SSRI class of drugs. Until then, see y’all…

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Uterus Transplant?: Whatever!!!!!

It was recently announced that a New York hospital is making plans to perform the first uterus transplant. The press release announced that "the hospital's ethics board has conditionally approved the plans." The physicians involved in the project have shown "that wombs can be obtained from organ donors, and now are screening potential recipients." Can a uterus transplant be done?...Sure. Will it be done?...Probably. But, should it be done?...I don't believe so, especially in this day and age of sophisticated and efficient assisted reproductive technologies.

The ethical issues here are foremost. This procedure offers no direct benefit to ANY woman. Indeed, the risks involved far outweigh any purported psychological benefits to women who were born without, or have prematurely lost, their uteri. The practitioners who will do this procedure will "be the first" (and for that will obtain some degree of fame, or notoriety) but there is likely to be no major contribution to medical knowledge or technology that will come out of this procedure either.

If the ultimate goal of this procedure (other than the joys of menstruation and validation of 'womanhood', without the cramping that would be felt in the presence of neural connections, and the opportunity to develop uterine or, more likely, cervical cancer while on immunosuppressive drugs) is childbearing, then the physicians involved need to step back, take their egos out of the picture, and think about what they are doing more carefully. Can a woman who has a transplant of any kind carry a baby? Certainly, and over the years I have taken care of many women with kidney transplants, and even the occasional liver transplant, and though challenging, the outcomes have generally been good. However, there are risks to the woman of transplant rejection, diabetes as a consequence of the immunosuppressive therapy, preeclampsia, early delivery, and potential risks to the fetus from all of these factors. But, apart from these other risks of organ transplants, we have no idea whether the vascular changes that are required to support a normal pregnant uterus, and the baby inside, can occur with a transplanted uterus, what the risks of transplant rejection of a uterus might be during a pregnancy to the woman,or the consequences of these events on a developing baby. To be the first woman with a transplanted uterus to take this chance on a baby is, in my opinion,a selfish and foolish proposition.

Years ago, I worked with a specialist in reproductive endocrinology who was very good at what he did, but unbearably cocky. A patient of mine, with whom I was good friends, asked for my recommendations for an infertility specialist to help her conceive another (high risk) pregnancy. I told her about my colleague, I assured her of his capabilities, but knew they might have a bit of a personality clash. We joked about it for awhile, and then decided together that she would indeed see him, but would do so "on her terms." The plan was that she would tell him at the time of her initial visit that she was "interviewing REI specialists" and that her primary criteria for selection was their "previous success rates with uterus transplants." She did this, enjoyed the look of shock and submission on his face when she told him what she wanted, pretended to be miffed at his response of "never having done one," pretended to get up to leave, and then filled him in on the joke. They got along quite fine after that and I eventually delivered her next baby. Truth in fact, the technology to perform such a procedure was already available at that time, but the ethical and medical contraindications could not be surmounted then, and probably should not be now.

One of the first things we are taught in medical school when we enter, and one of the last admonitions that is given to us as we leave, is "primum non noncere" - loosely translated, "above all, do no harm..." I believe the physicians and the institution that would support this procedure, especially when there are so many other good options available today to provide the experience of 'motherhood' to a woman who cannot bear a child herself, need to repeat this mantra from the Hippocratic Oath repeatedly to themselves before they embark on this endeavor...

P.S. for other comments related to this issue, check out a recent post by Dr. Anonymous.

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Drugs and Fetal Development: Focus, Paroxetine

Antidepressants are among the medications most commonly prescribed to young women; and, of those available, selective serotonin reuptake inhibitors (SSRIs) are among the most popular. It is estimated that as many as 2-3% of all women in their childbearing years may be on one of these drugs (Paxil, Prozac, Zoloft, and Lexapro). They were initially thought be very safe in pregnancy and began their distribution as FDA “Category C” compounds with no clear evidence of teratogenic effects (and no good studies) in pregnant women to prohibit their use. Since then, due to the ‘human experiment’ associated with widespread use, it has become apparent that these drugs may cause fetal malformations if taken early in pregnancy, a plethora of other short-term side-effects (apart from teratogenesis) if taken later in pregnancy, and the potential for long-term neurodevelopmental abnormalities in babies exposed throughout pregnancy. Today, let’s simply consider the teratogenic potential of Paxil (paroxetine), perhaps the most widely used SSRI, and recently reclassified by the FDA as a “category D” (drugs found to have harmful effects on the fetus).

