Restless Leg Syndrome (RLS), now often referred to as Willis–Ekbom Disease (WED, see sidebar), is a common sensorimotor disturbance with prevalence in the general population around 10 percent. Disturbed sleep, in particular, is more prevalent in females than males, and numerous studies have reported that women are affected by RLS about twice as often as males are across all levels of severity. It is much more frequent in pregnant (approximately 26 percent) than in non-pregnant women and frequently becomes worse or may appear for the first time during pregnancy. Approximately one-fourth of pregnant women experience RLS, with more intense symptoms experienced during the third trimester, and resolution of symptoms typically occurring within a few months after delivery, though RLS may resolve as early as two weeks after delivery.

Here, we talk to specialists about how they treat the condition in pregnant women.

What special considerations should neurologists take when treating RLS/Transient Willis-Ekbom disease in pregnant women?

“It is interesting how common there are situations where the patient does not complain specifically of [RLS], but only of a bad sleep, or sometimes they do not even complain of bad sleep, as women think this is normal in the pregnant state,” says Jose Pereira, MD, Emeritus Professor of Pediatrics, Jundiai Medical school, São Paulo, Brazil and Head (retired), Sleep Sector, Department of Pediatrics, Jundiaí Medical School.

“In the majority of the cases, the symptoms stop around delivery, so usually it is not necessary to start with a pharmacological treatment,” said Mauro Manconi, MD of the Sleep and Epilepsy Centre, Neurocenter (EOC) of Southern Switzerland. “Sometimes symptoms are severe and women ask for a treatment. All of the drugs used for idiopathic RLS belong to the category C, which means no indication during pregnancy for safety reasons. In case of ferritin deficit I suggest IV iron, which can help,” he said. He also recomends that patients stop caffeine and maintain good sleep hygiene. “Dopamine agonists have been used without major complications, however they can theoretically interfere with lactation. In women already affected by RLS before pregnancy the symptoms might worsen a lot during pregnancy and these are the women more severely affected,” he said. Opioids and small doses of clonazepam might be considered for these individuals.

“For all women affected, we educate about the natural course of RLS during pregnancy and suggest non-pharmacologic interventions such as exercise and avoiding aggravating factors,” said Daniel Picchietti MD, a neurologist in Urbana, IL.

Dr. Pereira says some non-pharmacological measures may be useful. “The pregnant woman should be warned about gaining too much weight; that could place [a burden] on the sensory receptors, an incremented tissue pressure that could enhance their signaling condition. That is, more inputs to cortex that may be felt as [RLS] symptoms. As the same varicose veins should be addressed, they also put more pressure on the somatosensory receptors in the calf.” He adds that logical reasoning points to the periphery as the site where RLS symptoms originate. “Massage may be of great value, and some women may find it useful to wear tight socks.”

Poor sleep hygiene habits must be addressed, he says, agreeing with Dr. Manconi. Sleep deprivation (SD) mightily increases RLS symptomatology, as the thyroid axis increases during SD. “Any hindrance to a good night sleep should be addressed and removed if possible; and, importantly, abstinence from caffeine must be total. Also, grape fruit juice must be entirely avoided. Caffeine and grapefruit are inhibitors of CYP3A4 isoform, where part of the thyroid hormone is metabolized. If CYP3A4 is inhibited, thyroid hormones increase.” Many drugs have the ability to inhibit CYP3A4, so, if possible, the clinician should avoid prescribing them, or, perhaps, should change them to others with minor CYP3A4 inhibiting profile.

“Pregnancy is a time when iron stores can be very low. Low iron can aggravate RLS symptoms. We check the serum ferritin level (a sensitive iron test) for women who are symptomatic with RLS and recommend oral iron if the ferritin level is below 50 mcg/L,” Dr. Picchietti says.

Why might RLS worsen during pregnancy?
“We know for sure that pregnancy is a strong risk factor for RLS and that symptoms reach a peak during the third trimester,” Dr. Manconi said. “We know that probably pregnancy itself lowers the symptomatic threshold for RLS. We do not know why it happens. Factors implicated might be hormones, iron deficiency, or dopaminergic alterations.”

The cause behind the increase of RLS rates in pregnant women is indeed frustrating to researchers, and research has cast more doubt than it is has solved problems. In a 2011 study, researchers distributed a questionnaire to postpartum patients and saw “no correlation between pregnancy-related restless legs syndrome and low hemoglobin levels in the first trimester.” The incidence of restless legs syndrome was not affected by use of iron supplementation. Further, improvement after delivery is not associated with the number of previous pregnancies, the RLS severity and iron intake during pregnancy, peridural anesthesia, caesarean section, delivery complications, newborn weight, breastfeeding, dopaminergic agent intake after delivery, and with the absence of RLS before pregnancy.

What should neurologists take away from recent research?
For his study, Dr. Manconi and researchers conducted a long-term follow-up study, planned as an extension of a previous survey on restless legs syndrome during pregnancy. After a mean interval of 6.5 years, 207 parous women were contacted again to compare the incidence of RLS among subjects who never experienced the symptoms with those who reported RLS during the previously investigated pregnancy.

“The main finding of my study was that women who suffered of RLS during pregnancy compared to those who did not suffer have a four-fold increased risk to develop a standard idiopathic RLS in the following eight years,” he said. “This means that behind pregnancy-related RLS there is a genetic background that predispose to RLS and pregnancy is only a transient precipitating factor which needs a genetic predisposition. The next step is to scan RLS genes in pregnant women with RLS.”

In summation, Dr. Pereira said, “as Dr. Karl A. Ekbom stated long ago, there will not be any doctor, of any specialty, that will not have to face some patient with [RLS].” “But, as to neurologists, they are ‘owners’ of this disease as it is, in my opinion, a functional peripheral neuropathy. Perhaps they share its property with endocrinologists, as its main derangement is an imbalance between two hormones, a classical one, the thyroid hormone, and a neuroendocrine one, dopamine. Neurologists and endocrinologists, perhaps, may be in a good [position] to observe RLS, to treat it, and to unravel more of it that is still hidden.”