Grand Rounds 4.36 at Parallel Universes!

Many thanks to Parallel Universes for this week's rendition of Grand Rounds 4.36 and for including a link to my recent post on the Evaluation and Management of Polyhydramnios.

The evaluation of amniotic fluid is an important part of every pregnancy and understanding the causes, complications, and management of the pregnancy with abnormalities of amniotic fluid, and being able to translate that information into understandable terms for the patient, is a necessary part of the daily routine of any obstetrical provider. I hope both patients and providers will find his series on amniotic fluid useful in that process! Thanks to all of you for reading!
Dr T

Labels: amniotic fluid; AFV

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Amniotic Fluid - 8 - Evaluation and Management of Polyhydramnios

In the last couple of posts we have reviewed causes and complications related to excessive amniotic fluid, otherwise known as polyhydramnios or, simply hydramnios. Although 50-60% of cases of hydramnios are idiopathic (no identifiable cause) and about 90% of cases are mild to moderate, about 10% are severe and these latter are the more likely to be accompanied by considerable fetal and neonatal morbidity and mortality secondary to an underlying fetal cause of the hydramnios – chromosomal abnormality, congenital anomaly, fetal anemia, inborn error, or congenital infection. Evaluation of the pregnancy with hydramnios, therefore, focuses primarily on these concerns.

The first step in any evaluation of hydramnios is to take a detailed medical, obstetrical, and family history and to review the course, medical complications, and basic laboratory studies performed to date in the current pregnancy. It is not necessary to cover the extent of such a discussion herein but examples of pertinent information include: the current pregnancy being a multiple gestation; a previous pregnancy accompanied by hydramnios, fetal macrosomia, or diabetes (and the outcome of that pregnancy); known maternal diabetes; known Rh- or other isoimmunization; history of blood transfusion; hemorrhage or trauma during the current pregnancy; history of known/suspected exposure to parvovirus B19 (Fifth’s disease) or illness accompanied by fever and/or rash during the current pregnancy; exposure to young children at home or in the workplace; family history of inborn errors of metabolism or congenital birth defects – particularly, cardiac, gastrointestinal, and neural tube, and neuromuscular disorders; past or family history of aneuploidy or recurrent pregnancy loss; advanced maternal age; report of decreased fetal movement; maternal history of medications and nonprescription (licit and illicit) drug use during the pregnancy. It is also important to get some feel for the onset of the hydramnios related to timing in pregnancy (e.g., gestational age when noticed; slow onset vs. rapid onset) and maternal signs and symptoms of disease and cardiorespiratory compromise.

The next step is to perform a thorough, high resolution ultrasound examination. In this, the degree of hydramnios should be documented objectively by a four-quadrant amniotic fluid index (AFI). This will be valuable as a ‘baseline’ for comparison during subsequent ultrasound evaluations of the pregnancy. Fetal growth should be assessed to determine if the baby is abnormally large or growth-restricted for the gestational age of the pregnancy – either of which might help narrow down the differential diagnosis. A detailed anatomical survey of the baby should include: central nervous system and spine; face and facial midline structures; neck; thorax; heart and rhythm; diaphragm; gastrointestinal tract; genitourinary tract; and, extremities. In addition, it is important to document whether or not the baby appears to have normal movement – flexion and extension – of the extremities since, if this is not present, it might suggest an underlying neuromuscular disorder. Evidence of fetal hydrops (indicative of fetal anemia or high-output cardiac failure) should also be sought.

If there is a twin (or higher order multiple) gestation, it is important not only to assess fetal growth and anatomy, but to determine chorionicity of the twins (i.e., dichorionic-diamnionic; monochorionic-diamnionic; or, monochorionic-monoamnionic) and if there is any significant discordance for growth or amniotic fluid surrounding the babies. Twin pregnancies are at higher risk for fetal anomalies, chromosomal abnormalities, abnormalities of placentation, and in monochorionic twins, a condition called ‘twin-to-twin transfusion syndrome (TTTS)’ (a discussion of which will be reserved for another post at another time).

A critical step in the evaluation of the pregnancy complicated by hydramnios (as it was in that complicated by oligohydramnios) is performing Doppler flow velocimetry (DFV) studies. These should be done at least on the fetal umbilical and middle cerebral arteries (MCA) and should be considered for the fetal ductus venosus and umbilical vein and the maternal uterine arteries. The goals of DFV under these circumstances are to ascertain if there is any difficulty perfusing the placenta (increased resistance indices) from either the fetal or maternal side; assess whether there is any evidence of fetal blood flow redistribution (“cranial sparing”) related to relative ‘placental insufficiency’ (decreased resistance to blood flow in the MCA); if there is increased peak systolic velocity (PSV) of blood flow in the MCA which would be suggestive of significant fetal anemia; or if there is evidence of fetal cardiac decompensation (abnormal wave forms – increased resistance or pulsatility - in the fetal ductus venosus or umbilical vein). DFV is a critical evaluation in the monochorionic twin pregnancy, especially if there is discordance for growth and/or amniotic fluid, that might help differentiate simple intrauterine growth restriction, or hydramnios related to aneuploidy or fetal anomalies, from TTTS.

Once a comprehensive ultrasound has been completed, a discussion should be held with the patient about what else can be done at this time, diagnostically and therapeutically, if indicated. Again, a detailed discussion of this is beyond the purpose of our post today, but some examples are as follows depending on the findings: 1) If the baby is growth-restricted and/or has visible abnormalities (major structural or subtle), an amniocentesis should be offered for fetal chromosomal studies and congenital infection, particularly, for cytomegalovirus (CMV). 2) Growth restriction with hydramnios and abnormal resistance to fetal placental-perfusion by umbilical DFV carries about a 50% chance of aneuploidy, even in the absence of visible abnormalities, so fetal karyotype should be encouraged with this combination of findings as well; 3) If there is increased PSV (> 1.5 MoM) in the fetal MCA, even in the absence of hydrops fetalis, then the baby may need to be evaluated for significant anemia – best done by percutaneous umbilical blood sampling (PUBS) with preparations made for coincident transfusion. This becomes even more critical if the baby already has hydrops; 4) If a fetal arrhythmia has been identified, medical therapy should be attempted to correct this condition; 5) If a twin gestation is present and there appears to be TTTS, then the patient should be counseled and offered a referral to one of the few sites in the country with the expertise to handle this condition.

As a routine part of maternal evaluation, especially if no readily apparent cause of the hydramnios is identified by ultrasound, I will frequently recommend the following: blood type and antibody screen; thyroid studies; a full 3-hour glucose tolerance test (unless the patient has already been diagnosed with diabetes); serologic testing for evidence of recent CMV or Parvovirus B19 infection and consider screening for toxoplasmosis and syphilis. If a woman is a known diabetic, I will include a hemoglobin A1C level and make efforts to optimize her diabetic control.

