Indications for Doppler Flow Velocimetry During Pregnancy

Recently, I received a phone call from our billing office reporting that an insurance company had declined to reimburse us for a claim that included charges for Doppler flow velocimetry for the indication of intrauterine growth restriction (IUGR). My response to the office personnel was simply that that is the most widely accepted indication we have for these procedures and that I would compose a letter of explanation to the insurance company, the contents of which are detailed below...

Doppler flow velocimetry (DFV) is a noninvasive method to assess resistance to, and velocity of, blood flow using ultrasound technology. In pregnancy, it has been proven to be a valuable adjunct to fetal assessment because often DFV abnormalities will precede detectable fetal abnormalities of growth, amniotic fluid, and placental insufficiency and can help assess the severity of fetal compromise when these abnormalities are suspected.

The principles underlying the most common indications for DFV are as follows:

Under normal conditions, the placenta offers little resistance to fetal and maternal blood flow, even during diastole (i.e., between heart beats); and, there is no preferential blood flow to the brain as reflected in normally high resistance, especially from late midtrimester on, at the expense of perfusion of other organs...

Under abnormal conditions, blood flow to the placenta may be reduced and accompanied by increased resistance to perfusion (fetal and/or maternal) and/or there is preferential blood flow to preserve ‘essential’ organs such as the brain (‘brain-sparing effect’) as manifested by low resistance Doppler patterns to these organs and eventually reduced perfusion (fetal blood flow redistribution) of ‘nonessential’ organs such as the kidneys.

Some factors that lead to aberrations in DFV patterns include:

• Abnormalities in placentation or of the umbilical cord
• ‘Placental insufficiency’ regardless of fetal size
• Fetal anemia resulting from maternal isoimmunization, viral infection (e.g., parvovirus B19 and CMV), twin-twin transfusion syndrome, fetal-maternal hemorrhage…
• Chromosomal abnormalities
• Cardiac and intracranial malformations

When indicated, DFV evaluation of the following may contribute valuable information with regard evaluation of the pregnancy, but should be performed by individuals trained and experienced in the performance and interpretation of the results:

Maternal:
Uterine arteries

Fetal:
Umbilical arteries
Middle cerebral arteries
Ductus venosus
Umbilical vein

Common indications for Doppler flow velocimetry studies include:

• Abnormalities of growth (both intrauterine growth restriction(IUGR) and excessive fetal growth (macrosomia)
• Fetal anomalies (e.g., cystic hygromas, cardiac, thoracic, diaphragmatic, neural tube, renal, and abdominal wall)
• Fetal hydrops
• Oligohydramnios (decreased fluid) and polyhydramnios (increased fluid)
• Poor OB history (e.g., preeclampsia, IUGR, previous stillborn…)
• Known maternal risk factors: hypertension, preeclampsia, diabetes, autoimmune disorders (overt and subclinical), thrombophilias (acquired and genetic)
• Abnormal maternal serum screening (e.g. elevated MSAFP and/or increased risk for fetal chromosomal abnormality)
• Multiple gestation
• Maternal trauma (fetal-maternal hemorrhage)
• Suspected placental abruption
• Known maternal isoimmunization
• Exposure to parvovirus B19

In recent years, DFV has become the primary means of screening related to fetal anemia. This is done by evaluating the peak systolic velocity (PSV) in the fetal middle cerebral artery. Its negative predictive value is so high that it has obviated the need for, and the expense of, repetitive invasive procedures when there is known maternal isoimmunization, Parvovirus B19 exposure, or other potential causes of severe fetal anemia such as trauma or placental abruption or placenta previa that might lead to fetal-maternal hemorrhage or fetal blood loss.

It is also the primary means of ruling out fetal anemia as a cause of hydrops fetalis and it is the mainstay in the assessment of multiple gestations as a means of screening and staging possible twin-to-twin transfusion syndrome. DFV of the fetal ductus venosus in early pregnancy has also proven useful in the identification of fetuses at risk for chromosomal abnormalities and major congenital heart defects. DFV of the branch pulmonary arteries can help predict the risk of fetal pulmonary hypoplasia in cases of premature and prolonged rupture of membranes.

