What is Aneuploidy Screening?

Patients have a hard time understanding the differences between screening tests and diagnostic tests. The most misunderstandings or misconceptions that seem to arise during pregnancy revolve around screening for aneuploidy (fetal chromosomal abnormalities). Even for providers, this can be a complex and confusing issue that can be difficult and time-consuming to explain to patients and, therefore, often is not given the attention it deserves.

Screening tests are used to provide presumptive identification of an unrecognized or unexpected disease or defect. They are usually designed to be relatively rapid and widely applicable to the population at large. They are not diagnostic, often are associated with what are perceived to be high ‘false positive’ rates, and are meant to have follow-up if ‘abnormal.’ Although, only a small percentage of the ‘abnormal’ tests are usually found to confirm the diagnosis of the abnormality in follow-up, the wide net that is cast by a good screening test does not often miss the opportunity to make the diagnosis either. In the case of aneuploidy, there are several relatively noninvasive approaches for evaluating the fetus ‘at risk’ without putting the fetus at risk by the screening process itself.

Many patients are put off by the screening tests for aneuploidy during pregnancy and the most common reasons cited when they are asked are: “The false positive rates are too high” (which I have found, interestingly enough, often means to them that they think they will be asked to make hard decisions regarding the pregnancy based on the screening test alone and don’t want to take the chance of terminating a normal baby); “I wouldn’t do anything about it anyway”; “I will take what I get and I don’t want to worry about it the whole pregnancy”; and, “My doctor told me that it wasn’t a very good test” (usually related to provider bias or misunderstanding regarding ‘false positive rates’).

Although I wish it wasn’t so, point in fact is that not all pregnancies are perfect; and, these screening tests can help detect completely unexpected aneuploid fetuses in young women who are at ‘low risk’ based on age alone, and also help to guide the ‘at risk’ woman in her decisions regarding the need for invasive diagnostic studies that could, potentially, put the pregnancy at risk by the procedure alone. Indeed, what I have learned in the two years that we have been offering “combined first trimester screening” (the topic for the next post) to ‘at risk’ women, is that most women end up with reassuring results, and sleep better as a consequence, and our number of invasive diagnostic procedures have declined dramatically with no increase in the number of chromosomally abnormal babies missed in women with ‘advanced maternal age.’ I have also learned over the years that some patients know they need to know (and need to be given the opportunity to find out); some patients don’t know they need to know (and benefit from unbiased counseling regarding the value and pitfalls of screening); and many (most?) don’t know what they would do with the information until after they find out.

If you haven’t gotten the message thus far, I believe that ALL pregnant women should be offered aneuploidy screening and I believe more would accept it if they got better counseling. The bottom line is that aneuploidy screening is recommended as a ‘standard of care.’ From the provider’s standpoint, there is proven liability associated with not offering it, not offering it in an unbiased fashion, and with inadequate documentation of informed consent and refusal. The greatest benefit to the patient is that in the vast majority of patients, it can reduce the ‘risk’ and therefore the anxiety related to possibly having an abnormal baby; reduce the need for invasive diagnostic procedures in many cases; and, in situations in which an aneuploid fetus is detected, it can provide time for preparation for the baby, or allow for timely decision-making for those who choose not to continue their pregnancies….

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Grand Thanks to Dr. R.W. Donnell

Thanks to Notes from Dr. RW and to Dr. Donnell himself for including my post regarding Infertility and Cervical Incompetence in patients with insulin resistance syndromes in his weekly edition of medical bloggers Grand Rounds vol. 10 no. 3

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What is Aneuploidy?

Recently, we did a routine ultrasound on a 16 year old in her first trimester to simply confirm her “dates” and found, incidentally, a baby with a large fluid collection on the back of its neck called a cystic hygroma. When this is identified in first trimester, more than 50% of the babies will be found to have a chromosomal abnormality. In the simplest terms possible, I tried to explain to her what that meant and how we could go about establishing the diagnosis. I knew I hadn’t gotten very far when her only question for me in the end was “Do you think the baby’s neck will look funny after it is born?” Since it was already late in the day, I asked her to think about things over night and return the next morning to talk with our genetic counselor. She did, and later that morning she had studies done that eventually confirmed the baby had an extra chromosome 21, or Down syndrome. Her own mother came with her after the diagnosis was made and could not understand how we could be correct because “My daughter isn’t 35 years’ old….”

Chromosomes contain the thousands of genes that orchestrate our growth, development, and biochemical functions. The normal human chromosomal complement is 46, or 23 pairs (22 pairs of ‘autosomes’ plus 2 ‘sex chromosomes’) with each parent contributing one chromosome per pair to the final genetic constitution of the baby. When a baby has too few or too many chromosomes, or even a small portion of a chromosome missing or extra, the baby is said to have a chromosomal abnormality, or aneuploidy. Most babies with an unbalanced amount of chromosomal material miscarry during the first trimester of pregnancy. Indeed, chromosomal abnormalities account for more than 50% of all spontaneous miscarriages in women who previously have had uncomplicated pregnancies. (Interestingly, they are NOT the most common cause of miscarriages in first pregnancies, a topic for a future post). Some babies with aneuploidy may be lost later in pregnancy and some will survive to be born.