If a correctible cause for the hydramnios, such as fetal anemia, has not been identified and/or there are significant risks to the pregnancy because of the hydramnios itself, especially, if the pregnancy is less than 30 weeks and there is premature labor to contend with, or the mother has developed cardiorespiratory compromise secondary to massive hydramnios, there are limited options for management. Acute management of maternal cardiorespiratory decompensation may require amnioreduction. This is an amniocentesis procedure in which a large bore needle/catheter is inserted into the uterus and the fluid slowly drained until the AFI is in a ‘normal’ range of 10-20 cm. The most common risks to this procedure are rupture of membranes, premature labor, and placental abruption if the fluid is decompressed too rapidly. Unfortunately, since under normal circumstances, amniotic fluid volume is replaced daily, the fluid will often reaccumulate within 48-72 hours, necessitating repetitive procedures. Under these circumstances, the risk of the previously noted complications, as well as of infection, increase further.

As an adjunct to amnioreduction, or if the situation is not so acute, another option is to use potent prostaglandin synthetase inhibitors that have the effect of decreasing fetal urine production (and, hence, amniotic fluid) and may also decrease uterine contractions that usually accompany hydramnios, thereby, decreasing the risk of premature labor. Indomethacin has had the widest experience in this regard and is relatively safe for both mother and baby. After an initial loading dose of 100 mg, I will frequently place the patient on 25-50 mg of indomethacin every 6 hours. It usually takes at least 4 days (sometimes much longer) to get any response to this regimen. Once indomethacin has been started, it is important to monitor both amniotic fluid and the fetal ductus arteriosus which can constrict in response to the drug and is a primary means of maintaining the “fetal circulation” (bypassing the lungs and allowing proper distribution of well-oxygenated blood throughout the body) while the baby is in utero. One must be especially careful about using indomethacin in women who have underlying kidney problems, cardiac disease, long-standing diabetes, hypertensive disorders, pregestational and pregnancy-related preeclampsia, or evidence of infection because if their renal output also drops significantly, they can be pushed into congestive heart failure.

Another prostaglandin inhibitor that has also been tried, and with which I must admit limited experience, is sulindac (usually dosed at 200 mg every 12 hours). Sulindac has greater selectivity for the cyclooxygenase 2 (COX-2) enzyme and appears to be capable of reducing fetal urine output with less of an effect on the ductus arteriosus, although its effect on the fetal kidneys is also less than that of indomethacin. It may be safer to use later in gestation than indomethacin which I will usually stop at 32 weeks (and no later than 34 weeks) gestation. The risk of premature delivery is so high with severe hydramnios requiring amnioreduction and/or prostaglandin inhibitor therapy that I often couple their use with a course of corticosteroids to accelerate fetal lung maturation in the event that delivery occurs or becomes necessary.

In closing, I would like to mention only one other caution about hydramnios that is often over-looked with regard to my last statement in the paragraph above. If hydramnios is present and associated with diabetes and/or fetal macrosomia, fetal lung maturation may be delayed as much as 2-3 weeks as the result of hyperinsulinemia in the baby. Hyperinsulinemia suppresses the development of lung surfactants and one last study that should be considered, and is highly recommended, prior to the elective delivery of baby because of hydramnios, or macrosomia, is an amniocentesis to assess fetal lung maturity, especially if the planned delivery is by cesarean section.

Well, this concludes our series on amniotic fluid. As I said at the outset, evaluation of amniotic fluid is an important part of every pregnancy and understanding the causes, complications, and management of the pregnancy with abnormalities of amniotic fluid is a daily part of my routine. I have tried to make our discussions digestible for the nonclinician as well as a valuable overview for the primary care professional involved in the care of women during pregnancy and hope that we have accomplished that here! Thanks for reading!
Dr T

Labels: CMV, diabetes, Doppler flow velocimetry, fetal macrosomia, polyhydramnios

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Amniotic Fluid - 7 - Complications Related to Polyhydramnios

When excessive amniotic fluid (polyhydramnios or, simply, hydramnios) is present, there are increased risks of complications for both mother and baby. Some of the risks to the baby are obvious if there is an identifiable etiology for the hydramnios, such as maternal diabetes, multiple gestation, congenital malformation, chromosomal abnormality, severe fetal anemia secondary to isoimmunization or Parvovirus B19, neuromuscular disorders, or congenital infection. Indeed, past reviews confirm the risk for poor outcomes when an etiology is found. For example, Stoll and colleagues (Community Genet 1999;2:36-42) identified 290 cases of polyhydramnios in 225,669 consecutive pregnancies and diagnosed congenital malformations prenatally in 44.5% of the cases. Among these, 10.3% of the infants were stillborn, 41% had more than one malformation, 14.5% had a chromosomal abnormality.

Similarly, Biggio and colleagues (Obstet Gynecol 1999;94:773-7) compared 370 women with singleton pregnancies beyond 20 weeks' gestation and hydramnios with 36,426 controls who had normal amniotic fluid volumes. “The perinatal mortality rate in all women with hydramnios was 49 per 1000 births, compared with 14 per 1000 births in the control group (P < .001). Women with hydramnios had 25 times more anomalies than controls (8.4% versus 0.3%; P < .001)…the cesarean rate was three times higher in women with hydramnios compared with controls (47.0% versus 16.4%; P < .001).” Interestingly, in their study, the increased risks were concentrated in the nondiabetic women with hydramnios.

However, as we mentioned previously, 50-60% of hydramnios is idiopathic (without an identifiable cause). So the question remains, are there increased risks to the baby if no identifiable etiology for the hydramnios is found? In other words, does the excessive fluid alone seem to contribute to or be associated with poor perinatal outcome. The scientific literature would indicate that it does. For example, Magann and colleagues (Obstet Gynecol Surv 2007;62:795-802) recently presented an extensive review dating back more than 50 years and found that idiopathic hydramnios was linked “to fetal macrosomia (in the absence of diagnosed maternal diabetes), an increase in the risk of adverse pregnancy outcomes, and a 2- to 5-fold increase in the risk of perinatal mortality.” So, what are some of the pregnancy risks, irrespective of the cause of the excessive amniotic fluid.

Common risks secondary to overdistention of the uterus include abdominal pain, premature labor and delivery, and premature rupture of membranes. There is also an increased risk of uterine rupture, although this is rare in the absence of a previous cesarean delivery or other operative uterine procedure. In the presence of severe hydramnios, especially in a woman of small stature, overdistention of the uterus can put so much pressure on the mother’s diaphragm that she has difficulty breathing in ANY position and maternal cardiorespiratory decompensation may occur under these circumstances.

Often under these circumstances, placental perfusion is also reduced, the baby develops relative placental insufficiency, and as a consequence of the baby’s (and probably the placenta’s) unhappiness, the mother develops preeclampsia. Doppler flow studies have shown a greater incidence of fetal blood flow ‘redistribution’ (an indirect indicator of ‘placental insufficiency’) in the presence of hydramnios and this is most likely due to the excessive pressure on the umbilical vessels and the placenta itself resulting in decreased fetal perfusion. Indeed, any fetal condition associated with hydramnios that places the baby in a ‘distressed’ situation, particularly, severe fetal anemia and other causes of hydrops fetalis, increases the risk for maternal preeclampsia.

