By Professor Peter Mortimer, LSN Chief Medical Advisor andDr Sahar Mansour, Consultant Clinical Geneticist, St. George's Hospital, London
Changes in a Normal Pregnancy
The cardiovascular system undergoes considerable changes during pregnancy with an increase in blood output from the heart by at least 50%. Blood vessels generally enlarge creating a relatively 'under filled' circulation and so to compensate, the kidneys try and conserve salt and water. This leads to fluid retention amounting to some 6-8 litres in the body. The dilution of the plasma proteins encourages fluid to leak from the blood vessels into the tissues. A fall in the threshold of the hormone that encourages a fluid diuresis maintains a fluid retention state. By the end of the pregnancy, 80% of healthy women will have some degree of oedema.
Very little is known about what happens to the lymphatic system during pregnancy. If blood vessels enlarge, i.e. relax, then by implication, lymphatic vessels are likely to do the same, in which case they will not be as efficient at draining fluid. Normally there is sufficient reserve in lymphatic transport so that any increases in tissue fluid will be compensated for by increases in lymph drainage. If the lymph drainage is already working close to capacity because of a genetic or constitutional weakness in the lymphatic system (but not so severe as to have produced lymphoedema before), then the extra demands of pregnancy may be all that is needed to manifest swelling for the first time.
Other factors that potentially increase the risk of oedema during pregnancy are weight gain and a reduction in exercise levels.While fluid retention will increase weight, so will obesity. Lean women who eat to appetite gain as much as 1kg in the first 10 weeks and women with a tendency to obesity will gain much more. Such weight gain will probably have an adverse effect on lymph drainage, particularly in the legs. It is difficult to maintain exercise levels during pregnancy because of tiredness and the awkwardness the pregnancy brings to walking. Exercise is, of course, crucial for good lymph drainage in the legs. Like other blood vessels, the veins in the leg tend to enlarge during pregnancy. Varicose veins often develop, which will result in a further filtration of fluid from the blood into the tissues of the leg and so make oedema worse.
Pre-eclampsia (used to be called toxaemia of pregnancy) is specific to pregnancy and manifests with hypertension (raised blood pressure), a leak of protein by the kidney, and oedema. The cause is not known, but the syndrome of pre-eclampsia usually develops from the mid-point in the pregnancy (20 weeks onwards), and resolves completely after delivery. Generalised oedema is an inconsistent feature. It may develop suddenly and is associated with accelerated weight gain (due to fluid retention). Although the ankles and feet will be the commonest site for the swelling due to the effects of gravity, oedema can occur anywhere in the body including the chest and the abdomen (ascites is free fluid in the abdominal cavity). The generalised nature of the oedema would suggest that the fault lies with the blood vessels leaking more fluid into the tissues rather than any failure of the lymphatic system, but nobody knows. As mentioned earlier, any such increase in tissue fluid will inevitably demand more of the lymphatic vessels to drain the fluid and any failure to do so will increase the oedema further. Diuretics are best avoided in pregnancy because they result in an even greater 'under fill' of the blood circulation. Drugs called 'calcium channel blocking agents' are recommended for the raised blood pressure, but do tend to interfere with the working of lymphatic vessels and may increase ankle oedema.
Lymphoedema in Pregnancy
A major concern of any young female patient with lymphoedema is "What will happen to my lymphoedema if I become pregnant?" The answer is that it is likely to get worse because of the fluid retention, but it should be manageable and fully recover once the baby is born. The extra bodily fluid retained during the pregnancy will include the part of the body affected by the lymphoedema; so extra effort will be required to ensure that this extra fluid is drained by the local lymphatic system that is already failing. So if a leg is affected by lymphoedema, for example, then extra measures to control the swelling may be necessary. These measures may include longer periods of rest with the leg elevated, manual lymphatic drainage, or an additional compression garment. Not every woman with lymphoedema suffers any exacerbation of swelling during pregnancy. In many, the lymphoedema remains unaffected, and so what is described here is the worst case scenario.
There is no reason to believe pregnancy harms the lymphatic system, and so a full recovery would be expected following delivery. Nevertheless, as with returning to one's original weight and bodily shape, recovery of the lymphoedematous limb may take a bit of time and effort. Increasing levels of exercise and dieting may be necessary.
