Medical Hypotheses 84 (2015) 448–450
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Hiccups and amniotic fluid regulation in early pregnancy Andrew G. Murchison ⇑ Oxford Health NHS Trust, Chancellor Court, 4000 John Smith Drive, Oxford Business Park South, Oxford OX4 2GX, United Kingdom
a r t i c l e
i n f o
Article history: Received 30 October 2014 Accepted 27 January 2015
a b s t r a c t Hiccups are an unexplained phenomenon and a subject of medical curiosity. They arise through a reflex arc with central control at the level of the medulla, and their primary physiological effect is the generation of negative intra-thoracic pressure. This paper presents the hypothesis that hiccups serve a purpose during the first half of gestation, when they are most prevalent; namely, that they promote amniotic fluid influx to the primitive gut, allowing fluid to be transferred to the foetal and then maternal vasculature. Furthermore, hiccups could be provoked by increasing amniotic fluid volume and pressure, and act in a regulatory capacity. This hypothesis could be tested by studying foetal movements in the first half of gestation, and assessing whether there is correlation with amniotic fluid flux in the developing gut. Ascertaining whether hiccups increase in frequency with increasing amniotic fluid volume would provide evidence for or against a regulatory function. Ó 2015 Elsevier Ltd. All rights reserved.
Introduction Hiccups are a universal but unexplained phenomenon. Some authors have suggested that they occur in response to foetal meconium aspiration; others, that they provide exercise for respiratory muscles in utero [1]. Alternatively, they may exist to expel air from the stomachs of suckling infants [2]. It has also been proposed that they are a vestigial reflex, existing because components of the gill breathing circuitry of bimodal breathers have been incorporated into central pattern generators for breathing or suckling in mammals [3]. This paper presents an alternative hypothesis; that hiccups have a role in the circulation of amniotic fluid in the early stages of gestation.
sympathetic chain can stimulate hiccups; this comes from observations that disease of the oesophagus can be associated with chronic hiccups, and the suggestion that hiccups are provoked by ingestion of carbonated beverages or over-distension of the stomach [1]. Meanwhile, the central component of the reflex arc resides within the dorsal medulla, as stimulation of this region can provoke hiccups in cats [6], and because medullary lesions have been described in association with pathological hiccups. The physiological effects of the efferent limb of the hiccup reflex have been more clearly defined. There is activation of inspiratory muscles including the diaphragm, and synchronous inhibition of expiratory muscles [7]. Airflow initially rises, and then falls abruptly 35 ms later with closure of the glottis. There is also reduction in oesophageal tone and relaxation of the lower oesophageal sphincter [8].
The hiccup reflex Hiccups, also known as hiccoughs or singultus, comprise a reflex arc with central control at the level of the brainstem. The components of the afferent limb of the hiccup reflex have been characterised with a surprising lack of clarity. Mechanical stimulation of the dorsal epipharynx can provoke a hiccup-like response in cats; this was found to be dependent on the pharyngeal branch of the glossopharyngeal nerve [4]. Small studies in humans have suggested that balloon distension in the proximal oesophagus can elicit hiccups [5]. It is commonly reported that the vagus nerve and ⇑ Address: Fulbrook Centre, Churchill Hospital, Oxford OX3 7J, United Kingdom. Tel.: +44 07921146449; fax: +44 01865 337477. E-mail address: [email protected] http://dx.doi.org/10.1016/j.mehy.2015.01.040 0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.
Amniotic fluid circulation Amniotic fluid has a number of purposes, including buffering the foetus from physical harm, providing a medium for the development of the body structures, and supplying nutrition for growth [9]. In the second half of pregnancy, four major pathways contribute to amniotic fluid balance [10]. Fluid enters the amniotic space through foetal urine and lung fluid production, and is either swallowed or moves across the amniotic membrane into the foetal vasculature through what is known as the intramembranous pathway. Production of fluid by the oropharyngeal mucosa, and absorption directly into the maternal vasculature via the transmembranous pathway may also play a minor roles.
