Pregnancy and VHL

When Dr. John Adler first asked me to speak about pregnancy and VHL and I started to research the topic a little bit, the first thing that struck me is how limited the data really was. There are essentially only case reports in the literature, which makes it very difficult to come up with any cohesive message to give to patients. What I have tried to do is to put together some of the highlights in the literature, and to raise some of the important questions.

I found this quote in the Journal of Maternal-Fetal Medicine.¹ I start with this because I think it is quite telling of the difficulty of bringing to bear some of the data on this disorder in pregnancy. "As many women start to develop clinical features in their reproductive years, one may wonder why so little is published regarding the association of pregnancy and VHL. It is likely that either most patients remain asymptomatic during their pregnancy, or the close clinical surveillance regimen results in recognition and treatment of tumors before or between pregnancies." The surveillance ameliorates some of the complications. But I think the last line is important: "Any complication of the disorder may present during pregnancy", and frequently does so quite unexpectedly, sometimes as the first diagnosis of the disease.

The case reports focus on four topics:

• Pheochromocytomas
• CNS hemangioblastomas
• Anesthesia, especially as it relates to surgery during pregnancy and during delivery, and the
• Mode of delivery, specifically vaginal delivery, forceps, vacuum assistance, cesarean section

Pheochromocytoma

In the general population pheos occur in once in 54,000 people. But pheos occur in about 20% of people with VHL, and they represent a very significant risk for a pregnant woman and her baby.

The classic symptoms of pheo are headache, palpitations, and perspiration. In pregnancy, these can be absent or can be misdiagnosed as a disorder known as preeclampsia, or toxemia of pregnancy. Preeclampsia is a placental disorder that occurs in about 9% of women. It manifests as hypertension, renal damage, liver damage, seizures, and if untreated, death. Because the symptoms of pheo are similar, it is mismanaged as preeclampsia.

Other manifestations of pheochromocytoma include: abdominal pain, postural hypotension² (which is a key factor in differentiating it from preeclampsia), visual disturbances, convulsions, adult respiratory distress syndrome (ARDS), collapse, shock, and death. All of these symptoms have been reported with pheochromocytomas in pregnancy.

The consequence of having an undiagnosed pheochromocytoma that is active in pregnancy is really tremendous. In the literature it results in a 40-50% maternal mortality rate³ — a shocking statistic until you consider what can go wrong. The good news is that with early diagnosis and appropriate management by the medical team, the mortality rate can be reduced to 0-11%.⁴ It is critically important to communicate fully with the doctor and make it known that you have a diagnosis of VHL, or that there is VHL in the family, even if you have no previous symptoms or no clear diagnosis of VHL. This information can make the difference between life and death for mother and child.

The high blood pressure created by the pheo not only affects the mother, but it can compromise the mother’s ability to maintain sufficient blood flow across the placenta to nourish the fetus.

In the setting of a pheo, a number of normal effects of pregnancy can cause a hypertensive crisis: the pressure of the growing uterus on the blood vessels, changes in the body catecholamine levels, uterine contractions, fetal movements, the pain of labor, and the expulsive forces during labor.

The fetal compromise that we worry about most obviously is fetal death, and it is felt to be associated with constriction of the blood vessels in the placenta caused by the elevated levels of circulating catecholamines. With severe hypertension you also see something called placental abruption, where the placenta prematurely separates from the uterus, and that of course disrupts the surface area for nutrition and oxygenation to the baby, and frequently results in massive maternal hemorrhage. Severe, uncontrolled hypertension may result in placental insufficiency leading to reduced amniotic fluid volume, cord compression and fetal jeopardy.

Early diagnosis and appropriate management are key. If the pheo manifests itself in the third trimester and the mother is treated with alpha blockade and the fetus is monitored carefully, you cut the risk of fetal compromise from 42% to nearly zero.⁵ If the pheo manifests itself in the early stages of pregnancy, when there is still a long way to go, management is more difficult, but the risk still drops from 75% without treatment to about 17% with treatment.⁵ So early diagnosis, aggressive intervention, can really alter the course of this disease in pregnancy. Meticulous monitoring of the fetus is essential, with ultrasounds, and something called a nonstress test which is an indirect measure of fetal central nervous system oxygenation by looking at the heart rate tracing of the baby.

In one of the reported cases,⁶ a 20-year-old healthy woman was admitted at 26 weeks with bleeding and a blood pressure of 160/100. I can tell you this happens 3-4 times a day on a high risk labor and delivery unit, and the first diagnosis that is going to come to any obstetrician’s mind is preeclampsia with possible placental abruption causing the bleeding. She had an obstetrical ultrasound that looked at the baby and incidentally they noted bilateral maternal adrenal masses. An MRI and 24-hour urine confirmed pheochromocytomas. They controlled her blood pressure with phenoxybenzamine, propranolol, and nifedipine.