The fetal heart is later to develop than the neural tube. In fact, the fetal heart only begins to partition into a structure that will eventually have four chambers about 28 days after conception (6 weeks gestational age), or about the same time the neural tube finishes closing. By day 32, the interventricular septum can be seen growing from the apex of the heart in the midline toward the center of the heart called the endocardial cushion. At the same time, the interatrial septum begins to undergo a more complex developmental process that eventually results in a large, valved hole between the right and left atria, called the foramen ovale, and fusion of the lower portion of the interatrial septum with the endocardial cushion. The foramen ovale, is positioned to allow the most well-oxygenated blood, coming into the heart from the ductus venosus, to bypass the right ventricle, enter the left atrium and then the left ventricle, and be pumped into the aorta, mostly to the fetal brain. The entire process is not entirely completed until about day 56 (10 weeks gestational age).

On October 4, 2005, the manufacturer of Paxil, GlaxoSmithKline, sent a letter to physicians warning that the drug might be linked to a higher rate of congenital malformations in babies exposed to the drug in first trimester. In an unpublished review of 3,500 pregnant women (taken from U.S. insurance claims and a Swedish national registry) taking antidepressants, 4% of those taking Paxil had babies with birth defects compared to 2% of those taking other antidepressants. The most common abnormalities were congenital heart defects, specifically, atrial septal and ventricular septal defects (ASDs and VSDs), and the rate for these was approximately twice that (2%) seen in the general population. As the result of these observations, the FDA released an advisory December 8, 2005, informing health care providers “to discuss the potential risk of birth defects with patients taking Paxil who plan to become pregnant or are in their first three months of pregnancy…should consider discontinuing Paxil…and not to prescribe Paxil in women who are in the first three months of pregnancy or are planning pregnancy, unless other treatment options are not appropriate.” Coincident with this release, Paxil was reclassified to a category D drug. Finally, November 30, 2006, the Obstetric Practice Committee of the American College of Obstetricians and Gynecologists announced support for the FDA recommendations and published that opinion in the December issue of Obstetrics and Gynecology.

In view of the known time course of development of the fetal heart, discontinuing Paxil early in first trimester might prevent some congenital heart defects. Of course, this needs to be balanced against the timing of discontinuation with regard to the actual gestational age, the risks of not treating the condition for which the drug was prescribed, and the risk of withdrawal symptoms that have been well-documented with SSRIs. Certainly, any woman who has been on Paxil in first trimester should be offered a fetal echocardiogram to assess the fetal heart as part of routine care. Although the evidence to implicate the other common SSRIs in congenital heart defects has not yet been established, these drugs can have effects later in pregnancy, resulting in neonatal complications, and these will be discussed in my next post…

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Drugs and Fetal Development: Focus, Valproic Acid

Recently, I was interviewed by a reporter who was interested in discussing stages of fetal development and factors that might contribute to congenital abnormalities during the same. This was a reminder to me that I have wanted to review recent concerns related to birth defects and certain medications that are now widely prescribed among young women during their childbearing years.

Most congenital birth defects result from perturbations of development that occur during what is technically referred to as the ‘embryonic period' of intrauterine life that encompasses the time from 3 to 8 weeks, or gestational ages between 5 to 10 weeks. By the end of this period, all primary organ systems have begun to develop and the baby assumes a distinctly human appearance. Many factors can contribute to abnormalities during this time, including underlying genetic predisposition, nutritional imbalances, and environmental ‘toxins’ such as medications, tobacco, alcohol, and radiation. Although development is along a continuum, and there is overlap in the time frames of development of specific organ systems, there are also times when these organ systems are more sensitive than others to the developmental process.