DFV is no longer considered ‘experimental’ and it has become a ‘standard of care’ in the hands of specialist in Maternal-Fetal Medicine for the evaluation and management of complicated pregnancies.

Labels: Doppler flow velocimetry, fetal hydrops, isoimmunization, IUGR, oligohydramnios, 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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Hereditary Hemorrhagic Telangiectasia (HHT) and Pregnancy

Below is a recent comment from a reader in which she asks several interesting questions, but the most important answer was to a question she did not ask...!

• At Sun Feb 17, 08:23:00 PM 2008, Seri said…

I read your answers to the patient who had a Du-positive blood type . I was 18 and gave blood and was informed I am O-positive (Du-positive). I was not sexually active and of course never pregnant and I am white. My Dad was O-positive and Mom was A-positive. How can that be? I have never had a blood transfusion, but my husband and daughter have HHT and both have required blood. Should I or we be concerned about transfusions?

• At Fri Feb 29, 06:49:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To Seri Feb 17: Given your parents' blood types, there is no reason you couldn't have the blood type you were born with. One (at least) of your Rh-positive parents is Du-positive, the other is likely to be heterozygous (a carrier of only one dose) for the Rh-D antigen, and you simply inherited the Du-variant of Rh and the chromosome from the other parent that was Rh-D-negative. The Du-variant is sometimes referred to as the 'weak' Rh-D antigen, but technically this still makes you Rh-positive. You only need only one dose of any Rh-D or -Du gene to have that expressed on your blood cells. Du-positive women cannot become sensitized to the D-antigen. Therefore, Du-positive women do NOT need Rh-immune globulin (Rhogam) during their pregnancies. If you get it inadvertantly, it would probably not cause any harm to the baby, but you just don't need it. Du is very common, but not exclusively found, in Black women.

As far as the HHT (hereditary hemorrhagic telangiectasia) in your daughter and husband is concerned, that does not put you or a baby you are carrying at any risk for needing blood transfusions. Your daughter got that only from your husband and not from you. It is inherited in an autosomal dominant pattern, i.e., it too requires only one dose of the bad gene to be expressed. However, your daughter needs to be concerned if and when she ever gets pregnant (but maybe we can cross that bridge when she comes to it!).

HHT is a condition that is actually caused by at least two different gene mutations and affects about 1 in 5000 individuals. A defect in the ‘endoglin’ gene is found in HHT type 1 (HHT1) and a defect in ALK-1 (activin receptor-like kinase-1), a type I receptor of the transforming growth factor (TGF)-β superfamily, causes HHT type 2 (HHT2). You will sometimes find HHT referred to in the medical literature as Osler-Weber-Rendu (OWR) after the doctors who first described it and suspected the hereditary nature of the disease. Clinical findings in individuals with HHT result from abnormalities in the development of some of their blood vessels.

Arteries carry the well oxygenated blood from the heart under high pressure through smaller and smaller vessels until the tiniest vessels (the capillaries) are reached and where most oxygen and nutrient is exchanged between the blood and the body tissues. The deoxygenated and nutrient-depleted blood then exits the capillaries into the veins that return the blood under much lower pressure to the heart. Individuals with HHT have a tendency to develop blood vessels that lack the capillaries (very small blood vessels) between their arteries and veins. This means that in HHT, arteries (with their thick muscular walls which are able to withstand the high pressures) are connected to veins that are only designed to tolerate relatively low pressures.

The site at which the artery and the vein are connected tends to weaken with time, eventually ‘balloons’ out (and remember, once a balloon gets past a certain point, it is easier and easier to distend), and can eventually rupture, resulting in bleeding. When these vascular abnormalities involve the small blood vessels in the skin or mucous membranes, we call these abnormalities ‘telangiectasias’ and if larger vessels are involved, we call these arteriovenous malformations (AVMs). Obviously, the abnormalities only involve a small percentage of an individual’s blood vessels, but the expression of the condition is highly variable between individuals, even within the same family.