A.G. Murchison / Medical Hypotheses 84 (2015) 448–450
It is thought that amniotic fluid volume is regulated to avoid the harmful effects of oligo- or polyhydramnios, but it is not clear exactly how this occurs. Swallowing has been found to increase when amniotic fluid volume increases [11]; however, volume returns to baseline after an initial polyhydramnios in studies involving ligation of the oesophagus of the ovine foetus [12]. Therefore, alteration of flow through the intramembranous pathway is considered to be a key method of regulating amniotic fluid volume. A portion of the intramembranous pathway is dependent on osmotic forces; this could be regulated by adjusting membrane permeabilities. Indeed, aquaporins have been found to be upregulated in the amnion of foetuses with polyhydramnios [11]. A second component of the intramembranous pathway is independent of osmotic forces [11]. It is proposed that water and solutes are extruded from the amniotic cavity by bulk vesicular transport; this is thought to be regulated by a factor in foetal urine and by upregulation of Vascular Endothelial Growth Factor. Little is known about amniotic fluid dynamics in the first half of gestation. Fluid ultimately enters the foetal compartment from the mother, presumably across the placenta [10]. There is relatively free movement of fluid and electrolytes between the amniotic and extracellular compartments, because the skin does not fully keratinise until around week 24 [11]. However, the amniotic and extracellular fluid are isotonic with foetal and maternal serum in the first half of gestation, and pressures within the foetal vasculature are higher than within other fluid compartments [10]. Therefore, there is no osmotic or hydrostatic force to promote movement of fluid into the foetal blood vessels and thence into the maternal circulation. This would suggest that transfer of fluid from the amniotic space into the maternal circulation is by an active mechanism in early gestation. Meanwhile, the 30-fold increase in amniotic fluid volume from 20 mls at 10 weeks gestation to 630 mls at 22 weeks [10] implies that regulatory mechanisms exist to prevent gross polyhydramnios during this period of development.
Hiccups and amniotic fluid ingestion Hiccups begin during the ninth week of human gestation, and the 14-week old foetus spends around 12% of its time hiccupping [13]. Swallowing behaviour, by comparison, is first detected at 11–12 weeks, and increases slowly in frequency until the second half of gestation. The pleuroperitoneal canals of the diaphragm close between weeks 8 and 10, and ultrasound studies demonstrate that the main features of the larynx and pharynx including vocal cords, epiglottis, and constrictor muscles are present by at least week 11 [14]. Generation of negative intra-thoracic pressures and glottis closure are therefore possible in the early foetal period. A prominent feature of hiccups is a sharp drop in intra-thoracic pressure, and a large swing in intra-oesophageal pressure has been measured in infants [15]. This could draw amniotic fluid into the oesophagus, creating a propulsive ripple into the primitive gastrointestinal tract. From here, gut solute and water uptake could generate a localised hydrostatic force to move fluid into the foetal vasculature. Increasing pressure within the umbilical vein causes movement of fluid to the maternal circulation by hydrostatic mechanisms [16]. Hiccups could thus permit the return of fluid from the foetal environs to the maternal circulation. As a reflex, hiccups could also act in a regulatory manner. Pressure increase within the amniotic space could be detected by mechanoreceptors within the developing pharynx and oesophagus. The glossopharyngeal and vagus nerves supply the branchial arches which surround the upper digestive tract; these are nerves associated with physiological and pathological generation of hiccups in adults. Thus, amniotic fluid in the pharynx and upper oesophagus
449