There are a variety of ways by which a baby can end up with aneuploidy, and detailing all of these is not necessary for this post; however, the one that results in conditions with which the most people are familiar is an event called ‘nondisjunction.’ During the final step in gamete (egg or sperm) production, the 23 pairs of chromosomes must line up and then separate so that one of each pair is incorporated into the sperm or egg (oocyte), producing two gametes each with 23 chromosomes. When nondisjunction occurs, both chromosomes in a pair move together, resulting in one gamete with 24 chromosomes and one with 22 chromosomes. If one of these unbalanced gametes participates in the production of an embryo, assuming the correct number of 23 is contributed by the other parent, the baby will end up with a total of either 47 chromosomes or 45 chromosomes and be aneuploid, in this case with one entirely extra or too few chromosomes. Again, most of the time when this happens, the result is lethal, and the pregnancy ends spontaneously in miscarriage.

Examples of aneuploid babies that may survive through delivery with which many of you may be more or less familiar are an extra chromosome 21 (trisomy 21, or Down syndrome), an extra chromosome 18 (trisomy 18) or, rarely, an extra chromosome 13 (trisomy 13). Babies may also be born with missing or extra sex (X and Y) chromosomes (a normal female is XX and a normal male is XY). Common examples of this are, respectively, Turner’s syndrome (45 XO), affecting 1 in 2500 girls, and Klinefelter’s syndrome (47 XXY), affecting about 1 in 600 to 800 boys. Even most babies with any these chromosomal abnormalities are lost early in pregnancy.

Reasons for nondisjunction are poorly understood, but it is the event that is associated with increasing risk with increasing parental (especially maternal) age, and it is also the most common cause of aneuploidy at any age. In the case of Down syndrome, for example, the risk of delivering a baby with trisomy 21 is about 1 in 1250 for women at age 25, 1 in 1000 at age 30, 1 in 350 at age 35, 1 in 100 at age 40, and 1 in 25 at age 45. Risk for delivering a baby with any chromosomal abnormality is more than twice that for Down syndrome at any given age, i.e., 1 in 178 at age 35, 1 in 63 at age 40 and 1 in 18 at age 45. Because chromosomally abnormal babies can be lost throughout pregnancy, the chance of finding an aneuploid fetus is far greater earlier in pregnancy than at the time of delivery. For example, at age 35, the first trimester risk of finding a baby with trisomy 21 is 1 in 141 and in midtrimester it is only 1 in 270.

Discussions related to aneuploidy risks have become a daily routine in my practice because the trend over the past 30 years has been to delay childbearing until later in life. Data from the National Center for Health Statistics complied in 2002 demonstrated a drop in teenage birth rates to 43 births per 1000 (aged 15-19), a drop of 30% over the 10 year period from 1991; during the same time, birth rates for women aged 35-39 years increased to 41.4 per 1000, and for women aged 40-44, rose to 8.3 per 1000. These are the highest rates for women in these age categories ever recorded in the U.S. and the trend up seems to be continuing. So, in my next post, I will address issues related to aneuploidy screening….

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Thank you Paul S. Auerbach, MD

On Thanksgiving Day, I always try to reflect on the things I have been grateful for in my life. It dawned on me as I awoke yesterday morning that one of the people I have been most thankful for, and never told, is an old friend, and fellow Healthline blogger, Dr. Paul Auerbach. Bet you didn’t realize that, Paul!

Paul and I met about 37 years ago on an airplane headed for Durham, NC. We were just about the only two people on the plane and had been seated next to each other. I have never been much one to start up a conversation, and I was also terrified because it was my first time on an airplane, but Paul wasn’t shy about introducing himself. Turns out we were both finalists for A.B. Duke Scholarships at Duke University and they had paid for our transportation for the interviews. It also turned out that one of his best friends in high school in North Plainfield, NJ, had also been my best friend while I was in elementary School in Bridgewater Township. Small world!

Thanks to their generosity, Duke was the only school I would actually visit. My family was poor, my father had been very sick for several years, and there was no way my mother was going to be able to take time off to drive me around for college interviews with 5 younger brothers and sisters at home. Interestingly, other than Duke, I had actually applied only to a bunch of engineering schools and had applied to Duke only at the last minute because a friend of mine with whom I played football had told me that his brother went there and thought I would fit in well. As will be apparent by the end of this post, these ‘impulsive decisions’ have led me to where I am today. Anyway, to make a long story short, the minute I got off the plane in Durham, I fell in love with the place, the campus, and the people. I got home, told the engineering schools, I wasn’t coming (which is just as well because I would have made a lousy engineer), and in the fall of 1969, Paul and I started as freshman at Duke.