Genetics, Lymphoedema and Pregnancy
Primary lymphoedema is due to an underlying abnormality in the lymphatics. Although the swelling may not be present until later in life, the abnormality is probably present at birth. It is now recognised that there are some causes of primary lymphoedema that are inherited. Therefore a woman (or man) with primary lymphoedema may have a child with the same condition.
The best indicator that there is a genetic cause of lymphoedema is the presence of other affected individuals in the family. The commonest way that primary lymphoedema is inherited is from parent to child. This mode of inheritance is called autosomal dominant inheritance. There are two copies of most genes. An autosomal dominant condition is due to an alteration, or 'spelling mistake', in one of the copies. The baby can inherit either the affected gene or the unaffected gene, so the risk to the offspring of inheriting an autosomal dominant condition is 1 in 2, or 50%. Some of the genetic causes of primary lymphoedema are well recognised and are described in more detail below.
Milroy first described a large family with lymphoedema presenting at birth in 1892. It was clear from the family history that this condition was autosomal dominant, and therefore being transmitted from parent to child.Milroy's disease presents predominantly at birth with swelling of the lower limbs, usually the feet. The swelling can increase, or improve, or remain stable. Boys sometimes have extra fluid in the scrotum, but this rarely causes any problems. Milroy's disease is not usually associated with any other abnormalities.Most of the carriers of this condition have some swelling of the lower limbs, but it is recognised that some carriers of the condition are not affected, but may have affected offspring. The lymphoedema in Milroy's disease is due to a lack of lymphatic channels in the lower limbs (hypoplasia or aplasia). The gene for this condition, Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) was identified only recently. This gene is important in the development of the lymphatics of the baby.
This condition is another autosomal dominant cause of primary lymphoedema. However, the lymphoedema usually presents in late childhood or puberty.
The age of onset and severity of the swelling varies even within families. The swelling is usually associated with the presence of extra eyelashes on the inner side of the eyelids.
Although the swelling presents later, it is still due to an underlying abnormality of the lymphatic channels. Lymph scans in affected individuals have shown that there are a normal or excess number of lymphatic channels with delayed uptake of lymph in the inguinal lymph nodes, suggesting an abnormality in the function of the lymphatic channels. The mechanism is still unknown. This condition is sometimes associated with other congenital abnormalities. About one third of affected individuals have drooping of the eyelid (ptosis) which occasionally requires surgical correction. There is a slightly increased risk of heart disease at birth (8%). This is not usually severe, but may require surgical repair. A few affected individuals also have a cleft palate (3%). The gene for this condition has been identified; it is a very small gene called FOXC2. It clearly has a role in the development of the lymphatics and eye, but very little is understood about its function.
Risk of Inheriting Lymphoedema
The risk of inheriting lymphoedema for those types where the gene is known and in which a family history exists, is approximately 50%, i.e. 1 in every 2 births. There are, of course, many other causes of primary lymphoedema.Many of these may be genetic but not inherited. Often the underlying cause is not known.
The baby is at an increased risk of inheriting the lymphoedema if any of the following are present:
- If one parent is affected and has a family history of lymphoedema
- If the affected parent has distichiasis (extra eyelashes)
- If the lymphoedema is symmetrical and bilateral.
- The affected parent has no family history of lymphoedema
- There is no distichiasis
- The swelling is unilateral (including lower limbs)
- The swelling is not in the lower limbs.
How Can You Tell If the Baby is Affected
Ultrasound examinations performed during the pregnancy may pick up oedema in a foot or around the back of the neck, both signs that the child may be affected. In the majority of cases, no abnormalities will be observed, and it may only be after birth or sometime later in life that the lymphoedema becomes obvious. In the future it may be possible to test the baby for the offending gene during the pregnancy, but this is not possible at present.
Prevention of Lymphoedema
In the years to come, we hope it will be possible to correct the faulty gene before the baby is born so that the lymphoedema can be reversed. This has been achieved in animals, but not yet in humans. Insertion of the normal gene instead of the faulty one is called gene therapy. It may be possible to do this in adults already affected by lymphoedema. There is hope!