At 30 weeks gestation she required a cesarean section for fetal distress and intrauterine growth restriction. Again, the concern with elevated catecholamines is the constriction of the blood vessels that can impair fetal growth and result in fetal distress. In this case they did combined cesarean section and removal of the adrenal tumors, which is frequently what has been reported in terms of the timing of removal of these tumors, and we’ll talk a little more about that. Both mother and baby did well.

Again, pre-conception counseling is ideal. Make the diagnosis prior to pregnancy, do the workup prior to pregnancy with urinary levels of catecholamines, CT scans and MRI. If the condition is diagnosed and the pheos removed before the pregnancy, the risks are considerably diminished.

The timing of the delivery can also be a critical element. It can be very complicated. It requires a real team approach.

The optimal timing for surgery is also debatable with pheochromocytomas in pregnancy. Delaying surgery until fetal maturity, is the ideal case scenario — so you are not delivering a profoundly premature baby that suffers all the consequences of prematurity. You have to balance that against the risks of continuing with an active pheochromocytoma long-term.

Each woman’s situation will have to be evaluated carefully. That said, the general recommendation would be that if you are in the first or early second trimester, you institute alpha blockade, and if you are that far away from fetal maturity the general recommendation would be to go ahead and surgically treat the patient. However no definitive recommendations can be made. In general if you have a viable baby (greater than 24 weeks gestation) and you have a reassuring maternal-fetal status – the mother is responding to treatment – you can try and delay resection until cesarean section at the time of fetal maturity. Again it requires a lot of monitoring, and possibly a long-term hospitalization.

If you look at the existing case reports, they generally time tumor resection in the third trimester with cesarean section -- a combined procedure. That can be very tricky. The vessels are hugely engorged, and there is a risk of hemorrhage and other complications to the mother. Increasingly people are doing laparoscopic resection. Obviously with a gravid uterus in the third trimester that is very very difficult to do. Delaying resection until postpartum in order to do it laparoscopically has been suggested, but is also extremely controversial.

During surgery in pregnancy, one obviously has to do intensive monitoring of both the mother and the fetus, measuring arterial pressures, perhaps using a Swan-Ganz catheter to help assess the volume of blood in the blood vessels, and cardiac function.

CNS hemangioblastomas

Hemangioblastomas of the retina, brain, and spine are another area that has been frequently discussed in the literature. The spinal cord and cerebellum are the main sites that have been reported. Growth in pregnancy is a concern. It is controversial, but there is some indication of progesterone receptor proteins that may contribute to growth of these tumors in pregnancy. In addition, the issue of increased maternal blood volume, increased cardiac output, all may predispose to growth of these tumors in pregnancy.

• Increased maternal blood volume
• Maternal cardiac output increased by 20%

If a tumor in these sensitive areas should hemorrhage, or grow to the point of needing surgery, the consequences can be severe: hemorrhage, intracranial pressure, hydrocephalus, paraplegia, and herniation of the cerebellum, all of which can be life-threatening.

There is a case report⁷ in which a 26-year-old woman with known VHL came in 7 weeks pregnant with headache and paraplegia that had been going on for two weeks. She had multiple cerebellar hemangioblastomas and obstructive hydrocephalus, an obstruction of the flow of spinal fluid through the brain, causing increasing pressure in her skull. The therapy was to place a shunt to divert the fluid buildup, which improved the symptoms and she continued the pregnancy. She was delivered by cesarean section at 33 weeks. After the baby was born they noted a decrease in the size of the cerebellar lesions. So there was apparently some growth or engorgement of these lesions during the pregnancy.

Another case study,¹ describes a 30-year-old woman with VHL at 30 weeks gestation who had symptomatic cerebellar hemangioblastomas. They performed a craniotomy for complete removal of the tumor. The remainder of the pregnancy was uneventful, and she had a vaginal delivery at term under epidural anesthesia.

In another case report,⁸ a pregnant woman, age 23, with a family history of VHL, came in at 35 weeks gestation with paraplegia. She was noted to have an acute intramedullary hemorrhage of the spinal hemangioma at the thoracic 4-5 level. A T3-6 laminectomy resulted in improvements. She developed pre-term labor, and had a cesarean under epidural anesthesia. The reason they chose cesarean in this case is that there was another spinal cord hemangioblastoma they were worried about rupturing during labor.