It wasn’t long after arriving there that Paul tracked me down one day and said, “Today, the Dean is meeting with all the premed students, and we have to go.” My comment was something along the lines of “I didn’t know that I was going to medical school.” Regardless, Paul insisted, and off we went to Page Auditorium to listen to what the Dean of premed students had to tell us. As I recall, about two-thirds of the freshman class at Duke was there. If that wasn’t intimidating enough, the premed Dean seemed to think that very few of us would ever be able to make the grade, especially if it required jumping through the hoops he detailed to us. Quite frankly, I agreed, and as I left the auditorium, my career in something science other than medicine seemed much more realistic. In fact, that was the last premed meeting I ever attended.

Over the next few years, I immersed myself in basic sciences, first thought about going into oceanography, but learned that I got seasick too easily, and then started doing research in the molecular biology of viruses. I hadn’t thought twice about medical school and since I had already been promised a slot in the graduate school by the Department of Biochemistry (if I could ever get around to filling out the application), I figured that’s where my future lay. But, my guardian angel, Paul, was not to be denied. Just before our senior year, he reminded me that I was already behind in filling out my applications for medical school. I told him about my graduate school plans (and my ambivalence about medical school) and his response was simply that I still needed “to fill out a few applications.” Since I really did not need to worry about graduate school and “there really wasn’t much to lose,” according to Paul, a few (I still didn’t have any extra money) applications to medical school were sent off. I didn’t know what I would do if I had to travel anywhere for an interview, or if I would go if I actually got into one of the schools to which I had applied. Besides, I was very happy, comfortable, and good at molecular biology.

As it turned out, I obviously did get in and go to medical school. And, except for my first day in Gross Anatomy lab, when I managed to stick a scalpel through the back of a finger in a basement laboratory with no air-conditioning, 100 degree heat, high humidity, and the air saturated with formaldehyde, I have not regretted the decision for a minute. It has been the ride of a lifetime and I cannot imagine having done anything else. So, on this Thanksgiving Day, thanks to Paul S. Auerbach, MD for being a friend, and knowing me better than I knew myself. Incidentally, my presence on this blog was also the result of Paul’s persuasiveness. I tried to talk myself, and him, out of my participation, but I am very glad now that that didn’t happen….

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Thank you Dr. Anonymous

Dr. A,
Thank you for including my Poignant Story post in your Grand Rounds this week. Mine wasn't the only 'poignant story' and the overall impact of this weeks' content is a refreshing change of pace. My compliments on the format and for trying something different. I know it probably took a little more work than usual to put things together, but I think it was worth it!

Best regards,
Dr. T

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Infertility and Cervical Incompetence: No Time for a "Stitch in Time" this Time

On Saturday night, we admitted a patient at only 19 weeks’ gestation with advanced cervical dilation, occasional contractions, and fetal membranes ballooning through the cervix into the vagina – a history consistent with severe cervical incompetence. Although she is only 26 years’ old, she had an 8 year-long history of primary infertility and this, her first pregnancy, was the result of ovulation induction and in vitro fertilization (IVF).

As in so many of these patients, there were multiple factors contributing to her infertility. She had been diagnosed with mild endometriosis in the past and had laparoscopic laser ablation for the same. She had had a small fibroid in the uterine cavity that was resected using hysteroscopy. Probably more significant with regard to her current problem, she was moderately obese, did not ovulate regularly, and had “insulin resistance” associated with glucose intolerance, elevated androgens (‘male hormones’), mildly elevated prolactin, and hirsutism (male pattern hair distribution). In addition to these factors, her husband had repeatedly had “low sperm counts.” Using drugs to induce ovulation and to reduce her insulin resistance, she had conceived with her first cycle of IVF. Although she worked as a nurse, the cost of her infertility care and the IVF had run more than $50,000 over the years and most of that was not covered by insurance.

I have learned that problems women have with infertility don’t go away with conception, and often contribute to complications during pregnancy. For example, the patient above was at increased risk for gestational diabetes and hypertensive disorders during pregnancy because of her hormonal ‘imbalances’ and ‘insulin resistance.’ Furthermore, patients who require ovulation induction and assisted reproductive technologies have a 3.5-fold risk of delivery less than 37 weeks, a 1.5-fold risk of having a low birth weight baby (less than 2500 g), and 1.8-2.6-fold risk of having a very low birth weight (VLBW) baby ( less than 1500 g). They have higher rates for these outcomes in both singleton and multiple gestations. In 2001, 57% of twins and 92% of triplets were born at less than 37 weeks; and, 10% of twins, 35% triplets, and more than 70% of higher order multiples resulted in VLBW babies with 80% of the triplets and higher order multiples resulting from interventions for infertility.

Reasons for these early deliveries and low birth weight babies are often written off as a consequence of multiple gestations or the medical complications these patients develop during pregnancy. But, many practitioners, including the infertility specialists who help these patients conceive, are not aware of the fact that such patients are also at extraordinarily high risk for cervical incompetence. The reason for this is not entirely clear to me. It could be the result of the underlying metabolic defects that lead to their insulin resistance, the insulin resistance itself, or some other unknown association that deleteriously affects the composition of cervical connective tissue. It also could be the result of the previous surgical procedures many of these patients undergo as part of their infertility evaluation and management that might compromise the integrity of the internal cervical os. Personally, I believe the ‘metabolic’ defect is the more significant but, regardless, when given the opportunity to counsel these patients preconceptionally, or in early pregnancy, I outline a course of management that includes ultrasound evaluation of the cervix during midtrimester to look, specifically, for evidence of cervical incompetence.

