Amniocentesis Q & A

Yesterday, I addressed the issue of ‘risk’ related to amniocentesis. I thought I should clarify that there are many different reasons we do an amniocentesis, and there are many different times during a pregnancy when it might be indicated that this be done. 'Risk' varies somewhat by time in the pregnancy and indication, and the outcome of a ‘complication’ can be quite different, depending on the gestational age. In the post yesterday, I was specifically addressing the issue of a ‘genetic amniocentesis’, most commonly done between 15 and 22 weeks to determine the fetal karyotype (chromosomes) and to look for evidence of a known or suspected genetic abnormality (inborn error of metabolism). The ‘risk’ addressed in the FASTER trial cited in the post from yesterday is only the risk of losing a baby (prior to viability) after a genetic amniocentesis has been done in midtrimester.

Whenever a woman is considering a genetic amniocentesis during pregnancy, usually one or more of the questions below are among those on her mind. Although the answer to these will vary by provider, let me give you my typical responses:

· “Do you have to stick the baby?” – No, we try to avoid that by looking with the ultrasound while we are doing the procedure. We are actually going to take some of the fluid (about 2/3 oz) from around the baby. The fluid is mostly fetal urine (“baby pee”) at this point in the pregnancy and it contains cells from the baby that we can then grow in the laboratory to determine the baby’s chromosomes. After we get done, the fluid around the baby will look no different to you and the baby will quickly replace the small amount we have removed.

· “Does it hurt? (usually phrased as “My friend told me this REALLY hurts!?!”)” - Usually it is SO painful that we have to have several large nurses sit on you while I do the procedure! No, seriously, we use a very thin needle, thinner than the one they use to draw blood or start an IV. You will probably not feel it much at all as I go through the skin and you will probably feel a cramp, like a menstrual cramp, when I go into the uterus. I will warn you when I am going to do that. You can have someone hold your hand while I am doing the procedure if you would like. Most folks say when it's over that "it wasn't as bad as I thought it was going to be."

· “Are you going to numb me up?” – I can if you would like, although I usually do not and hardly ever have since we started using these thin needles about 20 years ago. The numbing medicine usually hurts more than the needle stick and I can’t numb the uterus to stop the cramp I told you about. Also, if the baby moves, then I might have to stick you 3 or 4 times rather than just once.

· “What are the risks of the procedure? (usually phrased as “My baby moves a lot, what will happen if he/she gets stuck with the needle?”)” – The risk of losing the baby as a result of the procedure is less than 1 in 1000. Other risks include the possibility of breaking the bag of waters, that may or may not lead to delivery or other complications (which I usually do not discuss unless the patients asks at this point), the risk of introducing infection into the uterus, although this is so rare that we do not use any antibiotics to do this procedure and, to help prevent that, we clean your abdomen off first with an antiseptic solution (cold, wet, and scratchy, runs all over the place - the worst part of the procedure) and use sterile drapes (so please do not try to help me with this procedure), and the risk of bleeding either from the placenta if we have to insert the needle through that to get to the fluid, or from the baby, either because of hitting a fetal-placental blood vessel or the baby’s umbilical cord. Again, we try to avoid the latter events by watching with the ultrasound while we do the procedure; even if we do get some bleeding, which is not uncommon when we go across the placenta, it usually stops very quickly and we will watch it until it does. If you are Rh-negative, we will give you Rh-immune globulin after the procedure to help prevent ‘sensitization’ unless you know the baby’s father is Rh-negative too. (I usually do not discuss the possibility of isoimmunization in general unless the mother is Rh-negative or there is substantial bleeding afterwards). I will also be trying to avoid hitting the baby and plan, intentionally, to place the needle away from the baby’s head, but if the baby does move and hit the needle, I will tell you what part of the baby got hit so that we can follow up after the baby is born. Usually there are no long term consequences of this.

· “If I do this test, will it tell me that I am going to have a normal baby?” – That is not an easy question to answer. Chances are, if the chromosomal studies are normal, and we don’t see any abnormalities of the baby, the odds are in your favor the baby will be ‘normal.’ There are rare circumstances when the baby will have a chromosomal problem that is not picked up by the studies or a genetic problem that we did not know about so that we could look, specifically, for it. Other things can also happen during the pregnancy, unrelated to the amniocentesis that could cause the baby not to be ‘normal’ as well.

· “How long does it take to do? (usually phrased as “How long is that needle going to be in me!?!”)” – It usually takes me longer to clean and drape your abdomen than it does for me to do the procedure. Once the needle is in the uterus, it takes about 30 seconds to draw off the fluid because the needle is so thin.

· “How long before I get the results back (usually phrased as “You mean I am NOT going to find out today if my baby’s alright!?!”)” – If we see nothing wrong with the baby, or if you do not have a risk for a specific chromosomal abnormality, such as Down syndrome or trisomy 18 based on other studies, it usually takes 10 to 14 days to get the final results. We can do a rapid screen called FISH (fluorescent in situ hybridization) for a limited number of specific chromosomal abnormalities if one of these is suspected. The results of FISH are usually back within 72 hours, but it does not screen for all chromosomal abnormalities, so routine cultures are also done and you will still have to wait 10-14 days to be completely reassured. The FISH test is also expensive and may not be covered by your insurance carrier because they look at it as a ‘preliminary test’ result.

· “How many days will I have to stay at bed rest? (usually phrased as “Can you give me a note for work for the next week?”)” – Unless there is a complication of the procedure, you will not have to go home to bed rest. We do recommend that you avoid heavy lifting and other exertional activities today and drink some extra fluids. If you think today will be a problem at work, we will give you a note.

· “What do I look for to suggest a problem” – Leakage of fluid, cramping, pain, bleeding, fever – It is not unusual to have a little cramping over the first 24-48 hours after the procedure and you can take Tylenol, or even a few doses of over-the-counter strength ibuprofen, for this, but if it continues longer than that, or if you develop any of the other problems, you need to let your doctor know.

· “When can we have sex again? (usually this one comes from the partner, and the woman is usually grateful when I jokingly answer “NEVER”)” – I usually recommend that you avoid intercourse for 48-72 hours – wait at least 24 hours after the cramping has gone away.

· “How will I get the results” – We will call you as soon as they come back from the laboratory. Do you want to know for sure if the baby is a boy or a girl?

After we have finished the procedure, I usually ask if there are any more questions, wish them the best on the outcome, and tell them that, hopefully, they won’t need to come back to see me again during the pregnancy!

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Risk of Amniocentesis

Today I saw a 38 year old woman who came for genetic counseling and possible amniocentesis to rule out a fetal chromosomal abnormality. She was right at 16 weeks’ gestation. Her last pregnancy was 18 years ago and the 47 year old father of the current pregnancy had never had any children of his own. She made it very clear at the outset that she was reluctant “to do anything that might make me lose this baby unless I have to or there is a good reason.” I reassured her at the start that no one was going to make her do something she didn’t want to do – the ultimate choice was hers – and that it made absolutely no difference to me what her decision was! My role was to provide her with information, answer her questions, and do the procedure as safely as possible if she chose to have it done.

The first amniocentesis for chromosomal analysis of cultured fetal cells from amniotic fluid was described in a brief article by Steele and Breg in 1966 (Lancet 1966;1:383-5). Ten years earlier, Fuchs and Riis (Nature 1956;177:330) had reported doing the procedure just for fetal sex determination. In both instances, these procedures were done ‘blindly’ inserting a needle without any method of direct visualization into the uterine cavity.