As we have pointed out in a previous post on preconceptional counseling, the neural tube is one of the first structures to develop with complete closure of the upper (rostral) end by 24-25 days after conception and the lower (caudal) end by about 28 days, all within two weeks after the first missed menstrual period. Proper closure of the neural tube is clearly influenced by folic acid and, maternal deficiencies of the same, and the exposure to drugs that antagonize its action, increase the risk for a spectrum of ‘neural tube defects’ such as anencephaly, myelomeningocele, and spina bifida occulta. For this reason, if folic acid supplementation is to be successful in reducing risk (which it clearly can do), it is best to begin this prior to conception; and, this is specifically indicated in women who have had a child, or have a family history, of neural tube defects. Similarly, if the woman is on medications that affect neural tube development, modification of therapy, ideally, also should be started before the pregnancy is conceived.

One of the more commonly prescribed antiepileptic drugs (AEDs), valproic acid, has been known for awhile to be associated with neural tube defects, as well as hydrocephalus, craniofacial abnormalities, heart and skeletal defects. Recently, however, Dr. Kimford Meador of the University of Florida and his colleagues in the Neurodevelomental Effects of Antiepileptic Drugs Study Group, a consortium of 25 sites in the U.S. and the United Kingdom, published a study that supports the contention that valproic acid has the greatest teratogenic potential of all the most commonly prescribed AEDs (Neurology 2006;67:407-12). In this report, 323 women, and their 333 children, were followed prospectively. Of these, 69 of the babies were exposed to valproic acid, 98 to lamotrigine, 110 to carbamazepine, and 56 to phenytoin. Major congenital malformations occurred in 17.4% of the valproic acid babies compared to 7.1% with phenytoin, 4.5% with carbamazepine, and 1.02% lamotrigine. Not only was the malformation rate with valproic acid more than twice that of the next most teratogenic drug, but it was the only medication that appeared to show a dose-dependent relationship. Interestingly, death rates for carbamazepine and phenytoin exposed babies were both 3.6%, which were slightly higher than the rate for valproic acid (2.9%). None of the lamotrigine-exposed babies died during the pregnancy or postpartum follow-up period.

The authors of this study concluded that valproic acid should “not be used as the AED of first choice for women of child-bearing potential, and, when used, its dose should be limited, if possible.” Although studies have not been reported to establish efficacy, others have recommended that if valproic acid, or any other AED, is used the patient should be offered supplemental, high-dose folic acid (we use 4mg/day) as a means of possibly minimizing the teratogenic risk of these compounds. Since drug interactions can potentiate their individual risks, it is recommended by both the American Academy of Neurology and the American College of Obstetricians and Gynecologists that a single AED, rather than multiple drugs, be used whenever this is feasible.

Again, to address all of these issues, adjustment of medication type or dose, folic acid supplementation, and to gain an appreciation for the risk/benefit balance of therapy, it is best to consult a physician prior to conception. I have found over time, many instances in which a woman who, having been on AEDs for years because of “a seizure I had as a child,” has been safely taken off her medication for a period of time to ascertain the status of her seizure disorder and then been able to begin a pregnancy without the need for that medication during the critical phases of early fetal development.

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Intrahepatic Cholestasis of Pregnancy - Outcomes and Management

The other day we began a discussion of intrahepatic cholestasis of pregnancy, or obstetric cholestasis (OC). The post was prompted by the intrauterine death of an otherwise normal baby in a mother who had OC diagnosed late in pregnancy. Although women with OC can be absolutely miserable from the intense pruritus associated with this condition, they are at relatively low risk for serious complications themselves during the pregnancy. One maternal concern that has been raised is the possibility of increased risk for postpartum hemorrhage in women who have reduced blood-clotting factors secondary either to hepatic impairment or reduced intestinal absorption of vitamin K resulting from steatorrhea associated with OC, however, this rarely occurs.

Most women improve symptomatically within a month following delivery, but there is a recurrence risk as high as 90% with a subsequent pregnancy; and, about one-fourth of these women will develop intermittent pruritus, sometimes coinciding with stage of their menstrual cycle, or associated with oral contraceptive or other estrogen use. An excellent recent retrospective, cohort study out of Finland, looking at 10,504 women who had OC during the years 1972-2000, showed that these women also have significantly greater risk for developing complications related to hepatitis C virus infection, nonalcoholic liver cirrhosis, gallstones and cholecystitis, and nonalcoholic pancreatitis than case-matched controls (Ropponen A, et al., Hepatology 2006;43:647-9).