Indeed, the very first obstetrical patient I ever saw die (30 years ago) had a baby with hydrops secondary to severe maternal Rh-isoimmunization and polyhydramnios. An attempt was made to transfuse the baby in utero and afterwards she was sent to the antepartum unit for monitoring. I noticed her blood pressure was elevated and checked her urine to also find 4+ proteinuria. I remember notifying her attending physician ( I was a second year resident at the time) that she appeared to be developing severe preeclampsia and was brushed off that this was simply the ‘stress of the procedure that she had just been through.’ When I came in to round on her the next morning, she was not in her bed and when I asked if she had been discharged, I was told that she had had a hypertensive crisis in the middle of the night, a cerebrovascular accident, and could not be resuscitated. The occurrence of severe maternal preeclampsia in the presence of fetal hydrops has come to be known as “mirror syndrome” in which the mother’s condition reflects (and is probably driven by) the dire fetal condition (Vidaeff, et al. J Reprod Med 2002;47:770-4). Needless to say, there are some things one NEVER forgets!

Hydramnios can also cause several complications related to the onset and course of labor. Too much fluid often leads to lack of ‘engagement’ of the fetal head in the pelvis and/or an unstable fetal lie (breech or transverse). This can be a special problem when the membranes rupture (spontaneously or artificially) because if there is no ‘presenting part’ obstructing the cervix, the umbilical cord can suddenly prolapse with the gush of fluid through the cervix into the vagina turning a relatively uncomplicated situation into an emergency. Acute release of the fluid and decompression of the uterus can also cause sudden separation of the placenta (placental abruption) from the uterine wall. Stretching of the uterine muscle (myometrium) can also result in abnormal labor patterns secondary to poor contractility (myometrial dysfunction) and at times can result in poor contraction (involution) of the uterus following delivery, a situation that is usually accompanied by post-partum hemorrhage. All of these complications contribute to the increased rate of cesarean deliveries in pregnancies with hydramnios and the increased rate of maternal and fetal complications.

One other complication which occurs frequently (and is often not thought about) in the presence of hydramnios, particularly if this is associated with diabetes or simply, with fetal macrosomia, is immaturity of fetal lung development. As we have pointed out in earlier posts, late preterm (near-term) elective delivery of a baby just because it is “too big” can have tragic consequences. It is not unusual for macrosomic babies to have a 2-3 week lag in the functional ability of their lungs at birth because excessive insulin production (hyperinsulinemia) that often accompanies macrosomia can delay the production of the lung surfactants that reduce surface tension in the alveoli and are necessary for expansion of these so that oxygen exchange can occur normally. There is nothing sadder than seeing a 10 lb baby of a diabetic mother laying in the neonatal intensive care unit struggling to survive with severe respiratory distress syndrome and persistent fetal circulation as a consequence of an elective (often cesarean) delivery.

Having discussed some of the more common complications of polyhydramnios, in our next (and final!?!) post on the topic of amniotic fluid, we will address the evaluation and management of the pregnancy with too much amniotic fluid…

Labels: diabetes, hydramnios, polyhydramnios, Rh-isoimmunization

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Grand Rounds 4.35 at Musings of a Dinosaur!

Thanks to Musings of a Dinosaur for the effort and "Jurassic Park" spectacular presentation of this week's Grand Rounds 4.35. Thanks too for including a link to my recent post on "Polyhydramnios: Causes of Too Much Amniotic Fluid."

Grand Rounds offers us the opportunity to sample the diversity of ideas and perspectives currently circulating throughout the medical community at all levels of involvement. This week's offering certainly represents the community well and it was a pleasure to peruse. So, don't be shy, check it out and see how the whole world looks at this incomparable profession!

Labels: amniotic fluid; AFV, polyhydramnios

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Amniotic Fluid - 6 - Polyhydramnios: Causes of Too Much Amniotic Fluid

Polyhydramnios (excessive amniotic fluid), also termed hydramnios, is usually defined by vertical pockets of amniotic fluid > 8 cm or as a 4-quadrant amniotic fluid index (AFI) > 95th percentile for the gestational age. Polyhydramnios has a multitude of causes and associations but is seen in only about 1-2% of all pregnancies. It can occur gradually or rapidly depending on the underlying etiology. About 50-60% of polyhydramnios is ‘idiopathic’ which means we haven’t been smart enough to figure out why there is too much fluid. It is not necessarily associated with increased urine production by the baby, but it may have a genetic basis because it can recur in sequential pregnancies, even without an etiology being identified. In some instances there is just excessive fluid and it doesn’t necessarily increase significantly over time and in other cases, it gets progressively worse and may cause both fetal and maternal complications.

There are some specific conditions in which polyhydramnios is frequently associated. The easiest to understand are the fetal anomalies that inhibit or prevent fetal swallowing or block the passage of fluid through the fetal bowel. (Recall, much of the amniotic fluid around the baby is urine and the baby must be able to swallow that and move it through the bowel to the colon where it can be reabsorbed). Common structural gastrointestinal abnormalities that are accompanied by polyhydramnios include esophageal atresia (incomplete development of the esophagus), tracheoesophageal fistulas (aberrant connections, sometimes ending in ‘blind pouches’, between the trachea and the esophagus), duodenal atresia with the classic “double bubble” seen by ultrasound in the upper abdomen (and at least 30% of these associated with Down syndrome – trisomy 21), other small bowel atresias and obstructions (the lower in the small bowel the obstruction, the greater the number of fluid-filled loops of bowel), gastroschisis (a condition in which much of the small bowel is outside the abdomen through a small defect adjacent to the fetal umbilical cord insertion site), gastrointestinal ‘malrotations’ and ‘midgut volvulus’.

Other fetal anomalies associated with polyhydramnios probably have different reasons for contributing to the excessive fluid. Large neural tube defects and certain neuromuscular disorders (such as myotonic dystrophy), for example, probably exert their effects by impairing the ability of the baby to actually swallow fluid, even if the esophagus and gastrointestinal tract are patent. Certain cardiac defects and fetal arrhythmias may contribute by virtually putting the baby into congestive heart failure. Heart failure is also likely to be a major contributing factor when the baby has severe anemia secondary to maternal isoimmunization, a fetal hemoglobinopathy, or bone marrow suppression of red blood cell synthesis as is seen with congenital Parvovirus B19 infections.

Other congenital infections (e.g., syphilis, toxoplasmosis, cytomegalovirus) may also result in excessive amniotic fluid although the actual causes of this may be different depending on the organism involved. Indeed, any condition that results in immune or nonimmune fetal hydrops, including chromosomal abnormalities and inborn errors associated with severe metabolic or cardiac dysfunction, may be accompanied by polyhydramnios. One of the more unusual conditions that is associated with polyhydramnios and fetal hydrops is the so-called “mirror syndrome” that occurs in some cases of severe maternal preeclampsia. Lithium toxicity appears to cause polyhydramnios by causing the baby to have a condition called diabetes insipidus which results from inadequate vasopressin (antidiuretic hormone – ADH) secretion by the posterior pituitary gland and, subsequently, massive production of very dilute (unconcentrated) urine.