When I started my OB/GYN residency in 1979, our technique was barely better. We sent the pregnant woman to ultrasound (static), a fluid ‘pocket’ was identified, an “X” was placed on her abdomen at the “best place to stick a needle,” she was sent back to our clinic, and we BLINDLY placed an 18 gauge (large bore) needle into the uterus at the site of the “X.” It was not at all unusual to meet some resistance (some part of the baby – never felt real comfortable about that) or draw back blood (from the placenta, umbilical cord, or uterine blood vessels) before finally getting the fluid we needed to do the fetal chromosomal studies.

Despite the relative crudeness of this approach, the chance of losing the baby after this procedure was only about 1 in 200, and that has been the number routinely quoted to women for the “risk” of amniocentesis over the past 30 years, even though we now do these procedures using direct, real-time ultrasound guidance and a thin, usually, 22 gauge needle. Most of us who have done lots of these over the years (I put my numbers somewhere between 5 and 10,000) have known the risk is much lower. In fact, I only know one woman who lost a baby following an amniocentesis I have performed in the past 25 years (KNOCK ON WOOD), and she was probably well on the way to losing that pregnancy due to other complications. Anyway, it has been my routine for awhile to tell most women who come for amniocentesis that the “quoted risk is 1 in 200” but my “undocumented risk is less than 1 in 1000. Besides, I stayed at a Holiday Inn Express last night.”

Finally, as the result of a very large study that included documentation of outcomes following midtrimester amniocentesis, we have data to support the relative ‘safety’ of this procedure. In this study, the FASTER (First And Second Trimester Evaluation of Risk for aneuploidy) trial, the 3,096 women who underwent midtrimester amniocentesis (at many different institutions) were compared to 31,907 who did not (Eddleman, et al., Obstet Gynecol 2006;108:1067-72). The spontaneous fetal loss rate at less than 24 weeks following amniocentesis was 1.0% compared to the background loss rate in the control group of 0.94%. Therefore, the added risk of the amniocentesis was calculated to be only 0.06% (1.0% minus 0.94%) making the risk of the amniocentesis approximately 1 in 1600 – far less than the 1 in 200 (0.5%) risk that is usually quoted.

This information was presented to our patient today, but she was still very anxious about the prospects of the procedure. I told her that we saw no abnormalities of the baby at this time and that alone reduced her “age alone midtrimester risks” of 1 in 100 for Down syndrome (trisomy 21) and 1 in 51 risk for all chromosomal abnormalities by at least 50%. So, I offered her another option. “Why don’t you have a ‘quad screen’ (maternal serum screen) done today as a more reliable estimate of risk than that based on age alone. We will have the results back within 10 days, and you can use that information to further guide your decision regarding amniocentesis.” I then told her, that “because the odds were still in your favor that the baby is chromosomally ‘normal’, I am just going to schedule you for a ‘genetic sonogram’ at 18-19 weeks, and if the ‘quad screen’ results are scary, or if you just change your mind about the amniocentesis, we can see you back sooner and on very short notice.” She seemed happy with that plan…and it was the right decision for her at this time...so, I have a new friend!

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Second Verse Different from the First!

Today was a very special day for me. I delivered a young woman who had a perfectly normal 7lb 7oz baby boy at 39 weeks’ gestation. What made her so special was that her pregnancy outcome the last time around was not so wonderful; the success with the current pregnancy brought closure to that previously tragic experience, not only for the patient and her family, but for me as well…

I first met Tyra about two years ago. At that time, she was sent to me by her personal physician for management of the acute onset of severe hypertension in pregnancy. Unfortunately, she did not just have hypertension, she had one of the most severe forms of preeclampsia (pregnancy-induced hypertension), HELLP syndrome, and was only 22 weeks’ gestation. HELLP stands for Hemolysis (break down of red blood cells), Elevated Liver enzymes (secondary to damage to liver cells), and Low Platelets (secondary to consumption of these blood clotting factors). Not only was she just 22 weeks’, but the baby was severely growth restricted, had very little amniotic fluid, could barely push blood through the placenta, and was basically dying from placental insufficiency in utero. Despite our efforts to stabilize her disease, she deteriorated rapidly, and we had no choice but to inform her that she had to be delivered. We also had to tell her that we would not be able to do anything to save her baby. Using a prostaglandin drug called misoprostol, we were able to quickly accomplish this without a surgical procedure in a very short period of time. The baby’s heart rate was not monitored during her induction and he died sometime during the labor process. Other than being only half the size he should have been at 22 weeks, the baby was perfectly normal, and we all had tears in our eyes as she and her husband held their tiny stillborn child.

A few weeks afterwards, she returned for a consultation to review the events surrounding her delivery. I learned many years ago that only a small portion of any explanation is absorbed coincident to such tragic events, so it is usually worthwhile to repeat and expand upon any previous discussion when the patient is ready. All of her laboratory studies had returned to normal, but her blood pressure was still slightly elevated, and I suspected that she had some degree of chronic hypertension. Indeed, during the course of her hospital stay with us, we had found (unbeknownst to her previously) that she only had one kidney and it was thought that this might be the source of underlying hypertension that had contributed to the severe superimposed preeclampsia at such an early gestational age. We reviewed the placental pathology report and found changes that are often seen in abnormalities of placentation associated with autoimmune disorders or thrombophilias (conditions associated with an increased tendency to form or slowly dissolve blood clots). She had no family history, or other past medical history, to suggest she might have one of these conditions.

Baseline kidney studies were done and returned remarkably normal, despite her single kidney (and what it had recently been through!). Screens for subclinical autoimmune disorders and thyroid disease were also normal. She was found to be a heterozygote for a mutation in the methylenetetrahydofolate reductase (MTHFR) gene, but had no other evidence for a thrombophilia, and single gene abnormalities in MTHFR are rarely associated with the severe problems she had had. With this reassuring information in hand, I asked her to return when she thought she was ready to get pregnant again, and we would discuss options for ‘empiric’ therapy since she wanted to do “everything possible that was safe” to reduce the risk of recurrence for the problems she’d had and if there is nothing else I have learned through the years, it is that history does tend to repeat itself in the pregnancy complications arena.

About nine months later, she did return. She was “thinking about getting pregnant again” but wanted to know the unanswerable question, “Am I going to get sick and lose another baby?” My only response was that she was at greater risk, but in the absence of a specific medical problem or laboratory abnormality, I honestly did not know what that risk was (I usually tell folks 5-25% under these circumstances to account for the ‘unknowns’ we haven’t yet learned to look for), although I did tell her that if it happened again, it was highly likely it would happen a third time. She told me that she “appreciated my honesty” and asked what we could do to minimize her risks. To make a long story short, we started her on a prenatal vitamin, high-dose folic acid (4 mg per day), a baby aspirin (81 mg), and I told her to return within two weeks of a missed period and we would add prophylactic heparin therapy (5,000 U SQ twice per day) to this empiric regimen.

So she left and returned two months later, pregnant again. We confirmed fetal viability by ultrasound, did a few more laboratory studies, started her on the heparin, and embarked on another pregnancy with our fingers crossed. All the follow-up studies were normal, including a “quad screen” at 16 weeks, with specific attention to the alpha-fetoprotein level (frequently elevated in severe abnormalities of placentation such as she had previously). The baby had no gross abnormalities seen by ultrasound, grew well, and had no Doppler flow abnormalities detected on serial ultrasound examinations. At 28 weeks’, I recommended that we discontinue the heparin (which she did with some reluctance) and we simply plugged her into frequent office visits with ‘antepartum fetal surveillance.’ At 38 weeks’, her blood pressure began to rise and we admitted her (yesterday) for induction of labor which resulted in the outcome noted in paragraph one.