As part of the evaluation of OC, women should be screened for hepatitis C virus (HCV), since there is a higher prevalence of OC in HCV-positive individuals, and the virus infection itself is associated with short-term pregnancy, and long-term postpartum, complications. Other conditions that should be ruled out in OC are infections with hepatitis A and B, cytomegalovirus, and Epstein-Barr virus, and autoimmune hepatitis. With regard to the latter, antimitochondrial antibodies can be obtained to rule out primary biliary cirrhosis and anti-smooth muscle antibodies to exclude autoimmune chronic active hepatitis. Appropriate imaging studies should also be done to rule out obstructive cholelithiasis.

Although the pregnant woman herself is at fairly low risk for complications, it has been well-established that the baby is not. OC is associated with higher rates of spontaneous premature delivery, meconium passage in utero, fetal distress as assessed by heart rate monitoring, respiratory distress syndrome following delivery, intrauterine fetal demise (IUFD) and neonatal death (ND). Prior to the currently recommended therapeutic intervention of planned, early delivery, OC was accompanied by premature labor and delivery in 30-50% of affected pregnancies and IUFD, or ND, occurred in approximately 10%. In the 1995 report by the CESDI (Confidential Enquiry into Stillbirths and Deaths and Infancy) consortium in the United Kingdom, 5% of all term stillbirths were associated with OC. Since then, recommendations that women identified with OC are delivered, electively, no later 37-38 weeks, rates of IUFD associated with OC have been reduced to 0.5% or less. Of course, late preterm delivery can be associated with neonatal morbidity secondary to respiratory complications, but most pregnant women prefer this over the risk of losing their babies.

Management options prior to elective delivery are somewhat limited and inconsistent in their efficacy. Some providers routinely prescribe vitamin K (10 mg per day) orally once the diagnosis of OC is suspected, although the efficacy for this approach has not been proven in clinical trials. Absolute levels of serum bile acids do not reliably correlate with fetal outcome. Fetal heart rate (FHR) testing may provide some reassurance to providers and patients, but it is also not reliable in predicting fetal outcome. In our case that prompted these posts on OC, the baby had a beautifully reactive nonstress test and no FHR decelerations with maternal contractions to suggest any placental insufficiency within 12 hours of presentation with demise. Serial amniocentesis and transcervical amnioscopy (looking up through the cervix at the fetal membranes using a scope) have been used in OC patients to detect meconium and, if this is present, usually provides an indication for delivery, regardless of gestational age. Unfortunately, if meconium is not detected, this does not assure that the baby is not at risk.

Medications typically prescribed to relieve itching, such as diphenhydramine, hydroxyzine, and topical corticosteroids, seem to have very little effect on the pruritus associated with OC. Ursodeoxycholic acid (UDCA), taken in doses ranging from 500 mg to 2000 mg per day, seems to have the most consistent effect in relieving OC related symptoms. UDCA can take 2 to 3 weeks before an effect is noticed, but in some studies it has been shown to significantly reduce pruritus, serum bile acids, transaminases, and bilirubin. It has also been shown to reduce levels of bile acids in umbilical cord blood and amniotic fluid. Although the mechanism of action of UDCA is not entirely clear, it may protect hepatic and, possibly, placental cells from the toxic effects of bile acids and stimulate impaired hepatocellular secretion. Treatment with UDCA appears to reduce the risk for fetal complications related to OC and, as yet, has not been found to be associated with any short- or long-term fetal morbidity. High-dose dexamethasone therapy, may relieve some symptoms, but has shown inconsistent results in clinical trials and at this point, especially, in view of the recent concerns related to steroid administration and fetal growth and development, it cannot be recommended on a routine basis.