would elicit the hiccup reflex and promote return of excess fluid to the maternal circulation. As gestation advances, hiccups may become less frequent due to development of inhibitory neural inputs, such as the GABAergic pathways which have been shown to inhibit hiccup generation in the medulla of adult cats [17]. Tentative circumstantial evidence exists for this function of hiccups. In an ultrasonographic study of the foetal oesophagus between weeks 19 and 25 of gestation, the most common motility pattern was a ‘simultaneous, synchronised opening of the oesophageal lumen from the oropharynx to the lower oesophageal sphincter’ lasting around 3 s; the authors speculate that this could be associated with hiccups [18]. Interestingly, hiccups also cause a transient drop in flow through the umbilical vein [19], which could augment the regulatory action of hiccups by reducing blood flow to the foetus and the movement of fluid into the extravascular and amniotic compartments. Alternatively, this could increase umbilical vein pressure and promote loss of fluid to the maternal circulation. However, it is uncertain whether this change in umbilical vein flow is physiologically important. One caveat is that studies of hiccups in pathological settings have demonstrated an initial brief displacement of air towards the mouth, followed by abrupt decrease as the glottis closes [7], suggesting that hiccups would cause negligible fluid influx. Presumably, the high resting pressure of the upper oesophageal sphincter impedes the movement of air into the oesophagus during post-natal hiccups. The resting pressure of this sphincter is lower in premature infants aged 31–32 weeks compared to 35–36 weeks corrected age (gestational age plus postnatal age) [20]. It might be hypothesised that it is lower still in the first half of gestation, and that hiccups would lead to amniotic fluid flow in the absence of this impediment. This is supported by the observation that hiccups generate much higher inspiratory air flow in intubated compared to unintubated infants [15]. Investigation of the development of upper oesophageal sphincter pressure in early pregnancy might prove a useful test of the viability of the hypothesis that hiccups contribute to amniotic fluid ingestion. Conclusions The factors contributing to amniotic fluid production and resorption in the first half of pregnancy are poorly defined. Hiccups are very common between weeks 9 and 24 of human gestation; the sharp drop in intra-thoracic and intra-oesophageal pressure produced could lead to amniotic fluid ingestion. Furthermore, hiccups may be stimulated by an increase in amniotic fluid pressure, thereby providing a method of regulating volume. At present, only circumstantial evidence exists to support this role for hiccups. Ultrasound studies assessing correlation between oesophageal flow, foetal movements and amniotic fluid volume in the first half of gestation would provide a useful test of this hypothesis. Conflict of interest statement None declared. Acknowledgement None declared. References [1] Lewis JH. Hiccups: causes and cures. J Clin Gastroenterol 2007:539–52. [2] Howes D. Hiccups: a new explanation for the mysterious reflex. BioEssays 2012;34:451–3.
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A.G. Murchison / Medical Hypotheses 84 (2015) 448–450
[3] Straus C, Vasilakos K, Wilson RJA, et al. A phylogenetic hypothesis for the origin of hiccough. BioEssays 2003;25:182–8. [4] Kondo T, Toyooka H, Arita H. Hiccups reflex is mediated by pharyngeal branch of glossopharyngeal nerve in cats. Neuroscience 2003;47:317–21. [5] Fass R, Higa L, Kodner A, et al. Stimulus and site specific induction of hiccups in the oesophagus of normal subjects. Gut 1997;41:590–3. [6] Arita H, Oshima T, Kita I, et al. Generation of hiccup by electrical stimulation in medulla of cats. Neurosci Lett 1994;175:67–70. [7] Davis JN. An experimental study of hiccup. Brain 1970;93:851–72. [8] Graham D. Esophageal motor abnormality during hiccup. Gastroenterol 1986;90:2039–44. [9] Underwood MA, Gilbert WM, Sherman PM. Amniotic fluid: not just fetal urine anymore. J Perinatol 2005;25:341–8. [10] Beall MH, Van den Wijngaard JPHM, Van Gemert MJC, et al. Amniotic fluid water dynamics. Placenta 2007;28:816–23. [11] Beall MH, van den Wijngaard JPMH, van Gemert MJC, et al. Regulation of amniotic fluid volume. Placenta 2007;28:824–32. [12] Matsumoto LC, Cheung CY, Brace RA. Effect of esophageal ligation on amniotic fluid volume and urinary flow rate in fetal sheep. Am J Obstet Gynecol 2000;182:699–705.