The most common clinical condition that is often accompanied by polyhydramnios is diabetes, particularly, gestational diabetes and type 2 diabetes. It is much less likely to be found in long-standing diabetics, particularly, if they have significant kidney, cardiac, or vascular disease. In diabetics, polyhydramnios is more common if the diabetes is poorly-controlled and/or the baby is macrosomic. At times, even improving the diabetic control will not reduce the increased amniotic fluid. The etiology of the increased fluid in certain diabetics is unclear, but when present, it increases the risk for a poor fetal outcome.

In the next post, we will continue with a discussion of polyhydramnios – pregnancy complications, evaluation, and management….

Labels: fetal hydrops, fetal macrosomia, isoimmunization, polyhydramnios

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Grand Rounds 4.34 at Health Business Blog!

Thanks to David E. Williams at Health Business Blog for a most entertaining Grand Rounds and for including a link to my recent post regarding Consequences of Decreased Amniotic Fluid in pregnancy. This is the 4th post in my series on amniotic fluid that aims to provide a very basic understanding of what the 'bag of waters' is all about and the causes, complications, and managemnt of amniotic fluid abnormalities during pregnancy.

Thanks for reading and do check out this week's Grand Rounds!

Labels: amniotic fluid; AFV, oligohydramnios

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Amniotic Fluid - 5 - Evaluation and Management of Oligohydramnios

Just as the fetal outcome depends on the degree, underlying cause, timing during development and longevity of decreased amniotic fluid, to some extent, so do the management options. When the baby has complete absence of both kidneys (bilateral renal agenesis), or absence of functional kidneys (bilateral multicystic or polycystic renal dysplasia), and no amniotic fluid, then as we pointed out yesterday, the fetal outcome is clear – the condition (Potter’s sequence) is lethal. Since this outcome is inevitable, regardless of the gestational age at delivery, interruption of the pregnancy is a reasonable option if the patient wishes to proceed with that. When I trained, that was considered to be a reasonable option at any gestational age as well (whenever the patient was ready to proceed) and, in my mind, it still should be, however, there are many individuals and state regulations that consider this a ‘pregnancy termination’ and practitioners are reluctant to perform labor inductions in such women beyond the gestational age at which the state limits such procedures. Unfortunately, this might require a woman to carry her nonviable baby for 4-5 months after she has been given the diagnosis.

Another option under these circumstances is to offer the patient a program of ‘fetal hospice care.’ The goal of such programs is to allow women and their families the opportunity to spend as much time with the baby, before and after birth, as possible. We structure this with frequent office and ultrasound visits (for those who prefer) and ongoing counseling before and after delivery. In addition, we try to identify other families who have been through the same or a similar situation as a means of additional support. We will often identify one physician to lead the care of the pregnancy, avoid unnecessary testing and interventions, try to create a sensitive birth experience without fetal monitoring and with experienced nursing staff, have a neonatologist available to rapidly confirm the baby’s status following delivery, and allow the patient and any family members she welcomes to be present at the delivery to spend as much time with the baby as possible after birth. Although this approach is not for everyone, those that go through with it are almost always rewarded by the experience.

Less clear is the management of the ‘obstructive uropathies’ that are accompanied by reduced amniotic fluid and, indeed, discussion is beyond the scope of what we need to present herein. In brief, management and outcome depends on when in pregnancy the obstruction is detected and the extent of residual kidney function. As an example, if one is fortunate enough to detect an over-distended bladder and oligohydramnios as the result of posterior urethral valves (bladder out let obstruction) very early in pregnancy, there is the option to place a bladder shunt, diverting urine from the bladder into the space around the baby. Theoretically, this might help reduce the risk of pulmonary hypoplasia. However, the fetal outcome under these circumstances is highly variable. Sometimes the kidneys and the bladder have been too damaged by the obstruction to recover, sometimes the shunts have to be replaced repeatedly, and sometimes the babies still develop abdomens that remain distended and poorly muscularized as the result of the over-distention during critical stages of development – a condition called ‘prune belly syndrome' – and/or respiratory insufficiency. Complete, bilateral ureteral obstructions (between the kidneys and the bladder) are even more of a challenge, but fortunately these are very rare.

Management of premature rupture of membranes (PROM) also depends to a large extent on the timing in pregnancy. If this occurs prior to 20 (or even 22) weeks, the risk of fetal complications related to pulmonary hypoplasia and fetal deformations and the risks of maternal complications secondary to infection are so high that many practitioners will simply advise their patients to undergo pregnancy termination. Unfortunately, for counseling purposes, the outcome under these circumstances can be difficult to predict, particularly if the baby is able to maintain, even intermittently, a small amount of fluid within the uterine cavity. But it is likely that less than 5% of babies with PROM before 20 weeks have any chance at all of intact survivial.

For the patient who is reluctant to undergo pregnancy termination, an option is to simply counsel regarding risks and signs of infection (and the absolute necessity of proceeding with delivery once infection is suspected) and to follow the pregnancy over time. After initial stabilization and evaluation in the hospital, we offer most of these women outpatient management. Other than counseling there is no more that can be offered except perhaps antibiotics. There is no standard of care in the use of antibiotics under these circumstances (in fact some would decry it) but after several unexpectedly good outcomes under these circumstances, I have gotten into the routine of beginning, empirically, a broad spectrum IV cephalosporin antibiotic or penicillin to cover Group B Streptococcus, pending results of cervical-vaginal and urine cultures, as well as a 5-day course of azithromycin, and prolonged prophylactic therapy with metronidazole (the latter being given orally until delivery). Once the baby reaches the point of potential viability, hospitalization can be considered, if the patient desires more aggressive fetal surveillance.

Management of PPROM after viability has been obtained usually involves hospitalization from the outset, careful assessment for infection (even to the extent of including amniocentesis to evaluate the fluid around the baby for evidence of infection and inflammatory markers) and ongoing fetal monitoring to try to balance the risks and benefits of continuing intrauterine management versus delivery. Again, this topic is best suited for another entire post alone.

One of the more challenging, and more common, situations involving the management of pregnancies with reduced amniotic fluid is in the setting of ‘placental insufficiency’ that usually is the late culmination of abnormalities of placentation that occurred very early in pregnancy. As we discussed in our last post, when babies are not getting enough across the placenta to meet metabolic demands and to maintain normal patterns of symmetrical growth, they are able to ‘redistribute’ blood flow to essential organs such as the brain and heart. One sign that this is occurring is progressive growth of the fetal head out of proportion to that of the abdomen – asymmetrical fetal growth restriction. Eventually a critical stage is reached at which point so much blood flow is diverted away from the nonessential organs such as the kidneys, that fetal urine production drops and subsequently the amniotic fluid volume, placing the baby at risk for both cord compromise and too little oxygen. When babies truly start to become unhappy in these situations, it is not uncommon for their mothers to develop hypertensive complications of pregnancy (preeclampsia) and these frequently accompany intrauterine growth restriction.