The vascular malformations in individuals with HHT tend to occur more frequently in certain tissue areas although the reasons for this are unknown: the skin (especially face and hands), mucous membranes of the nose and mouth, lining of the stomach and intestines (GI tract), as well as the lungs, liver and brain. The larger (AVM) tend to occur more frequently in the internal organs and may be relatively asymptomatic for years before they expand and/or rupture. The diagnosis of HHT is considered definite if three or more of the following four criteria are present, or suspected if two of the following four criteria are present:

• Nosebleeds: spontaneous and recurrent
• Telangiectasias: multiple, at characteristic sites, including lips, oral cavity, fingers and nose
• Internal telangiectasias or AVM: lung, brain, GI, liver or spinal
• Family history: parent, sibling or child with HHT

As I mentioned above, I am more worried about our reader’s daughter when it comes time for her to consider pregnancy. I am not particularly worried about any children she might have with regard to pregnancy outcome (unless of course she had a complication related to her HHT). Because the mutations for HHT are inherited in an autosomal (non-sex chromosome) dominant fashion, they can equally affect both male and female offspring. However, while in the womb, it is quite unusual for babies with HHT to develop complications related to it. Arteriovenous malformations in fetuses have been detected, are quite rare, and can be quite devastating, but I do not believe these have been clearly correlated with HHT. Studies have shown expression of the genetic abnormality in fetal tissues (Abdalla, et al., Hum Mol Genet 2000;9:1227-37), but this is not associated with adverse pregnancy outcome for the baby as far as I am aware.

In contrast, the mother with HHT can be another story altogether. During pregnancy, the plasma volume normally expands 30-50% and to accommodate this, the cardiac output increases and the blood vessels must also relax, reducing peripheral vascular resistance. This involves some degree of ‘softening’ of the connective tissues in the blood vessel walls. One could easily see that this combination of events might lead to complications in the pregnant woman with HHT. Indeed, catastrophic events in pregnant women with HHT related to enlargement or rupture of AVMs in the lungs (e.g., intrapulmonary shunt deterioration and fatal pulmonary hemorrhage), brain (cerebrovascular accidents), and liver have all been described (Shovlin, et al., QJM 1995;88:879-87). However, if care is taken in the evaluation and management of young women with HHT, prior to and during pregnancy, risk for the mothers can be reduced (Schwebel, et al., Gynecol Obste Invest 2007;65:142-44).

There is one last concern I wish to mention regarding the woman with HHT who is considering pregnancy. If she has had bleeding problems that required transfusion, she is at risk for ‘isoimmunization’ to red blood cell antigens for which she was not crossed-matched prior to transfusion (this might involve Rh-antigens other than D and also non-Rh antigens). Depending on which antigens these are, her baby may be more or less at risk for hemolytic anemia and/or hyperbilirubinemia.

If a woman has HHT and is considering pregnancy, or is already pregnant, the HHT International Foundation can refer her to a clinic or center that specializes in the diagnosis, management and treatment of HHT, both here in the U.S. and around the world.

Thanks for writing. Bet you didn’t realize your questions were so GREAT!
Dr T

Labels: Du antigen, hereditary hemorrhagic telangiectasia, HHT, isoimmunization

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Percutaneous Umbilical Blood Sampling (PUBS)

In several previous posts, we addressed issues related to invasive diagnostic fetal testing, covering amniocentesis (early and midtrimester) and chorionic villus sampling. I got side-tracked by the ACOG Meeting in San Diego and just remembered that we had never gotten around to a discussion of the other common (though much less so than amniocentesis or CVS) invasive (and at times, therapeutic) procedure, percutaneous umbilical blood sampling (PUBS), otherwise known as cordocentesis or funipuncture.

This, quite simply (but technically tricky), involves the placement of a needle into the umbilical vein to remove fetal blood for a variety of testing purposes such as: chromosomal analysis; genetic studies; hemoglobin analysis (hemoglobinopathies); fetal anemia; platelet count; assessment of fetal acid-base status; fetal infection; coagulation system abnormalities; immune deficiencies. It is commonly used when rapid (48-72hr) and precise fetal chromosomal studies are indicated; in the definitive assessment of anemia under conditions of isoimmunization or parvovirus infection (and as a route of intrauterine transfusion if anemia is confirmed); in the evaluation of thrombocytopenia (= low platelets) resulting from either autoimmune or alloimmune (analogous to Rh-disease) conditions; in the evaluation of fetal hydrops; and, in the confirmation of fetal infections.