Tyra and her husband asked that I be present for the delivery “if at all possible” and I agreed. Indeed, I was grateful for the opportunity. We had been through a lot together with the first delivery, we had taken a chance with another pregnancy, we had tried a relatively ‘safe’ approach to empiric therapy, and we now had a good outcome (even if we will never know if the medical therapy was the difference). I was there today as much for me as for Tyra and her husband, not for the ego stroke, but to bring closure to the previous experience by sharing in the joy that they and their families (and many friends) got to share today - one of the rewards of this profession that I will always consider to be “priceless.”

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Call to Action: Help Raise the South Carolina Cigarette Tax

Despite the fact I trained at an institution (and am quite grateful for the opportunity that was afforded to me) that was built on tobacco money, and I do, admittedly, enjoy the occasional fine cigar (only in the presence of consenting adults), there is also no doubt today where I stand on the routine use of cigarettes – don’t do it, especially if you are pregnant or around young children. In the next few weeks, we will, in the State of South Carolina, have the opportunity to ‘make a difference’ as the State legislature considers raising the cigarette tax. So pardon my soapbox, but today I am going to get up on one!

The average state cigarette tax in the U.S. is $1.02. The current tax in South Carolina is $0.07! That tax has not been raised since 1977, despite what we have learned in the interim about the impact of cigarette use on health of the individual and overall health care costs and the widespread use of tobacco products in our state. Indeed, it is estimated that state and federally-funded health care costs are $7.66 for each pack of cigarettes sold in SC! We have good evidence to support that one out of every five low birth weight babies born in the U.S. is directly attributable to maternal cigarette use during pregnancy. We also know that low birth weight, either by itself, or as a consequence of prematurity, dramatically increases both short-term and long-term health care problems and costs for the child. Unfortunately, South Carolina is one of the country’s leaders in both prematurity and low birth weight with the combination of the two resulting in more than 15% of all births in our state. These babies typically incur neonatal health care expenses 10-20 times that of term and normally grown infants. This year, there will be about 6,000 low birth weight babies born in SC, and approximately 1,200 will be the result of maternal smoking, and therefore could have been prevented.

Anyway, it is my hope, and if you feel the same way, please feel free to participate at a grass roots level, that we can convince our state legislators to provide a significant increase in the cigarette tax (how about $1.00 per pack?!?). Hopefully, this will encourage some folks to quit, discourage others from starting, provide revenue to improve health care in South Carolina, and provide funds to counter the ongoing marketing by the cigarette industry that is still directed at attracting young people of ‘child-bearing age’ into their fold. If the increase is significant enough, it might also help with the illegal trafficking across state lines that is currently encouraged by the big profits to be made because of the current differential, as well as encourage comparable tax increases in adjacent southeastern states.

The bill (H 3567) to raise the cigarette tax is currently in the SC State House of Representatives. Representatives by district can be found by following the following link: http://www.scstatehouse.net/html-pages/housemembersd.html . A simple email or phone call can make a big difference. Since there is a reasonable chance some form of this bill will be approved by the House, it’s not too early to start talking to the State Senators as well: http://www.scstatehouse.net/html-pages/senatemembersd.html . Thanks for your help!

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Routine Screening for HIV During Pregnancy

Last week I was asked to represent our hospital system at a conference sponsored by the Centers for Disease Control (CDC) regarding “Implementation of HIV Screening in Acute Care Settings.” Several of the larger hospitals in the southeast were represented and HIV/AIDS has been an interest of mine, particularly as it relates to women and their pregnancies, since before we knew what caused the problem, so I was glad to be invited.

HIV seems not to get much press in the U.S. anymore, but the problem is NOT going away. Indeed, the southeast, where I practice, seems to be leading the epidemic in the U.S., and most folks here either are unaware, or are in denial, of that fact. There are now more than 1.2 million (1 in 300) Americans infected with HIV, 50-55,000 new cases per year, and more than 300,000 individuals unaware that they have the infection. It is estimated that since the epidemic began, more than 560,000 individuals have died from AIDS-related complications and 17,000 per year continue to do so, despite the advances that have been made in therapy. Since 1994, there has been a steady rise in AIDS cases among blacks and other ethnic minorities, women, and persons exposed through heterosexual contact. Perhaps the shifting demographics of HIV/AIDS have contributed to the decrease in its political visibility and the social activism that seemed to characterize the early stages of the epidemic in this country.

One of the bright spots in the HIV story has been in the care of pregnant women. As quoted in the CDC Morbidity and Mortality Weekly Report of September 22, 2006 (MMWR 2006;55(RR-14):1): “The number of children reported with AIDS, attributed to perinatal HIV transmission, peaked at 945 in 1992 and declined 95% to 48 in 2004, primarily because of the identification of HIV-infected pregnant women and the effectiveness of antiretroviral prophylaxis in reducing mother-to-child transmission of HIV.” During the same time period, the total number of babies born infected with HIV also declined more than 90% from a peak of about 1650 in 1991 to 138 in 2004. The success in pregnant women illustrates the value of a routine screening program, not only in the reduction of transmission, but in the identification of HIV in individuals, previously, unaware of their infections, who can then be offered ongoing care that might dramatically improve the length and quality of their lives. (Recent studies have shown that a significant percentage (more than 2/3) of individuals also reduce their ‘high risk behaviors’ once they are identified as being HIV-positive, thereby, further reducing transmission rates).

Today, with current therapies, HIV is a disease that can be managed as a ‘chronic’ condition, allowing a relatively long, uncomplicated, and productive life, but this is only true among those who have a diagnosis made early in the course of their infection so that appropriate counseling, follow-up, and therapy can be implemented. The tragedy is more than one-quarter of those who have HIV are still unaware of that fact and more than 40% will not have their positive HIV status identified until late in the course of their infection (<12 months before developing AIDS) despite multiple opportunities to identify their status during encounters with the health care system. (It is also from this group of individuals that 50-75% of all new cases of HIV infection will be transmitted).

These points were brought closer to home in another recent CDC report that focused on South Carolina (MMWR 2006;55:47). In this report, it was noted that among the 4315 cases of HIV reported in South Carolina between 2001 and 2005, 3157 of these individuals made 20,271 health care visits prior to their first positive HIV test. Forty-two percent of these HIV-infected individuals developed AIDS within 12 months of diagnosis and among these, 73% had made 7988 health care visits (median of 4 per patient) but were not tested for HIV. The bulk (79%) of these visits were to emergency departments. When the diagnostic codes for these visits were reviewed, more than 99% would not have prompted an HIV test! The point emphasized by these observations is that, even though identifying individuals with HIV is important in terms of prognosis, we often miss opportunities to do so at the portals in which they do enter the health care system such as emergency rooms, labor and delivery units, private doctors offices, and even community clinics when they are being seen for ‘other medical indications.’