One of the most effective means we have of ascertaining that these blood flow changes are occurring, sometimes even before significant growth abnormalities have taken place, is Doppler flow velocimetry. This is a noninvasive ultrasound-based technique that allows us to measure resistance to flow (and at times velocity of the flow) in blood vessels. In normal pregnancies, resistance to blood flow from the baby to the placenta as measured in the umbilical arteries is usually very low – indeed, blood normally continues to flow to the placenta even between beats (end diastole) of the fetal heart. At the same time, under normal conditions, resistance to blood flow to the fetal brain (usually measured in the middle cerebral artery, or MCA) is usually high. Though this resistance often decreases as pregnancy progresses, resistance to intracranial blood flow should always exceed resistance indices found in the umbilical arteries. In contrast, when there is decreased resistance in the MCA, this suggests fetal blood flow redistribution and it is often accompanied by increased resistance in the umbilical arteries reflecting the abnormalities in placentation (invasion of the maternal spiral arterioles) that led the pregnancy to this point. When the resistance in the MCA actually falls below that found in the umbilical arteries, the baby may well be at a critical stage requiring delivery, regardless of the gestational age.

When we follow the pregnancy with reduced amniotic fluid, there is not necessarily going to be a single test that tells us the baby is better off out than in. It is one of those situations where we may have to use several of the antepartum testing modalities – nonstress test (NST), contraction stress test (CST), biophysical profile (BPP), and Doppler flow velocimetry - we have at our disposal to aid in the decision-making process. This is especially important when there are complications related to oligohydramnios in the very premature baby. There are many times when the maternal condition must be factored into the decisions as well, particularly, when there is evidence of preeclampsia accompanying intrauterine fetal growth restriction associated with placental insufficiency. One must also be very cautious in the pregnancy with placental insufficiency because the baby often has had time to adapt to the chronic stress of its environment and can often appear better off than it really is even just before decompensating completely.

This concludes an overview of the pregnancy with decreased amniotic fluid. I apologize if I over-simplified some aspects of this discussion, but I wanted to present the information in a way that most of our readers could grasp the basic concepts. In the next post we will begin a discussion of increased amniotic fluid – polyhydramnios (or, simply hydramnios)...

Labels: Doppler flow velocimetry, oligohydramnios, preeclampsia, premature rupture of membranes

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Amniotic Fluid - 4 - Consequences of Decreased Amniotic Fluid

In the last three posts, we have reviewed basic aspects of amniotic fluid production and measurement and common causes of decreased amniotic fluid, or oligohydramnios. Now let’s look at reasons decreased amniotic fluid increases the risk for fetal (and newborn) complications and death. Complications related to decreased amniotic fluid depend on the underlying cause, the degree of the decrease, the timing during pregnancy, and the longevity during fetal development. First, let’s look at the worst case scenario – the baby that has no fluid (anhydramnios) from very early in the pregnancy on…

As mentioned in our last post, the most common conditions that lead to anhydramnios include absence of the fetal kidneys (bilateral renal agenesis), nonfunctional kidneys secondary to bilateral renal dysplasia (polycystic and multicystic kidneys), and complete bladder outlet obstruction (posterior urethral valves, or other anomalies associated with maldevelopment of the fetal bladder or urethra). In rare circumstances, complete bilateral obstruction of the ureters (ureteropelvic or ureterovesical junction obstruction) can also be found. Under these conditions, where the baby has essentially no amniotic fluid from late first trimester on, the outcome is uniformly LETHAL.

Interestingly, it is not the absence of kidney function that kills these babies – it is the fact that in the absence of amniotic fluid, the fetal lungs do not develop sufficiently to support breathing once they are actually born! Any of these conditions associated with early and sustained anhydramnios result in the same outcome secondary to pulmonary hypoplasia and insufficiency, and this has been labeled ‘Potter’s syndrome (or sequence)’ after the physician who first described it. Although, it is not known why the absence of fluid results in Potter’s syndrome, it is thought that the constant compression of the thorax contributes, that the production of fluid by the fetal lungs is suppressed, and even that some movement of amniotic fluid (fetal urine) into the lungs is essential for normal development of functional alveoli. Most babies who are born with Potter’s syndrome cannot even make any kind of respiratory effort at birth, and those that do, cannot get sufficient oxygen into their bodies to allow survival.

If you notice, I did not include premature and prolonged rupture of membranes (PPROM) in this category of inevitable lethal outcome. It is true that if PPROM occurs prior to 20-22 weeks, the baby is at risk for the full consequences of Potter’s syndrome, and the earlier the PPROM and the more severe the oligohydramnios, the greater the likelihood is that this will occur. Indeed, during my training, we were taught simply to offer such women induction of labor, not only because the fetal outcome was expected to be dismal but also because the risk of infection to the mother was so high. (Of course, when I trained, it was the rare baby born before 27 weeks that had any chance of survival anyway). But, I must admit, many patients I have had over the years have proven that old teaching to be incorrect, or at least not a certain death sentence for their babies. Some of these women will carry their babies to a point where there is potential viability (today, 23 weeks and beyond) and, though they are at risk for pulmonary hypoplasia, the degree of this is very difficult to predict and it may not be lethal. However, these babies may also be at increased risk for fetal deformations (particularly of the skeleton, thorax, and head) secondary to compression during development and in its most severe form, a condition termed the fetal akinesia/hypokinesia deformation sequence in which there are not only compression malformations but poor development of muscle, tendons, and enervation secondary to the lack of fetal movement in utero.

Although the above conditions are very serious, they are also all the least common complications related to oligohydramnios. Indeed, most babies will not develop decreased amniotic fluid until beyond 24 weeks gestation, so the issues related to pulmonary hypoplasia and major deformations are, fortunately, rare. The most common reasons for oligohydramnios in the latter part of pregnancy are PROM and placental insufficiency. In the case of the former, this can lead to the acute (sudden) decrease in amniotic fluid and in the latter, a more gradual reduction. Leaving infection out of the equation (as a common cause of PROM and associated with its own morbidity and mortality), the primary cause of fetal complications under these circumstances are related to umbilical cord compromise, and in the case of placental insufficiency, decreased fetal oxygenation (ultimately the cause with its own consequences, not the effect, of decreased amniotic fluid).

Normally, I tell patients that the umbilical cord is a lot like a fire hose. It is a ‘closed system’ and the blood contained within it is under some pressure. In other words, just because it is wrapped around the baby’s neck, or other body parts, or even tied into a knot, does not mean the baby is going to necessarily die as the result – in fact most don’t. At least one-third of all babies are born with the cord looped around the neck (nuchal cord) and most do just fine. However, the blood in the umbilical cord vessels is under differential ‘pressures’ depending on whether it is the poorly oxygenated arterial blood (higher pressure) coming from the baby to the placenta or the well-oxygenated venous blood (low pressure) coming back to the baby from the placenta. Obviously, when there is compression on the umbilical cord, the venous blood flow is much more likely to be impeded than the arterial blood flow.