Unfortunately, the problem our patient encountered occurred even earlier than usual for this group of ‘at risk’ patients. Most of these individuals do not exhibit this degree of cervical change before 20 weeks’ during their first pregnancies. Even more unfortunately, there was nothing that could be done for her because of the advanced cervical dilation and the membranes stretched and bathed in the unsterile environment of the vagina at the time of her transfer to our service. We have a relatively good track record with ‘rescue cerclages’ prior to complete prolapse of the membranes, but once that occurs, delivery is usually inevitable and, even if a cerclage can be placed, this is almost always followed by infection and spontaneous rupture of membranes necessitating delivery of the pregnancy. Although we provided her with counseling and educated her to the fact that she has an incompetent cervix that will require cerclage placement early in a subsequent pregnancy, that is little consolation for the disappointing loss of a baby for which she had invested so much time, emotion, and resources in conceiving and carrying.

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Late Preterm Birth - AGAIN

The other night I was preparing a Grand Rounds’ presentation on late preterm birth for the next morning. There was going to be a large group of resident applicants in the audience, and the competition for the cream of the graduating medical school students going into OB/GYN has gotten intense in recent years, so I wanted to make a good impression for our department. But, I could sense the talk was missing something; the inspiration for putting the finishing touches on the talk was also being interrupted by periodic pages to the labor and delivery unit because I was on call that night in the hospital.

At about 11:00 PM, the muse arrived in the form of a phone call. A physician in our perinatal catchments area had been caring for a 26 year old woman who was having her first baby. She was “about 37 weeks” and had told him that “the baby wasn’t moving as much as usual.” To assess fetal well-being, he had done a nonstress test that was “reassuring” and, despite this, had also done a contraction stress test that was “reassuring” as well. When I asked if there was “normal fluid” and if the baby was “normally grown,” the answers to both those questions was “yes” and “there had been no other complications to date in the pregnancy.” Then he told me that the patient “is a nurse on labor and delivery and a friend” and at that point, I knew exactly where the conversation was going…

“Because she was so late in the pregnancy, and she was worried, we went ahead and induced labor anyway.” Since her cervix was very unfavorable for induction, he had used a drug called misoprostol to “ripen the cervix and start the induction.” Her uterine contractions became too frequent on this and he could not be sure that the fetal heart rate pattern was still reassuring, so a cesarean section was performed for the delivery at 3:00 PM that afternoon. Shortly after delivery, the baby developed respiratory difficulties and needed to be transferred to our neonatal intensive care unit (NICU). He was calling now to see if I could accept the woman in transfer so that “she could be with her baby.” After we admitted her at 3:00 AM, I finished off my Grand Rounds preparations by including her ‘case report’ in the presentation.

We have previously discussed that about 13% of all births in the U.S. are preterm (less than 37 weeks’). The major contributor to the continuing rise in PTB over the past two decades has been late preterm births at 34-37 weeks. Indeed, these now comprise approximately 75% of all preterm deliveries, or more than 300,000 babies per year, and more than 75% of these babies come from Hispanic and non-Hispanic white populations. The rise in late PTB has been paralleled by the rise in births to women over 30, the rise in induction rates, and the rise in primary and repeat cesarean deliveries. At least half of all late PTB babies are delivered by cesarean section. Unfortunately, at least half of all late preterm deliveries are ‘iatrogenic,’ resulting from marginal maternal or fetal indications for delivery or inadvertent intervention because of uncertainty related to gestational age.

Although the relative risk for severe neonatal complications is fairly low, the cumulative risk, secondary to the large number of babies, is high. Many of these babies are delivered, intentionally or unintentionally, at Level 1 or Level 2 facilities and start off life in the normal newborn nursery. Under these circumstances, they may not be identified or managed as ‘preterm’ babies and this can result in delayed recognition of neonatal complications such as respiratory distress, hypoglycemia (low blood sugar), hypothermia (low body temperature), and pulmonary hypertension. These conditions result from ‘delay in transition’ from intrauterine to extrauterine life, can be quite serious, and require a higher level of monitoring and support than that available at many local hospitals. Other complications, such as jaundice related to hyperbilirubinemia and feeding problems, may not be recognized until days after discharge from the hospital, but also can have serious consequences. Delayed recognition of any of these problems can result in delayed transfer to a tertiary care center that, by itself, is well known to be correlated with greater risk for neonatal morbidity and mortality.

Late preterm birth means a lot more than the baby having to spend a few extra days in the hospital. Neonatal and infant mortality among these babies is 3- to 4-fold that of their term counterparts. As illustrated in our ‘case report,’ late PTB is associated with higher rates of NICU admission (inborn and by transfer), greater lengths of hospital stay, higher risk for hospital/NICU readmission, and a dramatic increase in health care costs. It is estimated that the average late PTB baby that requires special care adds $20,000 to $60,000 to the expenses expected at term. Although there is not much data at present to tell us the long-term morbidity and lifetime cost resulting from the complications of prematurity related to late PTB, commonsense tells me that these will be quite significant.