With regard to pregnancy, women should be informed that HIV affects ALL socioeconomic and ethnic groups and can be carried for years without any signs or symptoms related to the infection. Even without signs or symptoms, the disease can be transmitted to the baby before, during and, even after labor and delivery (by breastfeeding in those who are unaware of their infections). In 2002, for example, it was estimated that 6000 to 7000 HIV-infected women gave birth to infected babies (about 280); 40% of the infected babies were born to women who did not know their HIV status. The clinical course of HIV in babies who contract the virus in the peripartum period is often associated with an accelerated progression to AIDS, even if HIV infection is recognized relatively early. Indeed, an AIDS-defining illness during the first 12-24 months of life is often the only indication that a baby has contracted HIV from an undiagnosed and ‘unaware’ mother.

If HIV is identified, prophylactic therapy should be initiated during pregnancy and intrapartum to reduce risks of perinatal transmission. Transmission rates in the absence of prophylactic therapy are about 25%; this can be reduced to 9-13% if prophylactic therapy is initiated during labor in women previously not treated or not identified as having HIV before their delivery admission; and, they are < 2% in women treated prophylactically both during pregnancy and labor. With these points in mind, the updated recommendations for pregnant women can be summarized as follows:

• Opt-out testing is now recommended for ALL women by the CDC and ACOG as part of the routine screening strategies during prenatal care. Opt-out testing implies that the routine ‘consent to care’ that all women are asked to sign at intake includes an understanding that HIV screening will be performed, unless it specifically requested that this is not done.

• Extensive counseling prior to having an HIV screen is not necessary (although, may be warranted, perhaps, with the patient who is expressing the desire to ‘opt-out’ of screening).

• Testing should be performed, not only as a routine during the New OB evaluation, but again in third trimester in areas where HIV incidence is > 17 cases per 100,000 person-years (as is the case in South Carolina).

• All women having no prenatal care, having previously declined testing, or having no documented test results available should have rapid screening done on admission to L&D and, if this is declined, or if the mother’s status is unknown at delivery, the baby should be screened after delivery.

• Screening should be performed in the ‘acute care setting’ using a rapid diagnostic test. The tests currently available have virtually 100% sensitivity and 100% specificity and can provide results within 10-30 minutes (recommended turn-around time).

• If the rapid test is positive, appropriate prophylactic therapy, such as AZT, should be started based on the test results, even without having results of confirmatory testing.

It is hoped (and the most recent data would support the fact) that destigmatizing HIV screening by bringing it into the realm of the ‘routine’ will improve acceptance among all persons and, eventually, improve our management of the current epidemic. This approach would have seemed the most logical for many years, not only in pregnant women who, generally, want what’s best for their babies. I have said for years “If you don’t know who has the problem, how can you treat the epidemic” and this is clearly one situation in which “If you don’t take a temperature, you can’t find a fever” has been demonstrated not to be the most prudent approach to care.

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Grand Rounds 3.30 - Thanks FD!

Many thanks to Fat Doctor for the effort put into Grand Rounds 3.30 and for including a link to my penultimate post on recurrent early pregnancy loss which addresses 'empiric therapy'. Although such an approach might never pass the rigorous review of 'evidence-based medicine,' until we have more evidence upon which to base our medicine under these circumstances, the benefits and outcomes seem to more than justify the 'risks.'

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Recurrent Early Pregnancy Loss - 11 - Therapeutic Interventions

Our patient with recurrent early pregnancy loss has come to us desperately wanting to know” Why? What’s wrong with me? What can be done to help?” She is at the point where she needs more than simple reassurances, although that is still an important part of this process, and agrees to proceed with a diagnostic evaluation. She is told at the outset that nothing might be found (although ‘empiric therapy’ will be an option even under these circumstances), that we do not necessarily have all the answers for this problem, and that even if something is found (and corrected) this might not necessarily assure her a good pregnancy outcome. During the course of her work up, however, one or more of the following abnormalities is identified…

• Irregular menstrual cycles_ Many years ago, I found it helpful to restore the menstrual cycle to 28 days in women with recurrent early losses who had irregular cycles characteristic of aberrations in timing of ovulation. The initial thought for doing this was to be able to ‘time’ the date of conception, the testing detailed previously, and the therapeutic interventions. Other benefits included possible improvement in the hormonal milieu, preceding and following ovulation, and the synchronization of the endometrial development to maximize receptivity to a fertilized egg. To do this, I would simply use clomiphene citrate (Clomid), a drug that has been available for more years than I have been in this business. Today, with better understanding of the hormonal events surrounding ovulation and implantation, and the extraordinary advances in diagnostic approaches and assisted reproductive technologies (ART), I will usually refer a woman with menstrual irregularity to a specialist in Reproductive Endocrinology and Infertility (REI) to partner in her initial work up. The REIs not only have an intimate working knowledge of the reproductive hormones, but they also have the most experience and skill in the evaluation and management of the ‘uterine abnormalities’ that might be contributing to early pregnancy losses. They are a valuable resource and first-line partners in the care of these difficult patients.

• Hormonal abnormalities_ Patients with reproductive ‘hormonal imbalances’ accompanying irregular menstrual cycles are also at greater risk for having other abnormalities of the endocrine system that may deleteriously affect their chances for carrying a pregnancy. Thyroid disorders, diabetes, insulin resistance, androgenization (increased levels of male hormones), and elevated levels of prolactin (made by the pituitary gland) may be found in such women (particularly as part of the ‘polycystic ovary’ or ‘metabolic syndrome’ complexes) or as isolated abnormalities in reproductive age women. All of these will be picked up by the screening evaluation discussed in our earlier post, all are readily amenable to medical therapy (details of which do not need to be included here), and that therapy should, ideally, be undertaken (and stabilized) prior to embarking on another attempt to carry a pregnancy.

• Uterine abnormalities_ Congenital malformations, uterine fibroids, endometrial or cervical polyps, and Asherman’s syndrome (scarring of the uterine cavity) are, as noted above, best evaluated and managed by the specialist in REI. If any of these are considered to be factors in recurrent early pregnancy loss, surgical therapy is usually required to improve the likelihood of success. This may range from a simple procedure, such as the hysteroscopic resection of a polyp or pedunculated (polyp-like) fibroid, to a very complex procedure, such as resection of large fibroids, resection of a large uterine septum, or complete reunification of a bicornuate uterus. Whenever any uterine abnormalities require surgical intervention, the patient may be at increased risk for pregnancy complications such as placenta accreta, cervical incompetence, and uterine rupture, but let’s save that discussion for another time after we have managed to get you through the first trimester!

• Chromosomal abnormalities_ Chromosomal inversions and balanced reciprocal (partial chromosomal) translocations cannot be fixed; nor can complete translocations of one whole chromosome to another. In the case of the former, however, there usually is a reasonable chance over time that during the final stage of meiosis, the mother will eventually produce an egg (or the father sperm, if he is the affected parent) that does contain a normal complement of chromosomal material (totaling 23 different chromosomes) either normally configured or as a balanced abnormality like the affected parent’s. Specific risks for the couple need to be discussed with a Genetic Counselor once the actual abnormality has been identified. One approach, although not easy to accept, is truly the situation where “you just have to keep trying, and sooner or later you may get it right.” An alternative approach is to undergo ovulation induction, harvest a bunch of eggs, fertilize these in vitro, then take the healthiest looking embryos and submit a cell from each for ‘preimplantation genetic diagnosis’ before putting the chromosomally normal one(s) into the uterus. This is probably the wave of the future, but right now the cost is likely to be prohibitive to most.

