Ptyalism gravidarum

Abstract

Ptyalism gravidarum, or sialorrhoea, is a highly distressing maternal condition characterised by excess salivation and difficulty swallowing saliva, requiring the affected woman to frequently expectorate. The literature is sparse and somewhat conflicting. There are marked geographical and cultural differences in prevalence. The aetiology is not known, and no trials have been performed with respect to treatment modalities. A review of the available literature is presented, and possible future directions for research are suggested.

Introduction

Ptyalism gravidarum (PG) typically has an abrupt onset in the second-third week following conception, with 92% of affected women presenting by 8 weeks’ gestation.^1,2 In the majority of cases PG resolves in the second trimester, though symptoms may continue until delivery. ³ If symptoms persist beyond the second trimester, there is inevitably resolution at delivery. ¹ Saliva production increases from 0.5–1.5 L in volume preconception to 1.5–2 L per day. ⁴ The saliva produced is thicker, copious, and bitter. Attempting to swallow saliva results in a retching reflex. ⁵ Additional symptoms include distended cheek pouches, swollen salivary glands, a red enlarged tongue, excoriation of the buccal mucosa, maceration of the skin of the neck and chin, impaired swallowing, dysgeusia, disturbed sleep, fatigue, anxiety and depression.^2,6 Saliva production may be increased by speaking. ⁵ Difficulty swallowing may lead to decreased appetite, reduced food intake and weight loss. The symptoms and signs may lead to embarrassment, social isolation, and inability to work. Women carry tissues, cups, bags or towels to clear their saliva. The symptoms may be severe enough to prompt termination of pregnancy. ⁷ Some case series have reported increased rates small for gestational age infants, while other case series and case reports have noted no adverse outcome.^1,3

Objectives

To review the available literature regarding PG, with regard to presentation, aetiology, current treatments, and possible future therapies.

Methods

A search of Medline, EMBASE and Google Scholar from inception until May 2024, using the terms ‘ptyalism’, ‘sialorrhoea’, ‘hypersalivation’ and ‘pregnancy’ was performed, resulting in 154 manuscripts. Abstracts were used to filter results and exclude duplicates, resulting in 32 publications. References were manually reviewed to identify an additional 40 publications.

Case

A 24-year-old in her first pregnancy was referred to a medical antenatal clinic at 21 weeks' gestation because of ptyalism. She had noted severe hypersalivation from 6 weeks' gestation, with vomiting once/week. Symptoms persisted at night, interrupting sleep, and requiring her to sleep on a towel. She described postural hypotension following a sleeve gastrectomy 5 years earlier, and past history was also significant for familial hyperhidrosis, anxiety/depression and gastrooesophageal reflux (GOR) well controlled with esomeprazole. She denied the use of herbal or complementary therapies or geophagia. Amitriptyline prescribed by an otolaryngologist had resulted in worsening postural presyncope and syncope. She was a non-smoker. Examination revealed a young woman continuously spitting into a towel, and a 30 mmHg postural systolic drop. Serum cortisol and micronutrients were normal except for mildly reduced active B12 and iron stores which were replaced. Amitriptyline was ceased, and 0.05 mg of oral clonidine was commenced. Three days after commencement of clonidine there was a marked improvement in hypersalivation. The remainder of the pregnancy course was uneventful, proceeding to a vaginal delivery of a well 3584 g female at 41 weeks’ gestation. Symptoms of ptyalism resolved postpartum.

Salivary gland anatomy and physiological changes in pregnancy

Seventy per cent of saliva in the non-pregnant individual is from submandibular and 25% from the parotid glands ⁸ There is a baseline spontaneous secretion of saliva at rest, as well as a reflex stimulation of salivary flow in response to taste, smell or mastication. The submandibular/sublingual glands secrete more saliva under resting conditions, while the parotid gland secretes more saliva in response to stimulation. Nerve impulses in the afferent limbs of the salivary reflex pass from chemoreceptors in taste buds and mechanoreceptors in the periodontal ligament to the salivary nuclei within the medulla oblongata, from which efferent parasympathetic secretomotor nerves emerge to supply the salivary gland (Figure 1). ⁹ Efferent impulses reach the salivary glands predominantly by cholinergic parasympathetic fibres in the autonomic nervous system via the facial and glossopharyngeal nerves, with sympathetic fibres having a lesser effect in modulating saliva production. ¹⁰

Figure 1.