After presenting Grand Rounds, I went back to see the subject of our ‘case report.’ Her baby was doing well in the NICU, but she looked at me sheepishly and said, “We didn’t do right, did we?” I tactfully avoided answering the question, directly, because she already knew the answer, but I did take the opportunity to praise our NICU team and to tell her that I thought that “everything would turn out alright……this time.”

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November 14, 2006: National Prematurity Awareness Day

Today has been designated National Prematurity Awareness Day. I know I have devoted several posts to preterm birth (PTB), and actually have several more that will eventually be committed to this blog, but in recognizing today’s significance, it is worth summarizing some of the facts related to PTB.

• Premature births (less than 37 0/7 weeks’ gestation) now account for 1 out of every 8 deliveries in the United States and have now surpassed fetal abnormalities as the leading cause of neonatal mortality, accounting for 25% newborn deaths in the first month of life

• Rates have increased more than 30% since 1981, from 9.4% then to 12.8% now

• More than 500,000 babies are born prematurely in this country each year

• Estimates of the cost of prematurity exceeded $26.5 billion in 2005, or about $51,600 per baby (15 times the cost of a baby born at term)

• Premature babies are at greater risk for long-term complications that may continue to compromise them and put a burden on the health care system throughout their lives

• Despite a March of Dimes campaign starting in 2003 to increase the awareness of PTB and decrease rates to 7.6% by 2010, rates have continued to increase annually

• The very preterm birth rate (less than 32 weeks’) has remained relatively constant at 1.8% to 2.0% for the past 20 years

• The increase in PTB can be almost entirely accounted for by an increase in deliveries between 34 and 37 weeks’ (late preterm births) which now constitute more than three-fourths of all singleton preterm births

• A significant percentage of late preterm births are by cesarean delivery (more cost; greater maternal risks)

• There is a growing awareness that late preterm birth can be associated with higher morbidity (respiratory distress syndrome, hypoglycemia, hyperbilirubinemia, hypothermia - poor temperature control) that increase initial cost of care, increase risk of rehospitalization during the first month of life, put the baby at risk for long-term complications, and increase cost related to sequelae of prematurity

• A significant portion of late preterm births are iatrogenic (elective cesarean; induction of labor) and might be avoided by careful attention to confirmation of gestational age, to more stringent scrutiny of indications for early delivery, and to predelivery assessment of fetal lung maturity in situations when dates or indications are not clear

• Patients and providers need to be educated in this area and widespread efforts must be made to reduce the incidence of late preterm birth

Short of large, comprehensive, expensive (but a good return on investment for those willing to listen) programs for preterm birth prevention, which seem to get more lip service than support, there clearly are interventions that could reduce not only late preterm birth, but also a significant number of babies destined for very preterm birth, or at least lengthen the gestational age at delivery of the latter. Early confirmation of gestational age, identification of risk factors, and focused interventions (progesterone therapy; cervical cerclage; smoking cessation programs; emotional support) based on early and ongoing risk assessment can be done now. The only question at this point is what will patients, providers, and society be willing to do to make it happen….?

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A Poignant Story

Maternal-Fetal Medicine can be a rough business sometimes. The highs are great, but the lows can keep you down for days. I have always tried to abide by the admonition in the House of God that one should always remember “the patient has the disease,” but sometimes that really is easier said than done. I can usually keep things in perspective, explaining complicated problems to patients at most levels of understanding in a way that they can appreciate the basic issues, while maintaining a reasonable level of emotional distance myself, but the other day, I got blind-sided. It is a poignant story and is worth relating to my readers. Situations that tug at the heart remind us that feeling is a privilege that we should not take for granted.

I was called in to see a very poor Hispanic woman who was having her sixth baby. She had been sent because one of the baby’s kidneys could not be seen by ultrasound. She had had one son, the oldest child, about 11 years old, who was actually with her in the room as her only support person that day, followed by four daughters. She made it clear at the outset that she desperately wanted another son and had been told that this baby was, indeed, a boy. She was poorly educated, very frightened, and very anxious and communication with her, even with an interpreter, was limited because she spoke a ‘dialect.’

The ultrasound exam went very smoothly. The baby was appropriately grown and consistent with her ‘dates.’ She was about 33 and a half weeks’ and due on Christmas day. The baby was found to have a multicystic dysplastic (nonfunctional) kidney on the left side. But, the right kidney, ureter, and bladder were normal and all were working well because the baby had normal amniotic fluid (mostly fetal urine this late in pregnancy). The baby had no other visible abnormalities. In the simplest terms possible, I explained to her that the baby had only one kidney, but that he should do just fine after birth. Many people have only one kidney and this baby’s one good kidney had enlarged to compensate for the other kidney and should be able to support him through a long and normal life.