The primary question that remains unanswered in OC is why is the baby at such great risk? Do the elevated maternal serum bile acids cause damage to the placenta? To the fetal hepatobiliary system? To other organs, such as the heart? Do they stimulate the passage of fetal meconium directly? Or as the result of acute placental injury and ‘fetal distress’ secondary to reduced capacity of the placenta to transport oxygen or remove ‘wastes’? Or, is the mechanism of fetal compromise completely unrelated to the elevated bile acids? Once meconium has been passed, do some of the complications arise as the result of meconium aspiration before labor? If there is a genetic basis for OC, as there appears to be, does this put the baby at risk by itself for mechanisms that are unclear at this time?

Until we can elucidate a mechanism, and develop specific therapy to address that issue, or develop a specific test to identify the fetus at risk during an OC pregnancy, our best bet is UDCA and early delivery, knowing the occasional patient will still have a loss while under observation, or will lose a baby at term because OC was not recognized during the pregnancy….

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Intrahepatic Cholestasis of Pregnancy - A Bitch of an Itch

Recently, we had a woman diagnosed late in pregnancy with intrahepatic cholestasis of pregnancy, or obstetric cholestasis (OC). Despite reassuring fetal heart rate testing, the baby died in utero awaiting induction of labor that had been scheduled within 48 hours of diagnosis. As is usually the case in OC, no specific fetal or placental abnormalities were noted at the delivery. The baby had no evidence of growth restriction or infection, but had passed meconium (had a bowel movement) prior to delivery and was found to have aspirated that material into its lungs.

OC is an enigmatic, relatively common, and potentially serious complication of pregnancy, as the aforementioned case illustrates. Most women with this condition present in third trimester with intense itching (pruritus) without a rash. Generally, the itching is localized to the abdomen, legs, palms, and soles, but can be generalized. The itching can be so intense that these women develop excoriations, secondary infections, and even scarring as a result of their scratching.

Although specific criteria for the diagnosis are not agreed upon, the condition is characterized by some degree of hepatic dysfunction, as manifested by elevated levels of serum bile acids and, often, modest elevations of serum transaminases (ALT and AST). Generally, these abnormalities are not more than two- to three-fold normal levels, but more than 90%, if not all, patients with OC will have both bile acid and transaminase abnormalities. Itching is not uncommon in ‘normal’ pregnancy with complaints of the same occurring in about 50% of all gestations (particularly in first trimester and localized to the abdomen), but this is not accompanied by hepatic involvement to the extent that laboratory abnormalities are found early and only about 3% of these women will go on to develop true OC. Cases of OC have been described wherein the laboratory abnormalities did not develop until 15 weeks or more after the “itching” began.

There appears to be a genetic predisposition to the condition. About 0.5-1.0% of Caucasians develop OC, but these figures are doubled in women from Southeast Asia, and certain ethnic subgroups can have even much higher rates. For example, Reyes and colleagues (Ann Intern Med 1978;88:487-93) showed OC affects 5.5% of pregnancies in Chilean Araucanians. Others have also shown that sisters have a 17% coincidence of OC (Eloranta ML, et al., Clin Genet 2001;60:42-5). Recent studies have shown mutations in specific genes, MDR3 (ABCB4) and BSEP (ABCB11), that affect hepatic phospholipid and bile acid transport, respectively, and the presence of these mutations have been correlated with cases of poor fetal outcomes (Schneider G, et al., Hepatology 2007;45:150-8). As a consequence, women with OC seem to have an increased sensitivity to the cholestatic effects of pregnancy hormones, especially estrogens, but how this translates to fetal complications remains unknown. Women with true OC may have a history of “itching” while taking estrogen-containing oral contraceptives.

In the next post, we will go on to discuss maternal and fetal risks of OC, as well as management options…

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Experience Grand Rounds 3.15 at Musings of the Distractible Mind!

Thanks to Rob Lamberts and the Musings of a Distractible Mind website for including a link to my post "Poop is Part of Parturition" in his pyrotechnically correct and highly entertaining edition of the New Year's Grand Rounds 3.15. Glad I could contribute to the explosive theme in my own aromatic way!