Neural regulation of salivary gland function.

Saliva flow rates are also increased with fasting and with exposure to acid through parasympathetic cholinergic stimulation.^11,12 Malic acid spray has been used in the management of xerostomia as it increases both unstimulated and stimulated salivary flow rates. ¹³ Factors causing a reduction in saliva flow rates include an increase in saliva pH and exercise. ¹⁴

Unstimulated salivary flow rates in non-pregnant women are 0.48 ml/min, rising to 0.56 ml/min in the first trimester, then falling to 0.34 ml/min and 0.31 ml/min in the second and third trimester, respectively. ¹⁵ The increase in salivary flow in first trimester has been postulated to be due to an attempt to buffer the reduction in saliva pH in pregnancy. Unstimulated salivary pH is lower in pregnant women (mean 6.34) compared with non-pregnant individuals (mean 7.01). ¹⁵

The normal electrolyte concentrations in saliva in non-pregnant individuals are sodium 10 mmol, potassium 26 mmol, calcium 2 mmol, bicarbonate 8 mmol and magnesium 0.6–1.4 mmol. ¹⁶ During pregnancy the salivary electrolyte concentrations change, with a decrease in salivary sodium and an increase in salivary potassium. ¹⁷

Aetiology of ptyalism gravidarum

Sialorrhea can be either due to increased saliva production or failure of mechanisms that clear saliva from the oral cavity. The causes of ptyalism in non-pregnant individuals are summarised in Table 1. The aetiology of PG is unknown, with theories proposed including psychological, hormonal and neural causes. ¹⁸ Hormonal changes may be implicated in the pathogenesis of ptyalism, given PG resolves postpartum. ²

Table 1.

Causes of chronic ptyalism in non-pregnant individuals. ¹⁰

Drugs with cholinergic effect – clozapine, risperidone, nitrazepam, lithium, bethanechol

Neurologic disorders – cerebral palsy, Parkinson's disease, motor neurone disease, stroke, pseudobulbar/bulbar palsy

Secretory phase menstrual cycle

Heavy metal exposure – selenium, mercury, copper, arsenic

Wilson disease

Angelman syndrome

Fluoride

Oesophageal disease – obstruction, idiopathic achalasia, megaoesophagus

Excessive starch intake

Local – oral infection, oral inflammation, macroglossia, dental malocclusion

Infection – rabies, Trypanosoma cruzi

The basis of the psychological theory lies in the observation that a proportion of women do not have excess salivation during sleep, although this is not universal. ¹ Some authors have questioned the relative contribution of increased production against the difficulty in swallowing saliva. ¹⁹

Aetiology – other theories

Genetic predisposition

A positive family history has been found in 36.5% of women with PG indicating that there may be a genetic predisposition. ¹ The condition recurs in all pregnancies subsequent to the initial affected pregnancy. There is a significant difference in the prevalence of PG in different countries, which may partly be due to genetic differences. PG complicates 0.08% of pregnancies in the United States, 0.09% of pregnancies in Israel, and 0.3% of pregnancies in Japan, compared to up to 35% of pregnancies in Turkey.^1,3,18,20 Authors have also described a high prevalence of PG in Haiti and African countries, though this has not been quantified.^5,18 In two small case series totalling 12 women with PG in North America, six of the women were born in Haiti, two in Africa, and one each in Honduras and Iran, with only two born in Canada.^18,21

Hyperemesis gravidarum

There is a strong bidirectional relationship between PG and hyperemesis gravidarum (HG). A Canadian study found that 26% of women with nausea and vomiting complained of ptyalism in the first trimester. ²² An Israeli case series of 22 women with PG found that 40% of these women were also diagnosed with HG. ¹ Women with HG may have anxiety that swallowing saliva worsens nausea and vomiting and hence resulting in psychological difficulties in swallowing saliva. ²³