Despite my reassurances, and my insistence that I was not holding anything back, that we had seen many babies in this situation and all had done well, she began sobbing softly. I was at a loss for words but, at this point, her son reached out and grasped her shaking hand, softly stroking her fingers and telling his mother that everything would be all right, and that he could not wait to see his new brother and to help take care of him. She relaxed immediately with his touch, looked into his eyes, and began to smile herself. He was an angelic child, mature, handsome and soft-spoken, and he obviously had a much firmer grasp of the situation than his mother. I thanked him for his help and told him that his brother would be a wonderful Christmas present for him and his family and his eyes sparkled. I looked at him, nodded my head in gratitude, smiled, and then got up to leave. In the dim light of the exam room, I noticed that his skin was ashen and his lips were parched.

As I walked to the door, the interpreter came toward me and then clutched at my arm as I was going out the door. She thanked me for my help with the woman and then told me that she knew the family well. When I asked her if they were related, she looked back in the direction of the woman and her son and told me, “No, but you know that boy with her, he is her oldest child and her only son. She is upset because she really wants the baby to be normal. All the interpreters are close to them because her son is dying of leukemia and can’t have any more therapy. He just wants to live until Christmas to see his new brother before he dies.….”

I was glad I was at the door when she told me that. It had been a long week and I was tired, but the tears in my eyes would have been there regardless. And you know what; they come back each time I tell this story to someone, even now while I am writing it down. Life is short, and shorter for some than others, but we can all contribute something in our own way in the little time we have…

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Maternal Serum Screening in Midtrimester

Prenatal maternal serum screening in midtrimester (AFP, estriol, hCG, and inhibin-A) is without doubt the most misunderstood test routinely offered to women during pregnancy. Misconceptions and uncertainty abound on the parts of both patients and providers related to necessity, interpretation, and potential significance of this test. As a result, this test is vastly underused, even though it is recommended as a standard of care by the American College of Obstetricians and Gynecologists, and liability exists when not offering screening, when the case for screening is offered in a biased fashion, and when inadequately documenting that the test has been offered and declined.

Summarized below are comments, observations, and responses to common questions that have helped me to improve patient (and provider) acceptance of this valuable screening tool during my 20-odd years in the practice of maternal-fetal medicine:

1. What is Prenatal Maternal Serum Screening?

Maternal serum screening is a blood test done on the mother that measures several chemicals that are either unique to, or associated with, pregnancy. It is most accurate when done between 16 and 20 weeks’ of pregnancy.

2. What is the primary purpose of the test?

The test is performed to help identify babies at risk for neural tube defects (openings in the spinal column or head) and other open body wall defects (most commonly abdominal wall) as well as certain chromosomal abnormalities, such as trisomy 21 (Down syndrome) and trisomy 18. These latter abnormalities are usually unexpected, may occur at any age, and typically do not run in families.

3. Are there other benefits of the test?

Additional fetal abnormalities and pregnancies at risk for complications of “placental insufficiency,” such as fetal growth restriction, hypertensive disorders of pregnancy, fetal death in utero, and premature delivery may also be identified by abnormal test results.

4. What benefit is there in knowing the baby may have an abnormality or there may be a placental abnormality that could lead to complications?

In some cases, known abnormalities can benefit from corrective measures taken before delivery that may decrease morbidity. In other circumstances, awareness of certain abnormalities will help us to advise the patient on the best place to deliver the baby. At the very least, awareness allows the physician to provide information and counseling to help the patient and her family prepare for birth as well as events and decisions that might follow delivery. This proven benefit should not be denied to any patient because, in some instances, the time a family may have with the baby following birth may be limited.

5. Does an abnormal test result mean something is wrong with the baby or the pregnancy?

Not necessarily. It is a screening test rather than a diagnostic test. Abnormal results do NOT automatically mean that a baby has a problem or condition, but it does mean the pregnancy has a greater risk and needs further evaluation. Screening tests are designed to identify, and avoid missing, certain abnormalities; to do this most effectively, they may be accompanied by high “false positive” rates, i.e., situations where abnormal test result lead to further tests that reveals no problem Approximately 5% of maternal serum screening tests require further evaluation. Recently, a fourth biochemical marker (dimeric inhibin-A) has been added to the serum screen, which reduces the false positive rates for risk assessment of aneuploidy (chromosomal abnormalities). It is true that the more abnormal the test, the greater the likelihood there will be a problem with the baby or a pregnancy complication.

6. Are there “normal” conditions that can cause an “abnormal” test result?

Yes. Conditions such as twins or a pregnancy that is further along or less along than expected are common causes of abnormal test results. Nevertheless, unless a clear reason exists (e.g., 4 weeks off on dates) for the test abnormality, it is recommended the patient receive counseling and a targeted sonogram. Even if twins are found as the result of follow-up of an abnormal serum screen, a targeted scan is indicated because multiple gestations are at higher risk for birth defects and placental abnormalities.