Even if the blood in the umbilical cord is under pressure, in the presence of decreased or absent amniotic fluid it is possible for the baby to trap the cord in a position where blood flow is significantly reduced and the baby can be damaged or even die as the result of too little oxygen. I always worry about this most when there is sudden rupture of the membranes, or if the cord falls (prolapses) through the cervix, and, particularly, in women who are very heavy. It is also one of the causes of fetal morbidity and mortality in placental insufficiency sequences (accompanied by intrauterine growth restriction) because oftentimes in these circumstances, not only is the placenta poorly developed (and has less ‘reserve’), but the cord is often thinner and smaller and not endowed with adequate cushioning due to a reduction in the amount of Wharton’s jelly surrounding the blood vessels (normally two arteries and one vein) in the umbilical cord and, therefore, more likely to be significantly compromised when compressed.

Intermittent (and incomplete) umbilical cord compression can often be identified by distinct abnormalities of the fetal heart rate (FHR) tracing (most commonly, ‘variable decelerations’). These are quite common in labor, particularly after the membranes have ruptured either spontaneously or as the result of the provider’s intervention (artificial rupture of membranes, or AROM). FHR monitoring is, therefore, one means of identifying the baby ‘at risk’ for umbilical cord compromise. Most babies that have decreased fluid and normal placental function tolerate this type of FHR deceleration quite well, although they are still at increased risk for cesarean delivery if the FHR tracing begins to develop signs of ‘nonreassurance’ and spontaneous vaginal delivery is still remote. Since we seem to have spent a fair amount of time on this topic today, I will reserve further discussion on the evaluation and management of pregnancies with oligohydramnios to our next post…

Labels: amniotic fluid; AFV, anhydramnios, oligohydramnios, Potter's syndrome

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Amniotic Fluid - 3 - Oligohydramnios: Causes of Too Little Amniotic Fluid

Having discussed where amniotic fluid comes from and how we assess amniotic fluid volume, let’s address the most common amniotic fluid abnormality – too little fluid or oligohydramnios. There are 3 primary reasons why there is too little amniotic fluid: 1) rupture of membranes; 2) fetal abnormalities; 3) placental abnormalities.

Spontaneous rupture of membranes (SROM) can occur at any time in pregnancy. Most of the time, the membranes remain intact until the onset of labor, or just before labor, after the cervix has begun to change (efface and dilate). If membranes rupture prior to the onset of uterine contractions, it is called premature rupture of membranes or PROM, and if they are ruptured for more than 24 hours, prolonged premature rupture of membranes or PPROM. There are lots of things that can lead to rupture of membranes, but the ones we worry about most are infection, fetal anomalies that result in too much fluid (polyhydramnios or hydrammnios) and uterine overdistention, and cervical incompetence. The earlier in pregnancy that the membranes rupture, the greater the likelihood that it is associated with infection (with or without cervical incompetence) and this is usually infection with organisms that the mother carries in her body that get inside the uterus by ascending vaginal, blood-borne, or lymphatic transmission. However, the focus of this discussion is not to discuss SROM, but to remind readers that it is a very common cause of decreased amniotic fluid and when it occurs, the baby and the mother need to be evaluated carefully to look for causes. Since infection is often associated with PROM, that is usually what constitutes the greatest risk to the baby.

The least common, but often most serious, causes of decreased amniotic fluid are fetal abnormalities. If you recall in our first post on this subject, most of the amniotic fluid from early midtrimester on is fetal urine. Abnormalities of the fetal kidneys and urinary tract can lead to decreased urine output or the complete absence of amniotic fluid (anhydramnios) in the most severe cases. Babies can have the complete absence of both kidneys (bilateral renal agenesis), nonfunctioning kidneys associated with polycystic or multicystic renal dysplasia, or obstructive uropathies where there is blockage of urine at the urethra (usually the result of ‘posterior urethral valves’ in male children), or blockage of the ureters at various levels between the kidneys and the bladder (e.g., ureteropelvic junction (UPJ) or ureterovesical junction (UVJ)obstructions). An important point to note here is that if the baby only has ONE nonfunctioning kidney, or a blockage that affects only ONE side, the amniotic fluid is usually normal and the consequences of too little fluid for too long do not develop. However, if both kidneys are affected, this can lead to the complete absence of amniotic fluid and a condition that has been named “Potter’s sequence” which will be detailed in our next post on this subject.

Other causes of decreased fluid that may be transient (and therefore less serious) and/or reversible are congenital viral infections, such as cytomegalovirus (CMV) which has a predilection for the fetal kidneys, or conditions that affect maternal hydration. With regard to the latter, as we pointed out previously, if the mother becomes very dehydrated, or if she has a condition that severely decreases her plasma volume, the fluid around the baby, which depends so much on passive distribution from the mother across the placenta, can acutely decrease. Common conditions in which this is seen include: hyperemesis (too much vomiting), diarrhea, maternal sepsis, hemorrhage, placental abruption or previa, diabetic ketoacidosis, excessive fluid loss during fever or heat exposure, and severe preeclampsia. Oligohydramnios resulting from many of these conditions can be reversed or improved with expansion of the maternal plasma volume.

The last conditions I would like to discuss that lead to decreased amniotic fluid are those that result in decreased perfusion (blood flow) to the fetal kidneys. When it comes right down to it, the kidneys are ‘nonessential organs’ with regard to survival of the baby while it is inside its mother. For example, babies that have bilateral renal agenesis (no kidneys at all) can go all the way to term because the placenta and the mother serve as the means of removing ‘waste products’ from the baby. (They cannot survive after delivery for the reasons I will detail in my next post). Production of urine by the baby requires blood flow through the kidneys. When babies become dehydrated, or when they have to, preferentially, send blood to ‘essential organs’ such as the brain and the heart because they are not receiving enough oxygen and nutrients to support their whole bodies’ needs, their regulatory mechanisms of survival shut down blood flow to the kidneys, thereby, curtailing the production of urine.

This can occur as the result of primary fetal problems such as severe anemia associated with isoimmunization or parvovirus infections, or cardiac malformations or dysfunction from a variety of different causes. More commonly, however, this occurs as the result of abnormalities of placentation (small placentas and/or placentas that have not had normal invasion of the maternal spiral arterioles in the placental bed), wherein the babies have outgrown the capacity of the placenta to provide sufficient oxygen and/or nutrients. When ‘placental insufficiency’ occurs it is usually accompanied by intrauterine fetal growth restriction (IUGR). This usually means the baby is small for its gestational age, but there are occasions when this can occur in large babies, such as those seen in uncontrolled diabetic mothers, whose size also exceeds the capacity of the placenta to maintain their metabolic demands. When the amniotic fluid starts to go down in circumstances of placental insufficiency, this is also usually the result of ‘fetal blood flow redistribution’ away from the kidneys and to the essential organs necessary for survival.

Having discussed some of the more common causes of oligohydramnios, in our next installment of this series, we will address the evaluation, management, and consequences decreased amniotic fluid in pregnancy ….

Labels: amniotic fluid; AFV, IUGR, oligohydramnios, premature rupture of membranes

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Amniotic Fluid - 2 - Assessment of Amniotic Fluid Volume

We closed our last post with the comment that BOTH too much fluid (polyhydramnios, otherwise termed hydramnios) or too little fluid (oligohydramnios) are associated with fetal abnormalities and/or poor perinatal outcome. In fact, the greater the amniotic fluid abnormality, one way or the other, the greater the likelihood is of fetal complications or loss and, for that matter, maternal complications as well. The maternal complications are (usually) not related to the fluid abnormalities themselves (except in cases of severe polyhydramnios), but to the reasons the amniotic fluid volumes are abnormal to start with. That will become clearer as we proceed with these posts.