[13] Pillai M, James D. Hiccups and breathing in human fetuses. Arch Dis Child 1990;65:1072–5. [14] Liberty G, Boldes R, Shen O, et al. The fetal larynx and pharynx: structure and development on two- and three-dimensional ultrasound. Ultrasound Obstet Gynecol 2013;42:140–8. [15] Brouillette RT, Thatch BT, Abu-Osba YK, et al. Hiccups in infants: characteristics and effects on ventilation. J Pediatr 1980;96:219–25. [16] Brownbill P, Sibley CP. Regulation of transplacental water transfer: the role of fetoplacental venous tone. Placenta 2006;27:560–7. [17] Oshima T, Sakamoto M, Tatsuta H, et al. GABAergic inhibition of hiccup-like reflex induced by electrical stimulation of medulla in cats. Neurosci Res 1998;30:287–93. [18] Malinger G, Levine A, Rotmensch S. The fetal esophagus: anatomical and physiological ultrasonographic characterization using a high-resolution linear transducer. Ultrasound Obstet Gynecol 2004;24:500–5. [19] Zheng YT, Sampson MB, Soper R. The significance of umbilical vein Doppler changes during fetal hiccups. J Matern Fetal Invest 1998;8:89–91. [20] Rommel N, Van Wijk M, Boets B, et al. Development of pharyngo-esophageal physiology during swallowing in the preterm infant. Neurogastroenterol Motil 2011;23:e401–8.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Hiccups and amniotic fluid regulation in early pregnancy Andrew G. Murchison ⇑ Oxford Health NHS Trust, Chancellor Court, 4000 John Smith Drive, Oxford Business Park South, Oxford OX4 2GX, United Kingdom
a r t i c l e
i n f o
Article history: Received 30 October 2014 Accepted 27 January 2015
a b s t r a c t Hiccups are an unexplained phenomenon and a subject of medical curiosity. They arise through a reflex arc with central control at the level of the medulla, and their primary physiological effect is the generation of negative intra-thoracic pressure. This paper presents the hypothesis that hiccups serve a purpose during the first half of gestation, when they are most prevalent; namely, that they promote amniotic fluid influx to the primitive gut, allowing fluid to be transferred to the foetal and then maternal vasculature. Furthermore, hiccups could be provoked by increasing amniotic fluid volume and pressure, and act in a regulatory capacity. This hypothesis could be tested by studying foetal movements in the first half of gestation, and assessing whether there is correlation with amniotic fluid flux in the developing gut. Ascertaining whether hiccups increase in frequency with increasing amniotic fluid volume would provide evidence for or against a regulatory function. Ó 2015 Elsevier Ltd. All rights reserved.
Introduction Hiccups are a universal but unexplained phenomenon. Some authors have suggested that they occur in response to foetal meconium aspiration; others, that they provide exercise for respiratory muscles in utero [1]. Alternatively, they may exist to expel air from the stomachs of suckling infants [2]. It has also been proposed that they are a vestigial reflex, existing because components of the gill breathing circuitry of bimodal breathers have been incorporated into central pattern generators for breathing or suckling in mammals [3]. This paper presents an alternative hypothesis; that hiccups have a role in the circulation of amniotic fluid in the early stages of gestation.
sympathetic chain can stimulate hiccups; this comes from observations that disease of the oesophagus can be associated with chronic hiccups, and the suggestion that hiccups are provoked by ingestion of carbonated beverages or over-distension of the stomach [1]. Meanwhile, the central component of the reflex arc resides within the dorsal medulla, as stimulation of this region can provoke hiccups in cats [6], and because medullary lesions have been described in association with pathological hiccups. The physiological effects of the efferent limb of the hiccup reflex have been more clearly defined. There is activation of inspiratory muscles including the diaphragm, and synchronous inhibition of expiratory muscles [7]. Airflow initially rises, and then falls abruptly 35 ms later with closure of the glottis. There is also reduction in oesophageal tone and relaxation of the lower oesophageal sphincter [8].
The hiccup reflex Hiccups, also known as hiccoughs or singultus, comprise a reflex arc with central control at the level of the brainstem. The components of the afferent limb of the hiccup reflex have been characterised with a surprising lack of clarity. Mechanical stimulation of the dorsal epipharynx can provoke a hiccup-like response in cats; this was found to be dependent on the pharyngeal branch of the glossopharyngeal nerve [4]. Small studies in humans have suggested that balloon distension in the proximal oesophagus can elicit hiccups [5]. It is commonly reported that the vagus nerve and ⇑ Address: Fulbrook Centre, Churchill Hospital, Oxford OX3 7J, United Kingdom. Tel.: +44 07921146449; fax: +44 01865 337477. E-mail address: [email protected] http://dx.doi.org/10.1016/j.mehy.2015.01.040 0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.