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Abnormal First Trimester Screening Results

As one of my end-post promises, I wanted to return to the issue of dealing with ‘abnormal results’ that return with first trimester aneuploidy screening. Again, this is not a straightforward discussion. One of the first issues that has to be addressed is what constitutes an ‘abnormal result?’ Remember, this is not a diagnostic test, it is a screening test, and the result that comes back does not necessarily mean the baby has or does not have the condition for which it is being screened. It provides a risk estimate that is, albeit, generally better than that provided by ‘age alone’ counseling because specific data related to the pregnancy (fetal measurements; pregnancy-specific serum analytes; maternal characteristics and risk factors) are included in the actual risk assessment. Even then, there is not a ‘normal’ or ‘abnormal’ result (although some organizations have elected to classify results as either “risk positive” or “risk negative”) and, to some degree, because the result sits somewhere along a continuum, the risk assessment result needs to be interpreted within the context of the patient’s own risk tolerance. Some folks play nickels in Las Vegas and others hundred dollar chips. Still, as providers, we need to offer some guidance to the patient. It is not fair to place the entire burden of decision-making related to this very complex issue on the patient alone, although, in the end the final decision as to what they do with the information given to them is their decision. The goal should be to make them feel comfortable about their choices.

There are several steps that I take with patients when presenting their screening assessment results. First, I reiterate that we (me and our genetic counselors) are there to provide them with information, review the test results, review their options for further fetal evaluation, answer their questions, and help them to decide what the best course of action is for them, reminding them up front that we will not tell them what to do. In fact, I make it quite clear that I do not care what they do! I then present the risk assessment results and compare this to their age-related risks. I also remind them that this screening test is most successful at diagnosing trisomies 21, 18, and 13, that it may pick up some other, but not all, chromosomal abnormalities, and that it may also miss a small percentage of those abnormalities it is most reliable in detecting. Before I ask for any decisions on their part, I review the risks and benefits of other screening and diagnostic options and suggest that they use this information to help balance the decision-making process.

With regard to the diagnostic options, I focus on two procedures, chorionic villus sampling and amniocentesis, reserving a discussion about percutaneous umbilical cord sampling, or cordocentesis, for special circumstances. I explain the differences in techniques (CVS as a transcervical, or transabdominal, placental biopsy and amniocentesis as a transabdominal technique, sampling 20-30cc of the amniotic fluid with a thin needle) and the risks of pregnancy complications related to the procedures. For counseling purposes, I have stuck with a 1% risk for CVS over the years and have drifted from the classic counseling of 1 in 200-300 risk for amniocentesis to less than 1 in 1000 (which our own experience and recent publications would support). I also explain the options and limitations of rapid (48-72 hr) diagnostic techniques (such as fluorescent in situ hybridization, or FISH) and always suggest these be considered when a specific chromosomal abnormality is highly suspected. I always conclude this part of the discussion with a statement to the effect that they have the option for an invasive diagnostic test, regardless of the risk assessment results, and that the choice depends on their risk tolerance and their ‘need to know’ or need to get more information. I emphasize that these latter questions should take priority over the question of what they would actually do with the information once they had it. The reason I can state that with confidence is that, over the years, it has become quite clear to me that many people DO NOT KNOW what they might do (regardless of age, race, religious, ethnic, spiritual, or socioeconomic background), even with a documented fetal chromosomal abnormality, until they are actually faced with that decision.

I then ask if they have any questions and I always get the response, “Doctor, what would you do if you were in our position?” I can then answer that honestly by telling them that “I am not in your situation and I don’t know what I would do if I were. But, I can give you some general guidelines based on counseling that is offered in other places around the country and the world.” Many institutions routinely recommend CVS when the first trimester risk is greater than 1 in 100. If the pregnancy is beyond the gestational age at which the institution will do a CVS when the result comes back, then an amniocentesis at about 16 weeks is offered.