With the widespread use of ultrasound, we have come to use ‘semi-objective’ measures of amniotic fluid volume (AFV). Although what is “abnormal” has gone through various permutations over time, most practitioners assess AFV by one of two methods. The first method is to simply measure the depth of the single largest vertical pocket of fluid (free of umbilical cord and body parts) with the ultrasound transducer oriented perpendicular to the uterus and not just perpendicular to the abdominal wall and with a minimum of pressure on the transducer itself. If the single largest pocket is < 2 cm, the AFV is considered to be ‘decreased’ at anytime from midtrimester until term. If the single largest pocket is > 8 cm, the AFV is considered to be ‘increased’.

The second method that has gained perhaps the most popularity over time is the “amniotic fluid index (AFI).” This technique involves dividing the uterus into four ‘quadrants’ by imagining perpendicular lines running through the umbilicus of the mother, and then simply measuring the single deepest pocket of fluid in each quadrant and adding up the 4 results. At term, the mean AFI is 11.5 cm with 5th and 95th percentiles of 6.8 and 19.6 cm, respectively, and quite frankly, there is not much variation in those values from late midtrimester on. Oligohydramnios is then defined as an AFI < 5th percentile and polyhydramnios as > 95th percentile.

Either approach can be performed quickly and though the AFI technique would intuitively seem to give you a better total picture of AFV, in reality, there probably is no real difference in the reliability of the methods. Indeed, in experienced hands, subjective assessment of amniotic fluid by simply looking is probably just as good (may the lord of evidence-based medicine please not strike me down)! If there are only very small pockets of free fluid, the baby appears crowded, or in the most extreme cases, there is absolutely no fluid (severe oligohydramnios or anhydramnios) and the baby has gross pressure deformations of the head or extremities, or overlapping of the ribs, the diagnosis of too little fluid is readily apparent. In a similar vein, if the baby appears to be freely floating or turning and has no restriction of extremity extension, there is probably too much fluid. With all that said and done, since not everyone has ‘experienced hands’ and there is some beauty to numbers, we use the 4-quadrant AFI as our routine approach to the assessment of AFV.

In the next post in this series we will discuss specific conditions and complications associated with decreased amniotic fluid….

Labels: amniotic fluid; AFV, anhydramnios, hydramnios, oligohydramnios, polyhydramnios

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Amniotic Fluid - 1 - The Basics

We have readers with a wide range of backgrounds and medical sophistication. One of the things I have tried to do on this site is to provide information which appeals to readers across this spectrum. In some instances, we have discussed very basic information related to pregnancy and pregnancy complications, in others we have provided in depth analysis of subjects that may have more general interest, and in still others, we have focused on very narrow topics or even indulged in the arena of hypothesis.

While reviewing some of the subjects we have covered over the past 20 months to get some ideas for new posts, it dawned on me that we had never written about one of the most basic topics related to pregnancy that arises as a subject of discussion almost every day in my work for one reason or another - amniotic fluid. In today’s post, we will simply provide the basic background related to amniotic fluid production and clearance and in the posts that follow, we will discuss the significance (causes and effects) of abnormalities of amniotic fluid volume – too much and too little.

Most patients have no clue what amniotic fluid is and just take for granted that it is “just the bag of waters around the baby” that makes it easier to take pretty ultrasound pictures and gets “ruptured” by my doctor to help me labor faster at delivery. Indeed, when there is a clinical reason to discuss amniotic fluid, and I have the opportunity to tell them what it is and where it goes, they are often appalled or simply grossed out. Production and egress of amniotic fluid is a very dynamic process. It isn’t “just there.” Indeed it is estimated that more than 95% of amniotic fluid turns over on daily basis.

Very early in pregnancy, the fluid around the baby is the result of active transport of sodium and chloride across the fetal membranes juxtaposed to maternal tissues. As the salt moves, water follows passively. By the end of first trimester (between 8 and 11 weeks), however, an increasing proportion of amniotic fluid is the result of fetal urine production and later on production and expulsion from the fetal lungs. At the same time the fetal kidneys become the major source of amniotic fluid production, fetal swallowing and the lower gastrointestinal tract become the major means of removing that fluid from around the baby. In other words, the baby pees, then swallows it, then reabsorbs the fluid and passes it back (and forth) across the placenta to the mother. (It is this thought that tends to gross out the parents, so thank goodness the baby usually doesn’t poop much in utero). There are other sources of both fluid production and egress, but for the sake of simplicity, let’s begin our discussion with these basics. The amniotic fluid volume, then, is the sum of the inflows and outflows of the fluid in amniotic space around the baby.

At 16 weeks the amniotic fluid volume (AFV) is about 200 mL; AFV peaks at about 700 to 900 mL at 32-35 weeks in most normal pregnancies and then begins to gradually diminish. By term, the average baby produces about 700 to 900 mL/day of urine and 300 to 400 mL/day of fluid from the lungs. In many pregnancies, there is a dramatic drop in the amniotic fluid volume once the pregnancy gets beyond 42 weeks, corresponding to the time when, even in a ‘normal’ pregnancy, there is an increased risk of ‘unexplained’ fetal death in utero if a woman does not go into spontaneous labor.

In first trimester, the osmolality of amniotic fluid is comparable to that of blood (280 mOsm). However, from early on in pregnancy, the fetal kidneys are capable of retaining salt and other solutes, resulting in the production of urine that is ‘hypotonic’ (60-140 mOsm). This eventually results in a drop in the overall osmolality of the amniotic fluid as the pregnancy progresses. There is a tendency for the baby to lose salt across body surfaces exposed to the amniotic fluid, but usually the baby compensates for this much better than we do when we sit in a bathtub for a little too long and come out looking like a raisin! Fluid exchange between mother and baby occurs freely across the placenta. For this reason, acute changes in maternal hydration (reflected in her plasma osmolality) readily alter fetal hydration. Conditions during pregnancy that can affect maternal plasma volume (low and high), therefore, may be one of the factors that also influences amniotic fluid volume on a short- or long-term basis.

So, that is the basics of amniotic fluid production and overall volume. We actually understand very little about ‘regulation’ of amniotic fluid volume. What we do know, however, is that BOTH too much fluid (polyhydramnios or hydramnios) AND too little fluid (oligohydramnios) are associated with fetal abnormalities and/or poor perinatal outcome, and that’s where we will take this discussion in our next posts….