Gastrooesophageal reflux

Early in pregnancy, lower oesophageal sphincter pressure falls under the influence of oestrogen, decreasing smooth muscle tone through stimulation of nitric oxide synthesis. ²⁴ GOR symptoms are reported by 40–85% of pregnant women, with 26.1% of women complaining of reflux symptoms in the first trimester. ²⁵ Oestrogen also has a protective effect on oesophageal mucosa by maintaining tight junctions in the epithelial cells and upregulating occluding protein. ²⁶

Chemical irritation of the oesophageal mucosa will activate the oesophageal-salivary reflex by stimulating the chemoreceptors in the submucosal Meissner plexus, which will then enhance salivary flow.^12,26,27 Infusions of HCl, citric acid and acetic acid in the upper oesophagus of healthy male subjects increased parotid flow rate with a latency period of 12.4 s, compared with no change following infusion in the lower oesophagus.^28,29 Oesophageal acid infusion resulted in a 4-fold increase in saliva flow in women with reflux oesophagitis and a 2-fold increase in saliva flow in normal subjects, but only when accompanied by symptoms of heartburn. ³⁰ GOR is associated with a saliva pH of 4.9 compared with pH 6.5 in control adults'. ³¹ Four of six women who developed dry mouth having taken omeprazole for more than 12 weeks were demonstrated to have reduced salivary rates with a return to normal salivary flow after cessation. ³²

By contrast, however, other studies in non-pregnant individuals have shown no change in salivary flow rates and saliva pH with GOR, and that omeprazole therapy in individuals with chronic laryngopharyngitis secondary to GOR was associated with an increase in volume of saliva despite saliva pH rising from 7.15 to 7.58.^33,34 Also, against the theory of GOR being the primary stimulus for PG is that the prevalence of GOR increases during the course of the pregnancy to 51.2% in the third trimester, while ptyalism tends to resolve after the second trimester.

Geophagia

The geographical prevalence of ptyalism has some correlation with the practice of geophagia. Geophagia, the ingestion of earth or soil-like substances, has been described in 92.5% of pregnant Nigerian women compared with 0.007% of pregnant women in Denmark. ³⁵ Overall, the prevalence of geophagia in pregnancy in Africa has been estimated to be 44.8%. While not quantified, the practice of eating mud cookies or Galette, is highly prevalent in pregnant women in Haiti, as is geophagia in Turkish women. ³⁶ Geophagia has the potential to cause hypersalivation by several mechanisms. The pH of soil ranges between 3.1 and 6.1. ³⁷ In addition to multiple other heavy metals, Kichuguu soil derived from the walls of houses, ant hills or the ground in African countries contains significant amounts of mercury. ³⁸ Studies in the 19th century showed that even tiny doses of mercury given orally for the management of syphilis were noted to result in severe ptyalism within 24 h of exposure. ³⁹ Exposure to mercury may also result from the use of skin-lightening creams, a practice estimated to occur in 68% of pregnant women in Senegal. ⁴⁰ Mercury given percutaneously may cause ptyalism ²³ Additionally, the stimulation of salivary amylase production by starch may be an initiating factor of hypersalivation with geophagia.^2,19

An alternative theory proposed by some authors is that geophagia is a strategy for dealing with excess salivation and HG in pregnancy. Dry soils absorb excess saliva in the oral cavity and provide relief for geophagia. ³⁷ Soils of high acidity with a sour taste are preferred by women with PG. ³⁷

Treatment – pregnancy

The lack of knowledge regarding aetiology and treatment, and the highly distressing nature of the condition, mandate the need for supportive, compassionate, culturally sensitive care. ⁵ Patience from health carers is important in acknowledging speech difficulties as a result of ptyalism. Women must be supported in their need to spit, chew gum, or suck on candy, especially during antenatal visits. Ptyalism may be particularly challenging during times of pandemic when mask-wearing may be mandated. It is important to recognise that affected women may be sleep-deprived, and the toll that ptyalism may have on mood, social isolation and nutrition.