In the second situation, if a parent has a complete translocation of one chromosome to another, that couple can never together create a baby with a normal chromosomal complement. Under these circumstances, either egg or sperm donation (depending on the affected parent) is the only reasonable solution if a couple would like to share a chromosomally normal baby together. Some patients with balanced inversions or reciprocal translocations will often choose this route as well rather than suffer the emotional and physical trauma of repetitive pregnancy losses, especially if they have a chromosomal abnormality that could produce an aneuploid fetus which has a chance of surviving the pregnancy.

• Immunological and hematological abnormalities_ For the most part, here we are dealing with the immunologically and hematologically based ‘thrombophilias.’ As discussed previously, these are the conditions associated with an increased tendency to clot or to have difficulty breaking down clots once they have formed. Treatment of these conditions follows the ‘empiric therapy’ detailed in the previous post, however, either heparin or low-molecular weight heparin is added at the outset and titered to therapeutic levels (especially if the patient has a prior history of clotting complications). If the patient has a known autoimmune disease, such as systemic lupus erythematosus, this should also be controlled (prior to conception if possible) in collaboration with a specialist in Rheumatology. Ideally, the patient should be in remission (and on no medications) at the time of conception; however, if immnuosuppressive therapy is required, this is generally fairly ‘safe’, even in early pregnancy. We have cared for many women over the years that have organ transplants, requiring continuous immunosuppressive therapy, and for the most part, they do quite well.

The last immunologic condition I will address, although I will probably regret mentioning it, is ‘haplotype (perhaps, genotype?) similarity.’ Some couples with recurrent pregnancy loss have been found to share critical transplantation antigens (HLA antigens), those factors that are expressed on cells and recognized as foreign by the immune system. The clinical implication of a couple sharing too many of these antigens has been hypothesized to be that the woman might have a more difficult time developing an ‘appropriate’ immune response to the embryo, resulting in repetitive failed implantation. (It is also possible that couples too similar for transplantation antigens also share other ‘bad’ autosomal recessive genes that increase the likelihood of lethal combinations for the fetus).

Although I do not routinely screen for HLA anymore, I did in the past and recall one couple that had no other explanation for their recurrent losses (ten of them!) and were found to share six HLA antigens (more than most siblings share!). They had failed my ‘empiric therapy’ approach as well as my ‘enhanced’ empiric approach (which included the addition of prednisone, an immunosuppressive steroid). It was hypothesized at the time that if the mother could be stimulated (immunized) to react to paternal antigens (or foreign transplantation antigens in general) that she would have a better chance of carrying a pregnancy. ‘Therapeutic’ approaches fell into two camps. The first involved ‘immunizing’ the woman with her partner's white blood cells (which express HLA antigens); and, the second involved using pooled white blood cells from various donors. In the case of my patient, I chose the latter approach. She received two courses of transfusion with pooled white blood cells prior to conception and then received a third dose early in the subsequent pregnancy. Lo and behold, she successfully carried that pregnancy and the others she attempted after that!

Well, we have come a long way in our discussion of recurrent early pregnancy loss over the past month. There are other issues I have, undoubtedly, omitted, but the review is fairly comprehensive and covers most of the major points related to this topic. For those of you who have had your life challenged by this condition, let me remind you of something I said in a previous post…Despite the emotional pain, maintain your hope. I truly have had only a few couples over the years that did not succeed in fulfilling their desire for a baby together. So, “Keep your chin up” is not simply idle chatter!

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Recurrent Early Pregnancy Loss - 10 - Empiric Treatment

Most patients who have recurrent early pregnancy loss are desperate to try “anything and everything” to achieve a successful pregnancy. Because of this plea, I have adopted (and often combine) both ‘empiric’ and ‘specific’ approaches to therapy over the years, the former chosen for being relatively ‘safe’, potentially helpful, and offering the benefit of reducing stress (which alone might be valuable) because “something is being done,” and the latter directed at specific abnormalities detected during the diagnostic evaluation outlined in our last post.

If a woman has regular menstrual cycles and has never had trouble conceiving (and no abnormalities found during the diagnostic evaluation which is more often than not the case), I usually offer the following advice and empiric treatment regimen: discontinue smoking and alcohol and limit caffeine intake; begin a prenatal vitamin daily; start supplemental folic acid 4 mg daily; take a baby aspirin (81 mg) once daily (this antagonizes the ‘platelet side’ of the coagulation system); offer ‘progesterone support’ either in the luteal phase, or as soon as a pregnancy is confirmed and continue this until 10-12 weeks. I will also offer a course of a broad spectrum antibiotic (azithromycin or doxycycline) to BOTH partners early during the first cycle she attempts to conceive. These antibiotics treat organisms such as mycoplasma and ureaplasma (rather than culture for these organisms) among many others.

After conceiving, I ask that she return by about 6 weeks (two weeks after the missed menstrual cycle), perform an ultrasound to confirm an intrauterine pregnancy, repeat the lupus anticoagulant and anticardiolipin antibody screens (even if these were negative between pregnancies), and also screen for circulating complement levels. The complement system (the 'classical pathway') is activated by certain antibodies once they have attached to something ‘foreign’ (forming ‘immune complexes’) and help to destroy that to which the antibodies have attached. If complement levels are low or low normal during pregnancy (normally during pregnancy they increase), this might reflect ‘complement consumption’, the presumption being that the invading trophoblasts may be the targets against which the complement-fixing antibodies are directed. (Another possibility is that the 'alternative complement pathway', that does not require antibodies, is somehow being activated, but I do not want to get into that here and it doesn't change what I do at this point anyway!) I have used this approach (the low complement levels) over the years (although I have never seen a published study to justify it) to guide more aggressive therapy in women with known autoimmune disorders, lupus anticoagulants, or anticardiolipin antibodies, and even those with no other abnormal findings (the rationale being that there are things we still do not know, other factors which have not yet been found or implicated in pregnancy loss and, therefore, are not tested for at this time).

If the studies noted above are all ‘normal’, and the patient has a history of 3 or fewer losses, I recommend that no other therapy be started during this pregnancy. If the patient has had more than 3 losses, has previously failed this initial empiric approach to therapy, has any abnormal immunologic or coagulation studies, or just plain insists because "I want to do everything possible now," I offer to add either heparin (inexpensive) or low-molecular weight heparin (very expensive) therapy (which antagonize the other side of the clotting system), both of which must be given by subcutaneous injection. This regimen has replaced the immunosuppressive steroid (e.g., prednisone) therapy (except in the patient with an overt and active autoimmune disorder) that we used, also emprically, years ago when I first became interested in recurrent early pregnancy loss and it appears to be just as effective (with far fewer side-effects such as gestational diabetes, swelling, and increased risk for infection).

This approach to therapy is the foundation upon which I build for any woman with recurrent early pregnancy loss. In the absence of other specific abnormalities, 'success rates' are extraordinarily high using this approach. Others would argue that success rates in this group of patients are high regardless of what is done. I don't necessarily disagree with that, but I have had patients over the years who had far more than 3 losses who only successfully carried after starting this regimen, and quite frankly, I don't think any of us are smart enough at this time to know who actually needs it and who doesn't! In our next post let’s address what we do if specific abnormalities are found during the diagnostic workup, always keeping in mind that multiple factors may be in play and the 'empiric regimen' (or parts of it) might still be warranted, even after these other factors are addressed…

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Grand Rounds 3.29 - Thanks Dr. Dork!

Many thanks to Dr. Dork at Blogspot.com for including a link to my summary post on the basic evaluation of the woman (couple) with recurrent early pregnancy loss in this week's Grand Rounds 3.29. Gathering from the response I have gotten to my series on this topic over the past two weeks, it is a condition that has touched the lives of many readers. I am sure those who have been so affected will also appreciate the opportunity to learn more about the subject and have some of their questions answered. I will be concluding the series this week with my thoughts on therapy, so see y'all again soon!