Lipoedema and Pregnancy
Pregnancy may trigger or exacerbate lipoedema and worsen the lymphoedema component of lipoedema. Lipoedema is a condition that results in swelling of the hips, thighs or legs in females. Fluid does contribute to the swelling, but the main component is fat, but in a way different from obesity. In addition to swelling, which gives rise to a 'bottom heavy' or 'chunky, shapeless legs' appearance, symptoms of tissue tenderness and easy bruising are commonplace. Lipoedema tends to develop or deteriorate at times of hormonal change, e.g. puberty, pregnancy and menopause. The condition may not be apparent during the pregnancy because of all the other changes that take place. Following the pregnancy, however, weight loss may prove difficult from the lower half of the body (bottom, thighs and legs). Dieting tends to result in fat loss from face, neck and chest, but not the legs. Treatment is difficult, but a vigorous exercise regimen and healthy eating are recommended. The fluid component of lipoedema appears to be related to poor lymph drainage from the areas of fat deposition. As the fluid increases, so more noticeable oedema develops, particularly in the feet. This is called lipoedemalymphoedema syndrome (lipolymphoedema). Pregnancy may therefore trigger or exacerbate lipoedema.
In summary, in female patients with lymphoedema, pregnancy may create additional concerns with regard to adverse effects on the swelling and the fear of passing on the condition to any offspring. In most cases these concerns are unfounded. Any increase in swelling can usually be managed satisfactorily with the help of a lymphoedema therapist, with a full return to normal once the baby is born. In many individuals the lymphoedema will not change. In the event of a child inheriting lymphoedema, it does not follow that their condition will be the same or worse than that of the parent. The recent upsurge in our knowledge of the genes and proteins involved in lymphatic growth and development means that the possibility of curative or even preventative treatment for primary lymphoedema is greater than ever before.
This article is taken from the Summer 2004 issue of LymphLine, the LSN's quarterly newsletter available to all LSN members
Lymphoedema Support Network
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Pregnancy and Lymphedema
Several months ago one of our readers asked whether pregnancy caused lymphedema to get worse. I reviewed the published literature and, as is too often the case, found very little published information. In addition, what information was available was based on very limited numbers of patients. To gain additional understanding about pregnancy and lymphedema, I created a pregnancy survey for our readers. 13 women have responded to that survey and I am including a summary of their responses and insights.
12 of the 13 women had primary lymphedema. The average age of onset was 10 years of age and the range was from 1 to 16 years of age. 1 patient had breast cancer and a mastectomy and developed lymphedema during her first pregnancy 9 years later.
Of the 12 patients with primary lymphedema, 9 of 12 (75%) had the onset of lymphedema or developed worse lymphedema during their pregnancy. Most of these women found that the lymphedema got worse in the final months of their pregnancy. 2 women reported having persistent lymphedema after delivery.8 women reported second pregnancies and 5 of the 8 (63%) had worsening of their lymphedema and all reported that the lymphedema was worse with the second pregnancy. All 3 women who did not report worsening of their lymphedema had miscarriages that occurred between 3 and 5 months of gestation.4 women reported having third pregnancies and 3 of the 4 had worsening lymphedema with the pregnancy and all reported that the lymphedema became progressively worse with each pregnancy. The remaining woman had a miscarriage.
One woman reported a 4th pregnancy and had worsening lymphedema with the 4th pregnancy but that the lymphedema got better after the delivery of her child.
The one respondent with secondary lymphedema commented that she had been free of lymphedema for 9 years after her mastectomy but developed lymphedema in her hand and forearm during her first pregnancy.
The only women not reporting worsening of their lymphedema during their second and subsequent pregnancies had miscarriages. Miscarriages occur in about 10% of pregnancies so it is notable that so many of the women responding to this survey reported miscarriages. Please keep in mind that a small number of women responded to this survey and any results represent the bias of any small sample. However, it is also possible that the incidence of miscarriages is higher than the expected in women with lymphedema. I will continue to report on additional findings of this survey as we get more information.
Many of the comments made by the women provided interesting insight into the problem of lymphedema during pregnancy so I have included a sample of these comments below.
"I am currently in my eighth month of pregnancy and have doubled the size of my left leg. Prior to the pregnancy, I had not swelling in my right leg. Now in my eighth month of pregnancy, my right leg is swelling. I am hoping the swelling in my right leg will go away after the baby is born."