No controlled trials have been conducted regarding the management of ptyalism in pregnancy. Possible responses to treatment must be tempered by the possibility of the condition spontaneously remitting. Many women may self-treat with chewing gum, mouthwashes, hard candy, lemon drops and throat lozenges. ²⁰ One case report described the use of hypnosis in a woman with HG and PG. ⁴¹ HG resolved after the first session at 16 weeks’ gestation; however, PG did not reduce until following the third session at 28 weeks’ gestation, and data from a single case report may be misleading as the symptoms may have resolved spontaneously without the intervention. Psychotherapy was ineffective in one case report.

Belladonna alkaloids combined with promethazine resulted in relief of PG and HG after 10 days in two women. ¹⁸ Belladonna alkaloids inhibit acetylcholine at the receptor site and may cause dry mouth and constipation. Phenobarbital, piperidolate and Alpinia oxyphylla were not helpful in managing PG. ⁴²

Clonidine is a centrally acting alpha-2 adrenoceptor agonist which is used to treat hypertension. It stimulates alpha receptors in the medulla and hypothalamus, which subsequently inhibits sympathetic activity and inhibits parasympathetic reflex salivation. ⁴³ A common dose-dependent side effect occurring in up to 40% of women is dry mouth. ⁴² In 11 women, oral clonidine 0.05 mg/day commenced at a mean gestation of 11 weeks and was found to result in improvement in the symptoms of PG after a median of two days.^21,44 Previous human and animal studies have not demonstrated teratogenicity with clonidine. Clonidine therapy was associated with a mean fall in blood pressure of 16/11 mm Hg without maternal symptoms. One author stated clonidine dose of more than 0.15 mg/day used for the treatment of maternal hypertension may be associated with small-for-gestational-age infants; however, it is difficult to separate out the effects of medication versus maternal hypertension. ⁴⁴ Oral clonidine has also been effective in risperidone- and clozapine-induced sialorrhoea in non-pregnant individuals.^45,46

Treatment – non-pregnant

The most effective treatment for ptyalism due to neurological disorders in infants, children and adults is the injection of botulinum neurotoxin A (BoNT-A) into salivary glands. BoNT-A inhibits acetylcholine release from cholinergic nerve terminals causing the salivary glands to become inactive. A meta-analysis of eight studies which included 131 children found that BoNT-A significantly reduced sialorrhea. ⁴⁷ A systematic review of eight studies involving 317 adults with neurological disorders suggested the effectiveness of botulinum toxin in subjectively reducing drooling, resulting in an improvement in the quality of life. ⁴⁸ BonT-A is injected into bilateral parotid glands only, or bilateral parotid and submandibular glands under ultrasound control at an average total dose of 75–100 units. Treatment is generally well tolerated with potential side effects being dry mouth, dysphagia, paraesthesia, speech disturbance, thickened saliva, taste disturbance and dental caries with long-term administration. Retreatment may be required every 16 weeks. A study of 397 pregnancies with maternal exposure to botulinum A showed no increase in birth defects or adverse fetal outcomes compared with the general population, though numbers of exposures in second and third trimester were limited. ⁴⁹

Oral glycopyrrolate solution is the most used anticholinergic in children with ptyalism. Efficacy following six months of therapy in neurological disorders is 52.3%, with adverse effects in 47%. ⁵⁰ There is no data regarding the safety of glycopyrrolate in pregnancy. Topical therapies used in the management of ptyalism in non-pregnant individuals include atropine ophthalmic drops and ipratropium spray administered sublingually/periorally, and transdermal scopolamine.

Conclusion

Ptyalism gravidarum is a condition that occurs early in pregnancy and may cause significant distress, anxiety, social isolation, sleep disturbance and poor nutrition. Education of health providers regarding recognition, and the need for supportive, compassionate care is paramount, particularly in geographical areas where ptyalism is rare. Further examination of potential causative factors, including cultural practices and genetic predisposition, particularly in populations where ptyalism is highly prevalent may help guide prevention and appropriate treatment. Measurement of salivary pH and flow in affected women, as well as in women with gastrooesophageal reflux, and who practice geophagia may be illuminating. The safety profile of botulinum toxin in pregnancy suggests controlled trials in women with ptyalism may be reasonable. In resource-limited settings, trials of alkaline mouthwashes and sprays may be worthwhile. Given the association with hyperemesis gravidarum, and the desire to avoid oral therapy, trials of topical clonidine may also be valuable.