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Recurrent Early Pregnancy Loss - 9 - Evaluation

When I first see a patient in consultation for recurrent early pregnancy loss, I usually spend at least an hour with them. The first part of the appointment is spent in obtaining a detailed history – medical, social, and family. Since many different factors may be contributing to their difficulty carrying a baby, I ask them to be as accurate and honest as they can be in answering my questions. The following will give you some idea (by no means complete!) on the direction of my queries (and if you plan to see someone for a history of recurrent pregnancy loss, it is a good idea to be prepared to answer them!):

Were you born with any congenital problems? How old were you when you started having periods? Are they regular now? How many days in a cycle? How many days do you bleed? Bleeding between periods? Symptoms related to menstruation? Past/present gynecological problems and surgery (D&Cs, cervical procedures,…)? Past and current medical problems? Recent changes in weight, skin, appetite, hair, bowel habits, etc…? Medications? Over-the-counter therapies? Smoking, caffeine, alcohol, and substance abuse history? Work environment and exposures? Living situation? Family history (patient and partner!) with attention to thyroid disorders, diabetes, clotting problems, difficulty carrying pregnancies, repetitive miscarriages, chromosomal or genetic conditions, autoimmune diseases, mental retardation, birth defects…?

I spend a lot of time gathering details about their pregnancy losses: How long did it take to conceive? Have you been evaluated for ‘infertility’? What sort of evaluation did you have? Were any of your pregnancies conceived by infertility treatment and what kind? How far did you carry each pregnancy? What sort of pregnancy ‘symptoms’ did you have? How many weeks size were the babies when you were told they were lost? Was a baby ever seen? Was a heart beat ever seen? Did you have a D&C? Did you have the ‘products of conception’ analyzed by pathology or for chromosomal abnormalities? Were any abnormalities of the babies seen before or after they were lost?

Once this information has been gathered, a comprehensive physical exam is also warranted. Items of special attention include: height, weight, blood pressure, body type, thyroid gland, skin, hair and fat distribution, breast exam (to look for galactorrhea - milk production), and a very thorough gynecological evaluation to assess any gross evidence of congenital or acquired uterine, cervical, or vaginal abnormalities. It is only after all the above is done that I sit down with a pad of paper, discuss the various factors that may be associated with recurrent pregnancy loss, identify specific areas of concern based on the patient’s own history and physical findings, and outline a possible diagnostic evaluation. In reference to the individual posts I have written on these factors, among the diagnostic options to be considered are:

• Hormonal tests: Basic testing includes - thyroid stimulating hormone (TSH); mid-luteal phase (menstrual cycle day 21) progesterone; prolactin; fasting blood sugar (usually coupled with a ‘complete metabolic profile’ study) and if this is abnormal, a full glucose tolerance test. If there is a history of irregular menstrual and/or physical findings of excessive androgenization (male hormone) production, consider: early proliferative phase (menstrual cycle day 3) follicle stimulating hormone (FSH) and estradiol, and luteinizing hormone (LH) (cycle day 9 or 10); androgen levels, including free and total testosterone, dehydroepiandrosterone sulfate (DHEA-S), and 17-hydroxyprogesterone (17-OH-P). For these latter studies, I will often send the woman to a specialist in reproductive endocrinology and infertility (REI) for evaluation and, if necessary, management through conception.

• Chromosome studies: Offered to both partners (start with the woman if resources are limited).

• Uterine abnormalities: Sonohysterogram (uterine ultrasound done with fluid distention of the uterus), best coupled with hysteroscopy (looking inside the uterus with a small scope). If any abnormality is suggested, a diagnostic laparoscopy (to further evaluate the uterus and pelvis) and, perhaps, an intravenous pyelogram (IVP) since ‘Mullerian’ defects are often associated with urinary tract abnormalities as well.

• Immunologic and hematological tests: complete blood count (CBC); blood type and antibody screen; antinuclear antibodies (ANA); lupus anticoagulant, antiphospholipid antibodies (usually start with screen for anticardiolipin antibodies); Factor V Leiden; prothrombin mutation; methylenetetrahydrofolate reductase (MTHFR) mutations; antithrombin III; protein C; protein S; homocysteine levels. Further testing depends on the results of these initial studies. On rare occasions, or if consanguinity is suggested or the patient fails initial attempts at ‘therapy’, consider maternal and paternal HLA testing.

• Known medical conditions: If the patient has known diabetes, hypertension, autoimmune condition, seizure disorder requiring ongoing medical therapy, or some other chronic medical condition, further evaluation appropriate to that condition is also conducted.

In my next final posts on the subject of recurrent early pregnancy loss, I will outline general recommendations for ‘empiric’ treatment, as well as specific options for therapy, based on results of the diagnostic studies above, to help a couple achieve a successful pregnancy…

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Recurrent Early Pregnancy Loss - 8 - Maintaining Hope

We have provided a lot of information over the past two weeks related to recurrent early pregnancy loss. Before we begin to translate that information into the medical evaluation that can be used to try to identify specific problem areas and possible approaches to ‘therapy’, let me digress for one day. I would like to mention several points that help to explain (not, necessarily, to justify) the response of providers (not all) to the subject of early pregnancy loss. Indeed, several readers have had comments related to these concerns and forgive me, but this is my way of addressing them in the most efficient manner…

Many providers will not even offer any medical evaluation to a woman until after she has had three or more early losses and has been classified, unflatteringly, as a “habitual aborter.” The reasons for this are multiple. First, there is truly a high spontaneous successful pregnancy rate, probably greater than 70%, in healthy women who have one, or even two, early losses. Secondly, early pregnancy loss is such a common problem (although most women do not know this and they certainly do not want to hear it) that a provider who has a busy obstetrical practice, has to confront this problem every day or two. Thirdly, as can be gathered by the multiple posts that I have written on the topic, this can be a complex issue that is not easy to cover in a short period of time and, because of these first three points, most providers do not feel it is practical, or necessary, to devote the time or the energy to what they consider to be a ‘self-limited’ condition. Unfortunately, they may also not be very good (or feel very comfortable) in conveying this information to their patients. (One should realize that because early pregnancy loss is such a common problem, it may also have affected the life of the provider who may prefer not to relive that experience with every patient).

The fourth point is that the ‘work up’ can be quite expensive (and may not be covered by insurance), nothing may be discovered, or something might be found for which no solution is readily available (such as a maternal or paternal chromosomal abnormality), oftentimes ‘empiric therapy’ is chosen regardless of what is found and, again, the patient may well carry the next pregnancy, whether or not any therapeutic regimen is implemented. And, finally, providers may either be unaware of, or reluctant to, refer the patient to a ‘specialist’ for fear of losing that patient from their practice.

Unfortunately, even if they are told these things (and oftentimes they are not, or they do not hear it because of their emotional condition at the time), this is not very satisfying to most women (couples) who experience the loss of a pregnancy. Indeed, I have seen many women in self-referral who swore they “would never return to that doctor” because what they did hear, the “Honey, you are young and healthy and just need to wait a few months and try again,” did not adequately address the questions and emotional needs she (they) had at that time. When I chat with women about this, mentioning the points above, they usually come away with some understanding (although often unforgiving) that the hurt, despair, guilt, and anger they feel over the loss of their baby is part of the ‘grieving process’ and shouldn’t necessarily be redirected at their provider; she (he) was only the messenger.