Here again, pre-conception evaluation and baseline CNS imaging studies are critical to make the diagnosis early, to have the information early. Neurological status should be monitored carefully throughout the pregnancy. You can use CT scans, you can use MRI. It is possible to do elective repair if you make the diagnosis during pregnancy, but of course it is preferable to do repairs in the post-partum period.

However, if there are symptoms of acute or subacute spinal cord compression it’s a surgical emergency and regardless of fetal maturity you need to intervene. Frequently people can get very confused during pregnancy about the priorities. The priority is the mother. If you have a sick Mom, you’re going to have a sick kid. It’s really useless to focus on the baby and forget that your main patient, your main priority, is the mother.

Avoiding intraoperative hypotension is an important factor during neurosurgery. Hypotension is frequently used in neurosurgery, but in a pregnant woman that can cause poor blood supply to the uterus, a drop in the fetal heart rate, and fetal distress. The data on hypothermia, another technique used in neurosurgery, is limited. It has been associated again with fetal distress and bradycardia (an abnormally low fetal heart rate). Osmotic diuretics and loop diuretics are frequently used to decrease the intracranial pressure. Limited use of these agents is reasonable in pregnancy. The concern, though, is that if you are too aggressive with them you are going to lower the blood volume, damage the perfusion of the placenta, and result in fetal distress.

Dexamethasone decreases intracranial pressure and is used in patients with increased intracranial pressure. It does cross the placenta, but actually can have a beneficial effect. We use it in patients in pre-term labor to enhance fetal lung maturity. So in the proper setting, dexamethasone is quite appropriate.

Prednisone is also used. It is metabolized by the placenta, and the baby doesn’t really see it.

Anesthesia

There is also a lot of controversy about choices of anesthesia, especially in regards to the use of spinal and epidural anesthesia. Cerebellar herniation is a concern in the case of a spinal block where you have increased intracranial pressure. Rupturing of a hemangioblastoma by the spinal needle is a concern, and in the case of a pheochromocytoma, the sudden profound drop in spinal pressure that you can get with a spinal block can be problematic, both to the mother and to the fetus. But there are important benefits to spinal and epidural anesthesia.

With epidurals you get a reduction in the cardiac output during labor, which can be helpful in cases of pheochromocytomas and CNS hemangioblastomas. It decreases arterial pressure, and decreases the bearing-down reflex in the second stage of labor, where the mother has the urge to push.

While general anesthesia has no known long-term ill effects on the fetus or placenta, it has its standard risks, one of them being maternal hypertension during rapid-sequence induction intubation. So it’s not a panacea.

Again, it’s important to individualize the care: to evaluate the extent of the patient’s disease, to review the imaging studies of the CNS. If you are going to use regional anesthesia you need to know where these tumors are located, and an epidural is generally felt to be preferable to spinal for two reasons. One, it is thought to introduce less risk in terms of rupturing a hemangioblastoma, and second, the degree to which it reduces spinal pressure can be minimized. Both epidurals and spinals in the setting of pheos are very controversial.

Ergot medications, routinely used after delivery to treat post-partum hemorrhage, can cause hypertension and should be avoided in patients with pheochromocytomas and patients with CNS hemangioblastomas.

If surgery is performed during pregnancy, especially during the third trimester, appropriate positioning of the mother is going to be critical. It is important that she is not lying flat. She has to be tilted, to take the weight of the uterus off the major vessels in the pelvis and abdomen.

During any such surgery where there is a viable fetus, the fetus should also be monitored closely. In such situations we have used continuous fetal heart rate monitoring during surgery. If it’s the third trimester and there is fetal distress, you can intervene and perhaps deliver the baby early.

There are more questions than answers. The data is very limited. The patient needs to be a real participant in all of this. The patient, family, and medical team need to work closely together. It’s a tricky situation that calls for counseling, consent, and understanding of the ambiguities that are likely to arise.

Mode of Delivery

During labor the pressure rises both in the blood vessels and in the cerebral spinal fluid. Each contraction affects the pressure. In that setting there is risk of rupture of the CNS hemangioblastoma, and the risk of a hypertensive crisis in labor with pheochromocytomas.

With CNS hemangioblastomas, cesarean delivery has been recommended, especially where there are large lesions, elevated intracranial pressure, or neurological deterioration. In some situations, vaginal delivery and epidural analgesia is reasonable and appropriate if there is no acute neurologic deterioration. With careful management, the doctor can minimize the arterial pressure, and can do what is called a second stage assist to avoid the mother bearing down. Second stage assist is waiting for the mother to become completely dilated, and the fetal head to descend in the pelvis low enough to apply a vacuum or a forceps. There are some risks to both mother and baby with an operative vaginal delivery, but in the proper hands it is generally quite safe.