PUBS is performed under aseptic conditions and direct ultrasound guidance, much like amniocentesis. Without going into great detail, a slightly larger bore needle is often used than that used with amniocentesis, especially if the procedure is being done for suspected fetal anemia and a transfusion via intravenous access is warranted. When technically feasible, we prefer to access the umbilical vein within 1-2 cm of its placental insertion site. Unlike with amniocentesis, many of us actually prefer to go through the placenta to get to this site. This provides a more stable site for insertion than free cord floating around in the amniotic fluid, improves the prospects for success and probably reduces the risks of the procedure. (Fetal blood sampling can at times also be done directly from the baby, the most common sampling sites being the intrahepatic vein and the fetal heart, but special preparations and precautions must be taken under these circumstances and do not warrant discussion herein).

Although at times the fetal condition might justify earlier evaluation, most fetal blood sampling procedures are done in babies that are 23 weeks or beyond. Since we now consider almost all babies at this gestational age potentially viable, it is recommended that the procedure be performed at an institution that can handle extremely premature babies, and/or babies that may be compromised by the medical condition that led to the PUBS, and at a location in which an emergency cesarean section can readily be performed if a complication arises during or in the immediate post-procedure period.

The most common complications include fetal bradycardia (slow heart rate) during the procedure, hemorrhage or obstructing blood clot at the needle insertion site, and intrauterine infection. Fetal bradycardia is often transient and its mechanism is unclear, but it may be related to spasm in the muscles of the uterine arteries if these were inadvertently punctured during the procedure. Prolonged bradycardia is more common, and more ominous, if it occurs when a baby is severely anemic, hypoxic, acidotic, hydropic (in heart failure), or is hemorrhaging uncontrollably from either the umbilical vein or an umbilical artery. If this cannot be corrected by our typical intrauterine resuscitative measures, immediate delivery may be indicated if the baby is at a gestational age where viability is possible.

Significant fetal hemorrhage from the needle insertion site is a relatively uncommon event; however, it is more likely to occur when the baby has low platelets as may be found in autoimmune, alloimmune, or parvovirus-induced thrombocytopenia. Of these, the greatest risk is in alloimmune thromobocytopenia because the platelet counts are often dangerously low and the platelets that are present may not function normally in clot formation. Babies affected by alloimmune thrombocytopenia are also at great risk for intracranial hemorrhage remote from the labor and delivery process.

In my experience, introduction of infection at the time of the procedure, either from maternal skin bacteria or blood borne organisms such as HIV, CMV, and hepatitis viruses, is a very uncommon event. Rupturing fetal membranes also occurs infrequently, but slightly more often than with amniocentesis alone. Risks for any of these complications rises with the length and complexity of the procedure, the larger the bore of needle used, and maternal obesity.
There are theoretical risks of PUBS to the mother such as causing sensitization to fetal blood cells or platelets, causing damage to internal organs, introducing infection, or causing bleeding, but these are also very uncommon. Probably the greatest risk is that of an emergency cesarean section if this is required to manage a fetal complication.

Procedure-related fetal loss rate is difficult to ascertain but is probably in the range of 1-2% and again is related to the complexity of the procedure and the fetal problem that led to the procedure being recommended in the first place. Babies with an indication for PUBS may be critically ill and, for example, those with hydrops, especially nonimmune hydrops, may not be salvageable regardless of any interventions attempted. It is difficult to consider a loss of one of these babies to be a ‘procedure-related event’ when their morbidity is so high at the outset.

PUBS is the riskiest and most challenging of the more common invasive diagnostic procedures we perform, but it is usually reserved for the most severe fetal compromise as well. In recent years, one of the more common indications for PUBS, screening for fetal anemia, has been replaced by the noninvasive Doppler flow assessment of peak systolic velocity in the fetal middle cerebral artery. PUBS is now only done under these circumstances when a significant fetal anemia is suggested by an abnormal Doppler flow result. Also, with the recent advances in genetic and molecular technologies, many of the studies that required PUBS in the past can be performed simply on amniotic fluid and/or the cells contained within it. And, quite likely, many of these studies will be able to be performed on the small amounts of fetal cells and DNA contained in maternal blood specimens as these technologies continue to advance, further reducing the need for these invasive studies.

Labels: amniocentesis, CVS, isoimmunization, percutaneous umbilical blood sampling, PUBS

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