At the same time, by means of inquiry and explanation, it is important to identify potential problems, provide them with information, simple suggestions for what they can do on their own (even if a full ‘work up’ does not yet appear to be warranted), provide a detailed outline of a possible ‘work up’ if it does seem justified, try to dispel their feelings of guilt related to their loss(es), and above all, give them hope for the future. I always reassure them that in all the years I have been counseling and caring for patients with recurrent pregnancy loss, the ones who have not achieved a successful pregnancy can be counted on less than five fingers...

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Recurrent Early Pregnancy Loss - 7 - Immunologic and Hematologic Causes

Our blood clotting system helps prevent us from bleeding and also may potentiate an immune response since it is ‘activated’ by tissue damage. Blood clotting (coagulation or thrombosis) and the breaking down of blood clots (fibrinolysis or thrombolysis) are processes that go on continuously within our bodies. There is a delicate balance between the coagulation system and the fibrinolytic system and many factors can shift that balance in one direction or the other with resulting complications, respectively, of either too many (or persistent) clots (deep venous thrombosis; arterial thrombosis; pulmonary emboli; strokes; heart attacks) or excessive bleeding. Nowhere is that balance challenged more than at the site of implantation of the embryo in the uterus and the subsequent development of the placenta, a site where there is invasion of the mother’s tissues by fetal cells, interaction between fetal tissues and the maternal immune defenses, invasion and remodeling of maternal blood vessels, and proliferation of new blood vessels.

Normal pregnancy is considered by many to be a ‘hypercoagulable state.’ Many of our blood clotting factors are made in the liver and production of these is enhanced by estrogens, levels of which rise 100-1000-fold during pregnancy because of their production by the placenta. Although this would seem to place all pregnant women ‘at risk’ for blood clotting problems, few actually develop such complications (although this is still a major cause of morbidity and mortality for pregnant women). When such complications do arise, however, we have discovered that certain environmental, genetic, and acquired factors, working alone or in concert, may contribute to the imbalance. We have also come to suspect that some of these same factors may play a role in recurrent early pregnancy loss as well as later pregnancy complications such as small (growth restricted) babies, hypertensive disorders of pregnancy (preeclampsia; eclampsia; HELLP syndrome), intrauterine fetal demise, and early delivery, even if a woman has never had a problem related to clotting.

Perhaps the most common environmental influence associated with an increased tendency to ‘clot’ is smoking. I do not want to imply that smoking’s effects on the coagulation system is its sole contribution to pregnancy complications. Tobacco products have the potential to exert multiple deleterious effects on a pregnancy (and highly variable expression of those effects in different individuals). However, I have had several patients over the years that consulted me for repetitive miscarriages, had no other identifiable risk factors, and who only successfully carried a pregnancy after they were finally convinced to discontinue smoking. Although I do not want to dwell on ‘environmental factors’ in this post, certain prescription medications and over-the-counter ‘natural’ herbal preparations may also be culprits that need to be evaluated in the context of recurrent pregnancy loss.

The ‘genetic’ and ‘acquired’ factors have various mechanisms by which they effect the coagulation system, but the upshot is that those abnormalities which shift the balance in the directions of either increasing clot formation or diminishing fibrinolysis (the rate at which blood clots are broken down) have the greatest potential to cause pregnancy complications (although the contributions of these to early pregnancy loss is still highly controversial). Affectionately, these conditions have been termed ‘thrombophilias’ (= clot loving). Included among the common genetic abnormalities associated with an increased tendency to form or retain clots (and without going into detail about the specific mechanisms of action of any!) are gene mutations such as Factor V Leiden, prothrombin gene mutations, antithrombin III deficiency, methylenetetrahydrofolate reductase (MTHFR) deficiency (especially when associated with hyperhomocysteinemia which is also correlated with risk for neural tube and congenital heart defects), and deficiencies in Protein C and Protein S.

With regard to ‘acquired factors’ (perhaps also a misnomer because genetics also plays a role in the development of autoimmune conditions), in my last post we discussed a patient who had recurrent pregnancy losses and a ‘lupus anticoagulant.’ Lupus anticoagulants were named such because of their ability to prolong clotting in certain laboratory assays, but they are actually associated with a greater tendency to form blood clots in humans. They were first detected in patients who had systemic lupus erythematosus, but are now known to occur spontaneously in individuals who do not have lupus and may not cause any problems except difficulty carrying a pregnancy (as was the case with our patient). Lupus anticoagulants are only one of a host of autoantibodies (antibodies directed against ‘self’) classified as antiphospholipid antibodies. Others include anticardiolipin and antiphosphatidylserine antibodies among others.

As demonstrated by my patient with the lupus anticoagulant, the effects of antiphospholipid antibodies on different individuals is highly variable and probably dependent on other components of the person’s own genetic make up. In the most extreme cases, some individuals have severe and life-threatening problems related to these antibodies. Indeed, the triad of recurrent pregnancy losses or poor obstetrical outcomes (related to severe preeclampsia, intrauterine growth restriction; fetal deaths, and preterm delivery), recurrent episodes of venous and arterial thrombosis, and persistence of antiphospholipid antibodies has been termed the “antiphospholipid syndrome (APS).” In individuals with APS, successful pregnancy may not only be difficult to achieve, it could prove deadly, even with aggressive medical management.

In closing today’s post, I would be remiss in not mentioning another characteristic (and when dysfunctional, perhaps, an aberration) of the immune system that may be associated with recurrent early pregnancy loss. In fact, as I have alluded to previously, this may be the barrier which must be overcome to carry any pregnancy and also may be the most common cause of first pregnancy losses and, in some cases, consecutive miscarriages in many women who have no other identifiable ‘risk factors’ before they can successfully carry a pregnancy. It appears to be necessary that the maternal immune system recognizes the fetal tissues as ‘foreign’ (i.e., become ‘immunized’ to them) before it is able to generate a response that will nurture their growth (while maintaining certain boundaries).

It has been proposed (and is indeed the basis for some forms of empiric therapy) that the maternal immune response at times has difficulty properly recognizing the fetal tissues in this way. This may be more likely to occur if the fetal tissues are too similar to the maternal tissues. Indeed, some couples that share multiple ‘transplantation antigens’ seem to have the greatest hurdles to overcome in this regard. The reasons for this are unclear. Our immune system has both humoral (antibody) and cell-mediated components. It has been proposed that failure to elicit ‘blocking antibodies’ might be involved (and in some cases may be) under circumstances of recurrent early pregnancy loss. However, we also know that some women, who have a condition called ‘agammaglobulinemia’ and don’t make measurable levels of certain antibodies, may successfully achieve and carry a pregnancy. My own bias in this regard is that the important actors are components, perhaps, both nonspecific and specific, of the cellular immune system.