There is only limited literature on how best to deliver patients with pheochromocytomas. This data include patients who were treated and untreated, and patients who came in at term with terrible hypertension, no treatment, and no diagnosis. It shows that with vaginal delivery there is a 31% risk of maternal death; with cesarean section, the risk dropped to 0-19%.³ As such cesarean section has been advocated, primarily now because of concerns over hypertensive crises in labor, concerns regarding conduction anesthesia, and because of the tendency until recently to do a combined delivery and resection of the tumor.

Today there are a number of physicians, including myself, who have tried to delay resecting the tumor until after the mother has recovered from delivery. If the patient is in her third trimester, and is well controlled with established alpha blockade, we watch the blood pressure intensively during pregnancy and delivery, and decide whether we feel we can wait and do a laparoscopic procedure after recovery rather than exposing the mother to a more risky major operation at the time of delivery. Again, there is no consensus on these matters.

The largest series that I could find in the literature⁹ is an analysis of 56 pregnancies in 30 women with VHL. It’s a low-risk group. All but one had asymptomatic lesions. Symptoms related to VHL developed in 5.4% of the pregnancies. The live birth rate was 96.4% and all infants survived. Mean gestational age 38.2 weeks, which is well into term. Weight 3.1 kilograms. These are excellent outcomes. There are risks for women with VHL, but you can have good outcomes. Again, this is data on a low-risk group.

The authors of this paper feel that pregnancy should not be discouraged in women with VHL if the screening results are negative, or if the lesions are asymptomatic and have been adequately treated.

Counseling. There is no good data on pregnancy and VHL kidney issues specifically. In counseling women with renal insufficiency from multiple causes, it is important to explain that pregnancy places a major additional burden on the kidney. So normal renal function is important. If there is moderate or severe renal insufficiency the risks in terms of prematurity, or permanent loss of renal function, can be significant.

No matter how good our intentions are to achieve more widespread pre-conception counseling, the reality is that at least half the pregnancies are unplanned. It is important for the patient to inform the medical team that VHL is in the family, even if she herself does not have a diagnosis of VHL. In the absence of symptoms it is important to have a high level of suspicion. In a patient with VHL It is important to check for all possibilities — pheochromocytomas, CNS involvement, retinal involvement, 24-hour urinary collection, eye exam, abdominal ultrasound, MRI, CT – so you know what you’re doing, and so the patient and the medical team can be prepared for possible complications.

Critical to all this is a multi-disciplinary approach. The patient who has VHL and has lesions of any kind, needs to be delivered in a place that has all the specialists necessary to take care of this patient – obstetricians, surgical specialists, anesthesiologists, endocrinologists, neurologists, radiologists, geneticists – it’s a big effort on everybody’s part.

See related stories from  Pat (pheo)  Karen (brain)  Renée (spinal)  Laura (CNS treated) Note: Whenever you have the opportunity to check things out before entering into a pregnancy, be sure to have a complete set of "before" tests. This will also help us collect data on the question of whether and to what extent tumors grow, or temporarily inflate, during pregnancy. What is very hard to sort out is how many people in fact experience tumor growth during pregnancy, and of those, how many tumors grew because of the pregnancy, and how many of them grew simply because it was their time to grow.

Footnotes:

1. Delisle MF et al. Central Nervous System Complications of von Hippel-Lindau Disease and Pregnancy; Perinatal Considerations: Case Report and Literature Review. J. Matern.-Fetal Med. 2000;9:242-247.

2. Postural hypotension: a significant drop in blood pressure when standing versus when sitting.

3. Schenker JG, Granat M. Pheochromocytoma and pregnancy: An updated appraisal. Aust NZ J Obstet Gynaecol 1982;22:1-10.

4. Harper MA. et al. Phaeochromocytoma in pregnancy. Five cases and a review of the literature. Br J Obstet Gynecol 1989;96:594-606.

5. Burgess GE. Alpha blockade and surgical interventionof pheochromocytoma in pregnancy. Obstet Gynecol 1979;53:266-270.

6. Kothari A et al. Massive bilateral phaeochromocytomas in association with Von Hippel Lindau syndrome in pregnancy. Aust N Z J Obstet Gynaecol 1999 Aug;39:381-4.

7. Naidoo K, Bhigjee AI. Multiple cerebellar haemangioblastomas symptomatic during pregnancy. Br J Neurosurg 1998;12:281-4.

8. Ogasawara et al. Pregnancy complicated by von Hippel-Lindau Disease. 1995;85:829-831.

9. Grimbert P. et al. Pregnancy in von Hippel-Lindau disease. Am J Obstet Gynecol, 1999;180:110-1.

As printed in the VHL Family Forum  9:5, December 2001.  For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.