If the risk is less than 1 in 270 (in the range of the risk of a 35 year old woman to have a baby with Down Syndrome and also the risk range typically quoted for amniocentesis), we currently offer maternal serum α-fetoprotein (MSAFP) screening only at about 16 weeks and a ‘targeted’ ultrasound examination at 18-20 weeks. The MSAFP screening can provide information about risks for certain fetal abnormalities, such as neural tube defects and abdominal wall defects (usually readily detected at the time of ‘targeted’ ultrasound alone), but of equal importance may suggest, if the results are abnormal, an abnormality of placentation that could put the pregnancy at increased risk for complications and might warrant a change in our recommendations for follow-up.

If the risk falls between 1 in 100 and 1 in 270, amniocentesis is generally offered and if the patient is averse to this, then the second approach outlined above is recommended. Many women will choose the latter approach because, during their counseling, we also inform them that a completely ‘normal’ targeted ultrasound probably reduces their a priori risk (based on the combined first trimester screening result) for aneuploidy by 60-80%., thereby placing them below the risk of a 35 year old woman without the need for an invasive diagnostic study. Indeed, we have found that one of the primary advantages of first trimester screening and midtrimester screening, coupled with ultrasound, is that we have found ourselves performing far fewer invasive procedures than we have done in the past (putting fewer pregnancies at risk from that standpoint).

I want to make it clear. At present, there is no uniform approach (‘standard of care’) to management of the results obtained by first trimester screening. This is the approach we have chosen and, it may change next week, or be very different from that offered at other institutions. The important things are to provide a reliable service within the constraints of the diagnostic capabilities available locally and to make the patient feel comfortable with the decision they make for additional screening, a diagnostic study, or no follow-up at all.

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New ACOG Practice Bulletin Regarding Fetal Aneuploidy Screening

HAPPY NEW YEAR to all of you! I only have one New Year’s resolution this year. I resolve to try to finish up all of the ‘to be continued’ discussions I started in other posts and have been slow to revisit due to my ‘flight of ideas.’ I resolve to do this even though I am going to ignore the promise I made at the end of my last post to tell you today what a 55 year-old man (me) would like to see happen in his ‘birth plan.’ I know it’s hard for you to swallow the disappointment, but we will get to it eventually. In the meantime, just keep breathing. Nope, instead, I would like to return to a discussion we began in mid-December related to first trimester screening for aneuploidy. I am not doing this because I feel guilty about leaving you hanging. I am doing it because early screening for aneuploidy hit the news channels big time today and I wanted to direct you to the source of the information.

In the January issue of Obstetrics and Gynecology (2007;109:217-227), the American College of Obstetricians and Gynecologists (ACOG) published its revised recommendations on “Screening for Chromosomal Abnormalities” during pregnancy. It is one of the most comprehensive reviews I have ever seen presented on any subject in an ACOG Practice Bulletin; it presents an overview of a complex subject in very understandable terms; and, I am sure it will be a “milestone” in helping to establish first trimester screening for aneuploidy as a standard of care in the U.S., not only for ‘at risk’ women, but for all pregnant women, something that has already been widely accepted and implemented over the past decade in other industrialized nations.

The review points out the advantages and disadvantages of aneuploidy screening compared to diagnostic testing, the many different options for screening, and the value of combined and sequential assessments in terms of increasing screen detection rates and minimizing false positive results. It also recognizes the current limitations to providing all options to all patients, encouraging a flexible approach based on “tests…available in your area”…and “the needs of your patients.” For example, even if a provider does not have the special training and certification necessary for combined risk assessment, requiring nuchal translucency measurement, the option for “serum integrated screening (i.e., maternal blood tests done in late first and early midtrimesters)” can be offered with detection rates for trisomies 21, 13, and 18 in the range of 85-88%! Quite frankly, I believe at some point, the need for ultrasound specialty training for initial screening, and its inherent subjectivity, regardless of standardization and certification, will be replaced by a reliable panel of serum markers in the not-to-distant future anyway. I also believe that within the next 10 years, fetal diagnosis of aneuploidy by detection of cells and DNA in maternal serum will replace the diagnostic studies (chorionic villus sampling and amniocentesis) we currently rely upon, thereby, eliminating the barrier of ‘risk’ imposed by these invasive procedures.

Anyway, if you are interested in the subject, as either patient or provider, I would commend this practice bulletin to you. And, while you are reading that, I am going to work on my 'birth plan...'

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