7. How is a pregnancy with an abnormal test result evaluated further?

Under ideal circumstances, an abnormal test result is best managed by collaborative consultation with a genetic counselor and a specialist in maternal-fetal medicine. A good genetic counselor provides up-to-date, accurate, and unbiased information as a foundation for further evaluation; this professional also serves as a focal point for additional counseling if an abnormal pregnancy is eventually detected. The genetic counselor should see the patient even before a targeted sonogram is performed to educate and prepare the patient for indications and options regarding further testing. Patients who have abnormal screens, but apparently normal babies, are still at risk for placental insufficiency syndromes. Doppler flow studies in mid-trimester, which measure blood flow resistance patterns in the umbilical cord, brain, uterine arteries, and sometimes other blood vessels, may anticipate these because abnormal Doppler flow patterns usually precede significant deviations of fetal growth.

8. Who follows a patient if an abnormality is found?

Usually, the patient can continue to receive routine prenatal care, and perhaps even delivery, with her primary care provider. Even if an abnormality is found that will be best handled at a tertiary care center, the patient often can be followed at home until delivery. Depending on the abnormality, follow-up consultation with the genetic counselor and maternal-fetal medicine specialist and care team will also be recommended.

9. What can be “done” if an abnormal pregnancy is found?

That decision is ultimately up to the patient. It is the responsibility of the healthcare team to provide the patient with sufficient information, depending on the specific diagnosis, to make decisions with which she feels comfortable. In some cases this involves intervention by MFM specialists, or referral to other tertiary sites that may specialize in the management of a particular abnormality. Other circumstances may involve preparation for delivery and consultation with specialists who will coach the patient through decisions that will have to be made at that time. Actions range from finding appropriate support groups for the patient to terminating the pregnancy. The latter is of great concern to patient and providers alike, and it is the option that is chosen least for further management of pregnancies involving non-lethal abnormalities.

10. Is the patient at risk for aborting a “normal” baby because of a suspected abnormality?

No recommendations or decisions regarding pregnancy outcome are EVER made based on the maternal serum screening test alone. While this may seem obvious to providers, it is not so clear to many patients. Many patients choose not to have screening done because they are concerned about the “false positive” rates. They tend to extrapolate this occurrence to mean they might have to make a decision that could lead to termination of a pregnancy that is really normal. With current diagnostic tools, a patient today should never find herself in this situation.

11. If a provider is hesitant to recommend routine maternal serum screening, are there certain indications where this is readily justifiable?

Yes. Examples include patients who have had poor obstetrical outcomes, intrauterine growth restriction, severe preeclampsia, insulin-dependent and pregestational diabetes, autoimmune disorders, known thrombophilia, recurrent pregnancy loss, infertility, placental abruption or accreta, fetal demise of unknown etiology, previous child with chromosomal abnormality or syndromic problem, family history of certain birth defects, and other conditions associated with placental insufficiency syndromes.

Now that we have had the opportunity to address midtrimester maternal serum screening, we will be in a better position to discuss first trimester screening in a subsequent post. It is very likely that this will become the new standard of care within the next 5-10 years…..

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HAPPY ANNIVERSARY RITA!!!!

Thanks to Rita at MSSPNexus BLOG for including my post on the importance of preconceptional counseling in the SECOND ANNIVERSARY edition of your Medical Grand Rounds! It is quite flattering to be included amongst such an erudite 'faculty.' For those of you who haven't seen this site, you are missing out on a great source of information, and in this week's edition, a great laugh as well. Thanks again Rita and keep up the wonderful work!

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Importance of Fetal Heart Evaluation

Early last week, a 17 year old woman, carrying her first baby, was seen in the office for a routine ultrasound at about 18 weeks’ to confirm gestational age and assess fetal anatomy. During that examination, the baby was found to have a heart abnormality called an endocardial cushion defect, or A-V canal. This particular abnormality is very common in babies with trisomy 21 (Down Syndrome). She was informed of this association and offered an amniocentesis which confirmed that diagnosis. At her age, the expected risk of having a baby with trisomy 21 is approximately 1 in 2000, and the overwhelming likelihood is that the diagnosis would not have been made until the time of delivery if a thorough evaluation of the fetal heart was not part of even our most routine examinations.

Fetal heart abnormalities are found in 0.4% to 1.1% of all live births. Such defects are the most common abnormalities detected following delivery and these are the leading cause of infant mortality related to birth defects. More than one-third of all malformations found after delivery are congenital heart defects (CHD); despite the widespread use of ultrasound during pregnancy, only 4-7% of malformations detected before delivery are cardiovascular defects. Thus, the vast majority (80-90%) of fetal heart abnormalities are not suspected prior to the birth of the baby. Prenatal diagnosis of CHD can be difficult, but is valuable because outcome for certain abnormalities can be dramatically improved by accurate diagnosis and adequate preparation.