Well, we have come a long way in our discussion of factors that contribute to recurrent early pregnancy loss (and there are more we could mention!). But, I plan to conclude this series by devoting two more posts to this subject that will focus on the practical aspects of using the information we have presented to formulate plans for both evaluation and management of this problem. Thanks for hanging in there with me and I hope the thoughts will help those of you who have had their lives affected by this condition…

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Recurrent Early Pregnancy Loss - 6 - A Special Patient

Before I get into details regarding specific abnormalities of the maternal immune system and clotting system that appear to be related to recurrent early pregnancy loss, let me tell you a story about one of those ‘special patients’ in my life who changed forever the way I practice medicine…

I remember being fascinated with patients who had recurrent pregnancy loss from early on in my training. The prototype patients for this problem were those with known autoimmune disorders, specifically, systemic lupus erythematosus (SLE). The curious thing about that was not all patients who had SLE had difficulty with pregnancies. The ones who seemed to be at the greatest risk were those who had lupus nephritis (kidney damage) or a history of blood clotting complications (deep venous thrombosis, arterial thrombosis, strokes, and pulmonary emboli). Many of these patients were also found to have false-positive RPRs (a test for syphilis) and later, as laboratory evaluation evolved, positive ‘lupus anticoagulants’ (in some ways a misnomer, because these actually increased the risk for persistence of blood clots).

In the early 1980’s, I took care of a woman who had history of recurrent early pregnancy losses who also happened to be the wife of the director of our Coagulation Laboratory. She was a ‘healthy’ woman who had no known medical problems. I first saw her on referral early in another pregnancy and during the routine evaluation, found that she too had a false-positive RPR. Out of curiosity (and with her husband’s blessing) we also screened for and found that she had a ‘lupus anticoagulant.’ She had no physical, symptomatic, or laboratory evidence of SLE, so by definition, she did not have this condition. She lost that pregnancy shortly after her first visit with me before any medical intervention could be tried. When I saw her back between pregnancies, her ‘lupus anticoagulant’ was no longer detectable! Regardless, I told her to start taking a baby aspirin (80 mg) daily (because of its known benefits in preventing clotting initiated by platelets on one side of the coagulation cascade) and to contact me the “minute you think you’re pregnant again.”

About 3 months later, she presented at about 5-6 weeks, still taking her baby aspirin. The RPR came back ‘false-positive’ again, and the ‘lupus anticoagulant’ had returned! At this point, I added high-dose prednisone to her treatment regimen ('immunosuppression' was one empiric approach to management of patients with lupus anticoagulants at that time). Her pregnancy survived the first trimester, so rather than arguing with success, we continued her on this regimen. Indeed, at many institutions back then, she would not have even been started on the prednisone until the pregnancy had gotten through the first trimester. At about 26 weeks, she was found to have developed ‘gestational diabetes’ probably as much the result of the prednisone therapy as any predisposition for this she might have brought to the pregnancy. We admitted her to the hospital to begin insulin therapy for the diabetes and during the course of her routine evaluation, an ultrasound was performed and the baby was found to be severely growth restricted. Within two weeks, she developed severe preeclampsia (HELLP syndrome) and needed to be delivered by cesarean section. Although small, that baby did just fine, but did require a long stay in the neonatal intensive care unit, and my friends had their first baby. When she returned for her postpartum examination, the lupus anticoagulant was gone again!

A year or so later, she again began taking the aspirin and conceived shortly thereafter. This time her RPR returned ‘negative’ and no lupus anticoagulant was detected either. Not knowing what to do with this information, but also with the history of her previous complicated obstetrical history fresh in our minds, we compromised on a plan. We started the prednisone again in early pregnancy, decided to follow the growth of the baby, and if that was normal, planned to begin tapering the prednisone at 24 weeks and to discontinue it completely by about 26 weeks, just before we ordinarily did our diabetes screening. The growth of the baby was normal, the lupus anticoagulant was never detected, and so we followed through on the plan. Stopping the prednisone when we did prevented the onset of gestational diabetes. The fetal growth continued to be normal, the patient never developed preeclampsia, and she was delivered close to term by repeat cesarean section, having a bouncing 8 pound+ baby. She subsequently conceived one more time, never redeveloped a lupus anticoagulant, and again carried to term with no therapy other than the baby aspirin (and who knows if that was even necessary at this point!).

This patient taught me several things: 1) ‘Healthy’ people can have abnormalities of their coagulation system that either are associated with early pregnancy loss, or are ‘markers’ for an abnormal immune response for pregnancy; 2) These ‘markers’ may only be apparent during a pregnancy in some cases; 3) Treatment may help, but it might not completely prevent an ‘abnormality of placentation’ that can still result in severe fetal growth restriction and maternal preeclampsia; 4) Resolution of a ‘marker’ (in this case a ‘lupus anticoagulant’) might also reflect having overcome an abnormal immune response to pregnancy (finally successfully immunized???) and should remind us to be flexible in designing empiric management strategies for these difficult patients.

Keeping this patient in mind, let’s now look at specific abnormalities of the immune and clotting systems that may be associated with recurrent early pregnancy losses….

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Recurrent Early Pregnancy Loss - 5 - Introduction to Immunologic Causes

The last two major categories I would like to discuss related to recurrent early pregnancy loss are immunologic and hematological (thrombophilias) abnormalities. These may well be the most common causes, but they are also by far the least well understood and much of what I will tell you is conjecture. There is considerable overlap and synergy in their deleterious effects on a pregnancy and there is also overlap in their evaluation and ‘treatment’ so discussing the two together has always made sense to me. I hope that I do not oversimplify this discussion to the point of inaccuracy…

Under ‘normal’ conditions, our immune systems are designed to protect us from things that are foreign to our bodies and also to recognize that which is ‘self’ and allowing it to elude immune destruction (‘tolerance’). There are many components of the immune system. The first line of defense is the ‘innate’ immune system. This is comprised of cells (macrophages, neutrophils, natural killer cells), cytokines (chemicals produced by these cells), and one arm of the complement system that are capable of ‘recognizing’ something foreign, limiting its invasion, and eliminating it but without necessarily producing a specific memory for the immune response to the invader. This is sometimes referred to ‘nonadaptive immunity.’

The other side of the immune system results in the production of specific antibodies (made by B-lymphocytes) and clones of T-lymphocytes, also directed against the specific invader, that are capable of ‘remembering’ the invader and, therefore, can more quickly respond if they are attacked again by the same (or in some cases, a similar) organism. This ‘specific’ immunity is often termed 'adaptive immunity.’ When tissue destruction occurs, as the result of either a specific or a nonspecific immune response, the blood clotting system is often activated as well. This may help to ‘finish off’ the invading organism or limit its access to oxygen and spread throughout the body by clotting off the blood supply at the site of the battle. This is the ‘synergy’ between the immune system and the blood-clotting system referred to above in the first paragraph.

The implanting embryo inherits and expresses characteristics from both the mother and father. Although certain major ‘transplantation antigens’ are not expressed on the invading placental tissues, the maternal immune system, both nonadaptive and adaptive, appears to be able to recognize the fetal tissues as ‘foreign’, but in a way that facilitates, but limits, the invasion, permits remodeling of the spiral arterioles of the endometrium, and then 'tolerates' the persistence of these fetal tissues, lining the spiral arterioles and the placenta itself, throughout the duration of the pregnancy. It would appear that if the maternal immune response either under-reacts or over-reacts, the implantation, placentation, and ultimate survival of the fetus are in jeopardy. The balance is both remarkable and delicate. As we have mentioned in one of our earlier posts on the subject of miscarriage, a proper maternal immune response requires some degree of ‘education’ and this might only come at the expense of an otherwise ‘normal’ embryo, accounting for the high frequency of ‘first pregnancy’ miscarriages in early pregnancy and perhaps the higher incidence of pregnancy-induced hypertensive disorders (preeclampsia) more often seen in first pregnancies that survive the first trimester.

In the next post, we will address specific abnormalities of the maternal immune system and clotting system that may be related to recurrent early pregnancy loss…

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