Labels: amniotic fluid; AFV

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Low PAPP-A in Presence of Low Risk for Fetal Aneuploidy

Below are comments from a woman aged 44 who is carrying a pregnancy conceived by in vitro fertilization (IVF) using a ‘donor egg’ from a 21 year old woman. She had combined first trimester screening done with composite results that were very reassuring with regard to risks for having a baby with trisomy 21 or trisomies 18 or 13, however she is concerned that the PAPP-A level in the screen was only 0.269 MoM (at about the 2.5 percentile). She is 44 years old, and that alone increases her risk for pregnancy complications related to abnormalities of placental growth and complications related to that during pregnancy and, indeed, low PAPP-A levels may reflect those abnormalities. However, I want to remind our readers at the outset that the ‘positive predictive value’ for low PAPP-A is not very good and means the chance of one of these events is higher with a low PAPP-A but does not mean that she will inevitably develop complications during her pregnancy…

• At Mon Apr 28, 02:45:00 AM 2008, Anonymous said…

Hi Dr T,
I am having trouble getting anyone to take my numbers seriously. The NT scan showed up a low PAPP-A result and the sonographer told me to ask my GP to watch this and to make sure my OB consultant knew about it. My GP wrote to the OB consultant and she has just told me this morning that "Don't worry - they are not concerned as the PAPP-A result is low which is good!" Even I know that this does not make sense. Can you please help me by giving your opinion as most info I have read on this amazing site seems to point towards a possible problem:

CRL:57.9mm
NT: 1.6mm
Placenta:posterior high
Free B-hcg: 0.956 MoM
PAPP-A: 0.269 MoM
Egg was IVF donor egg -maternal age 21 yrs.
I was 11weeks and 6 days when the scan was done.

I look forward to hearing from you.
Many thanks,
Jackie

• At Wed Apr 30, 05:05:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To Jackie Apr 28: I wish I knew how old you are, what sort of medical problems you have, what was the cause of your infertility, and have you ever had any pregnancies (successful or not)? Barring that, it would be helpful to know what the calculated risk assessment result was for Down syndrome and trisomies 18/13 based on your test results.

Regardless, the low PAPP-A may not be good, but it may not be bad either! If you have read the posts I have written on this subject, and some of the comments from our readers and my responses, you will better appreciate why I seem to be talking out of both sides of my mouth. The reassuring components of your screen are the normal NT (nuchal translucency) and hCG measurements. With a "21 year old egg", I doubt your calculated risk for aneuploidy was very high. You are probably at modest risk for a small baby and the things that might go along with that, such as preterm labor, early delivery, preeclampsia, and cesarean section, but there might be other factors you have not told me about (or are not aware of) that might also put you at risk for these. My bet right now is that you will do fairly well with the pregnancy and nothing is wrong with your baby! Let us know how things turn out.
Dr T

• At Thu May 01, 03:16:00 AM 2008, Anonymous said…

Hi again Dr T,
I am so grateful for your reply and apologies for omitting some of the info. I am 44 years old with no medical problems except a fibroid which has appeared with this pregnancy. The infertility was unexplained, save for mild endometriosis. I had one pregnancy last year (natural) which ended after just 6 weeks with no explanation. I have had 2 previous rounds of IVF - the first produced 4 follicles and 2 embryos were implanted but did not take. The second produced no follicles.

The adjusted risk for Downs was 1:1804 and for Trisomy 18+13 was 1:18628. I was advised that no amniocentesis or CVS (chorionic villus sampling) would be necessary. My main concern is the IUGR/stillbirth scenario which seems to go hand in hand with a low PAPP-A result. Do you imagine that my doctors would keep a closer eye on me - in your opinion what should I be pushing for at my 20 week scan? Will the AFP result throw anything in to the mix as I am yet to receive that?
Thank you again.
Jackie

• At Thu May 01, 10:49:00 AM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

Hello again Jackie. When the PAPP-A is low, the women at greatest risk for complications are those that also have a placenta that is smaller than normal and/or did not have normal growth into the lining of the uterus (specifically into the uterine spiral arterioles). The MSAFP (maternal serum alphafetoprotein test at 16 weeks can sometimes provide an insight to that as a possibility. If the AFP is abnormally high, and there are no apparent abnormalities (such as a neural tube or abdominal wall defect) of the baby to be seen, then that "false positive" result may actually reflect an underlying placental problem (that may not manifest itself as a problem such as fetal growth restriction or maternal preeclampsia until later in the pregnancy).

The other procedure we use that can also anticipate risks down the line is Doppler flow velocimetry. This is an ultrasound technique that can help us to detect degrees of 'resistance' to blood flow. If you and/or the baby are found to have trouble pushing blood through the placenta by virtue of increased resistance in the uterine or umbilical arteries, respectively, this can be another reason to keep a closer eye on the baby's growth, development and overall well-being. None of these will accurately predict outcome, but if they are abnormal, can justify more intensive antepartum fetal surveillance so that chances of delivering a healthy baby, regardless of the gestational age, are improved. So, do not panic at this point! Again, thanks for your questions and let us know how things turn out!
Dr T

COMMENT:
As we have pointed out before, first trimester screening for aneuploidy can have some benefits for detecting potential complications of pregnancy other than certain chromosomal abnormalities. Our reader reports that her ‘composite’ first trimester screening result was reassuring with regard to risk for a chromosomally abnormal baby, but one of the maternal serum markers, PAPP-A (pregnancy-associated plasma protein-A), was “low” at 0.269 MoM (multiples of the median).

PAPP-A is produced by the placental trophoblasts, especially, by the extravillous cytotrophoblasts (Handschuh, et al., Placenta 2006;27 suppl A:S127-34). It is a ‘protease’ for insulin-like growth factor (IGF) binding proteins 4 and 5 (Boldt and Conover. Growth Horm IGF Res. 207;17:10-18). It has the ability to help release IGF from these binding proteins so that it is free to interact with its cell receptor (Laursen, et al., Mol Endocrinol 2007;21:1246-57). IGF is thought to play an important role in trophoblast invasion and hence the early development and vascularization of the placenta and the placental bed. These early events in formation of the placenta are critical to pregnancy outcome and, when abnormal, are associated with miscarriage, intrauterine growth restriction (IUGR) of the baby, pregnancy-induced hypertensive disorders, fetal death in utero, premature delivery, and even cesarean section for indications of fetal or maternal compromise. It has been postulated that low levels of PAPP-A, resulting in less release of IGF, could be a pathway by which placentation abnormalities occur that culminate in these poor pregnancy outcomes.

Several studies confirm the association of ‘pregnancy complications’ with low levels of PAPP-A. In the First and Second Trimester Evaluation of Risk (FASTER) trial, it was found that women with PAPP-A at or below the 5th percentile “were significantly more likely to experience fetal loss at less than or equal to 24 weeks, low birth weight, preeclampsia, gestational hypertension, preterm birth (P < .001) and stillbirth, preterm premature rupture of membranes, and placental abruption (P < .02)” (Dugoff, et al., Am J Obstet Gynecol 2004; 191:1446-61). Spencer and colleagues (Ultrasound Obstet Gynecol 2006;28:637-43) evaluated first trimester markers in 54,722 chromosomally normal singleton pregnancies. They found that the odds for fetal loss at anytime in pregnancy was about three-fold that of ‘normals when the PAPP-A levels were at or below the 5th percentile (0.415 MoM).

Labels: aneuploidy screening in first trimester, Doppler flow velocimetry, PAPP-A

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