"By 11-12 weeks of pregnancy, my leg was fuller and growing uncomfortable. I was able to continue working full time as a nurse until the 20th week of pregnancy. At that point my leg was heavy and uncomfortable. I was comfortable, however, if I was lying down. During the pregnancy, I gained over 60 lbs., I was very congested in my entire body. I remember having to put my left leg and foot under cold water to reduce the discomfort. I was unable to wear any shoes other than ballet slippers, and could only do minimal walking around the house. After my daughter was born, one to two weeks after her deliver, my leg returned to essentially a pre-pregnancy baseline. My leg improved as I took off the weight gain of fat that naturally occurs with pregnancy. "
"I am currently at the last stage of my third pregnancy, and the swelling is once again more pronounced than in previous months. I tend to be lazier about the stockings this time, so my swelling could probably be better."
"Thank you for posting this survey, I would have enjoyed having some preview of the effects of childbirth on lymphedema. Overall, pregnancy was a temporary setback, which is an important consideration. However, I was still uncertain enough not to attempt my good luck with a second pregnancy. Who knows what the outcome would be, especially after age 35. My personal experience with this condition has led me to believe that insect bites are far worse for my leg. If I get bites on my left leg, my leg gets worse, and doesn't want to return to baseline. It's as if I "loose ground" whenever this happens. The increase with pregnancy, although very substantial, was reversible. It seemed to me to be in indication of lymphatic system overload, rather than tissue scaring or damage. I did notice that as my weight returned to normal, my leg kept improving."
Tony Reid MD Ph.D.
Peninsula Medical, Dr. Reid's Corner
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Pregnancy and Lymphedema: Followup
Last year I presented data on the relationship between pregnancy and lymphedema. Since that time more women have responded to the survey and I presented the update of that survey at the Lymphedema conference held in Dallas, Texas sponsored by Healthtronix.This survey was prompted by several questions that were sent to me asking whether pregnancy worsens lymphedema. For example, a woman had primary lymphedema and was considering an abortion because she was very fearful of her lymphedema getting worse. She already had a bad case of lymphedema and felt that if it got much worse she would no be able to function. There was no published data to help answer these questions and so I posted a survey on our web site to help find some answers to this question.
First, I want to say that the results of the survey are limited by a number of factors. The number of women answering this survey, while growing, is still relatively small. In addition, this is not a random sample of all women with primary lymphedema who have had a pregnancy and effective treatment may change the outcome. This survey only documents the experience of the women who have responded. However, I appreciate the fact that these women have taken the time and effort to answer these questions and I hope that this project will continue to develop and provide additional information that is helpful to women facing this problem.
33 women responded to the survey. Of these, 26 had primary lymphedema and this survey will focus on those 26 responses. Most women with secondary lymphedema have it as a result of treatment for breast cancer. As a result, the majority of these women are past their child bearing years. In addition, the treatment, especially chemotherapy, generally causes infertility. So, most of the women who have lymphedema during their child bearing years have primary lymphedema. I will analyze the results of the women with secondary lymphedema separately. Since there are only a few responses, the data is still limited.
The average age of onset of lymphedema in this group of women with primary lymphedema was 10.7 years but the range of responses was very wide. Some women developed lymphedema at birth while others developed lymphedema in their late teens or twenties.
Of the 26 women with primary lymphedema who responded to this survey, 12 of 26 (46%) reported worsening of lymphedema with the first pregnancy. Of the 12 who had worsening of lymphedema during pregnancy, 7 reported that the lymphedema returned to baseline after delivery so that 5 of 26 (19%) reported persistent lymphedema after pregnancy. However, among the women who improved after delivery, 2 of these women subsequently had worsening of lymphedema within a year. As a result, 7 of 26 (27%) reported lymphedema that was worse following their first pregnancy.
Here are several comments from these women.
"After delivery my leg went back to it's prior size before becoming pregnant. However, after 7 months my leg again became swollen and progressively got worse."
"In my second trimester my ankles began to swell and the doctor assumed it was all normal. After the delivery of my child the swelling in my right leg / ankle went away but the swelling in my left leg continued."
These results suggest that about half of the women with primary lymphedema experienced worsening of lymphedema during their pregnancy. Among the women who reported that their lymphedema worsened with pregnancy, about half of these women reported improvement after delivery of the baby. As a result about 27% (7/26), of the women with primary lymphedema experienced persistent worsening of the lymphedema with pregnancy.
Some of these women had additional pregnancies and I will present the analysis of the results in the subsequent edition of eNews.
Tony Reid MD, Ph.D
Lymphedema Pregnancy and Followup
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