Obstacles to performing a fetal heart evaluation can be the result of many factors: fetal heart size (only about 2 cm at 18 to 20 weeks); rapid heart movement; fetal movement; fetal position; placental location; maternal habitus; and, calcification of the skeleton, especially, the rib cage and upper extremities at later gestational ages, that causes ‘shadowing’ of the cardiac silhouette. Nevertheless, even practitioners without specialized training can improve CHD detection by paying careful attention to the heart during routine fetal ultrasound evaluation and by having a low threshold for referral to centers that can perform a more thorough cardiac examination. This threshold can be based on actual suspicious diagnostic findings (remember, it is much more important to recognize or suspect that something is 'not normal' than to know what the abnormality actually is!), by the inability to visualize adequately the fetal heart (never assume something is normal if you cannot see it!), and by attention to CHD risk factors.

Approximately, 90% of major cardiac malformations can be ruled out by methodically evaluating an adequate '4-chamber view' of the fetal heart. Documentation of a good 4-chamber view remains the standard of care for evaluation of the fetal heart in the office setting when an anatomic survey is performed. The optimum view for this evaluation is obtained with the fetal back down and with the cardiac axis at 30-60 degrees to the plane of the transducer. In this view, the cardiac axis, integrity of the interventricular septum, comparability of the chamber diameters, and free movement of the atrio-ventricular valves (mitral and tricuspid valves) can be readily assessed using ultrasound equipment currently available in most office settings. In more experienced hands, evaluation of the pulmonary venous return to the left ventricle can also be seen in this view. A suspected abnormality of any of these parameters, or the detection of a cardiac arrhythmia noted during the study, is an indication for a thorough fetal echocardiogram. A ‘targeted’ scan (detailed anatomical evaluation) is also recommended if noncardiovascular abnormalities are found due to the increased likelihood of cardiac malformations associated with other congenital defects. Major limitations of the 4-chamber view alone are inadequate assessment of the aortic and pulmonic outflow tracts, the aortic and ductal arches, the major branches of the pulmonary tree, and the vena cava.

Risk factors for CHD include family history; previously affected baby; pregestational diabetes; advanced maternal age; multiple gestation; use of certain prescription medications (e.g., lithium; anticonvulsants; isotretinoin); polysubstance abuse; autoimmune disorders; and, known phenylketonuria. Although CHD is often considered to be the result of multifactorial contributions, a strong family history warrants genetic counseling and possible evaluation for specific genetic markers such as the chromosomal microdeletion 22q11.2. If a woman has had one affected child, the risk to a subsequent child is 2-5%; if two affected children, subsequent risk is 5-10% or higher. If the mother herself has had a congenital heart defect, the risk to her offspring can be as high as 18%; if there are two affected first-degree relatives, the risk can approach 50%!

In addition to these risk factors, other indications for fetal echocardiography include: intrauterine growth restriction and, occasionally, macrosomia (big babies); suspected exposure to certain teratogenic viruses (CMV, rubella); nonimmune hydrops; abnormality of amniotic fluid volume; and, known or suspected fetal chromosomal abnormality. Maternal morbid obesity is associated with greater risk of various congenital abnormalities, especially neural tube defects and cardiac malformations, and is an independent risk factor that warrants a targeted sonogram that includes more complete evaluation of the fetal heart than can ordinarily be performed in the office setting.

A major reason for detecting CHD in the fetus is to ascertain the optimum site for delivery. Minor abnormalities, unlikely to need immediate attention, often permit a safe delivery at the primary care facility. Babies with more complex abnormalities are better delivered at a tertiary care center. Such is the case with the prenatal diagnosis of a group of disorders called ‘ductal dependent abnormalities’ such as hypoplastic left heart sequence, pulmonary atresia, transposition of the great arteries, severe Tetralogy of Fallot, critical aortic stenosis, and severe coarctation of the aorta. These abnormalities place the baby at increased risk for sudden decompensation if the ductus arteriosus closes before the cardiac malformation can be addressed medically or surgically. If these conditions are suspected before delivery, arrangements can be coordinated, time permitting, for the patient and her fetus to be evaluated at a facility that can best provide appropriate support services following the birth of the baby.

New advances in sonographic techniques will further improve the detection and the accuracy of prenatal diagnosis of CHD. Measuring the nuchal translucency (clear space between the skin and underlying soft tissues of the baby’s neck) at 11-14 weeks’ gestation by specially certified individuals has not only been proven to increase the early detection of aneuploidy (chromosomal abnormalities), but is also of great value in detection of major cardiac malformations in euploid ( chromosomally normal) fetuses. A chromosomally normal fetus with a nuchal translucency greater than the 95th percentile has a 1 in 23 chance of having a major congenital heart defect. Using this indicator of risk to guide further diagnosis, many major heart defects can be accurately defined sonographically by 14-16 weeks’ gestation.

In addition to earlier diagnosis, more specific categorization of abnormalities is now possible later in pregnancy using 3D/4D sonographic technology. A complete 4D 'volume' of the heart can be rapidly obtained in the 4-chamber view and then can be analyzed following acquisition using post-processing software capable of reconstructing the heart and vasculature, permitting detection of abnormalities not readily visualized in 'real-time.' This approach is revolutionizing the evaluation of the fetal heart, minimizing the time and frustration of the real-time fetal echocardiogram, and improving the accuracy of diagnosis.

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