Amniotic fluid circulation Amniotic fluid has a number of purposes, including buffering the foetus from physical harm, providing a medium for the development of the body structures, and supplying nutrition for growth [9]. In the second half of pregnancy, four major pathways contribute to amniotic fluid balance [10]. Fluid enters the amniotic space through foetal urine and lung fluid production, and is either swallowed or moves across the amniotic membrane into the foetal vasculature through what is known as the intramembranous pathway. Production of fluid by the oropharyngeal mucosa, and absorption directly into the maternal vasculature via the transmembranous pathway may also play a minor roles.
A.G. Murchison / Medical Hypotheses 84 (2015) 448–450
It is thought that amniotic fluid volume is regulated to avoid the harmful effects of oligo- or polyhydramnios, but it is not clear exactly how this occurs. Swallowing has been found to increase when amniotic fluid volume increases [11]; however, volume returns to baseline after an initial polyhydramnios in studies involving ligation of the oesophagus of the ovine foetus [12]. Therefore, alteration of flow through the intramembranous pathway is considered to be a key method of regulating amniotic fluid volume. A portion of the intramembranous pathway is dependent on osmotic forces; this could be regulated by adjusting membrane permeabilities. Indeed, aquaporins have been found to be upregulated in the amnion of foetuses with polyhydramnios [11]. A second component of the intramembranous pathway is independent of osmotic forces [11]. It is proposed that water and solutes are extruded from the amniotic cavity by bulk vesicular transport; this is thought to be regulated by a factor in foetal urine and by upregulation of Vascular Endothelial Growth Factor. Little is known about amniotic fluid dynamics in the first half of gestation. Fluid ultimately enters the foetal compartment from the mother, presumably across the placenta [10]. There is relatively free movement of fluid and electrolytes between the amniotic and extracellular compartments, because the skin does not fully keratinise until around week 24 [11]. However, the amniotic and extracellular fluid are isotonic with foetal and maternal serum in the first half of gestation, and pressures within the foetal vasculature are higher than within other fluid compartments [10]. Therefore, there is no osmotic or hydrostatic force to promote movement of fluid into the foetal blood vessels and thence into the maternal circulation. This would suggest that transfer of fluid from the amniotic space into the maternal circulation is by an active mechanism in early gestation. Meanwhile, the 30-fold increase in amniotic fluid volume from 20 mls at 10 weeks gestation to 630 mls at 22 weeks [10] implies that regulatory mechanisms exist to prevent gross polyhydramnios during this period of development.
Hiccups and amniotic fluid ingestion Hiccups begin during the ninth week of human gestation, and the 14-week old foetus spends around 12% of its time hiccupping [13]. Swallowing behaviour, by comparison, is first detected at 11–12 weeks, and increases slowly in frequency until the second half of gestation. The pleuroperitoneal canals of the diaphragm close between weeks 8 and 10, and ultrasound studies demonstrate that the main features of the larynx and pharynx including vocal cords, epiglottis, and constrictor muscles are present by at least week 11 [14]. Generation of negative intra-thoracic pressures and glottis closure are therefore possible in the early foetal period. A prominent feature of hiccups is a sharp drop in intra-thoracic pressure, and a large swing in intra-oesophageal pressure has been measured in infants [15]. This could draw amniotic fluid into the oesophagus, creating a propulsive ripple into the primitive gastrointestinal tract. From here, gut solute and water uptake could generate a localised hydrostatic force to move fluid into the foetal vasculature. Increasing pressure within the umbilical vein causes movement of fluid to the maternal circulation by hydrostatic mechanisms [16]. Hiccups could thus permit the return of fluid from the foetal environs to the maternal circulation. As a reflex, hiccups could also act in a regulatory manner. Pressure increase within the amniotic space could be detected by mechanoreceptors within the developing pharynx and oesophagus. The glossopharyngeal and vagus nerves supply the branchial arches which surround the upper digestive tract; these are nerves associated with physiological and pathological generation of hiccups in adults. Thus, amniotic fluid in the pharynx and upper oesophagus
449
would elicit the hiccup reflex and promote return of excess fluid to the maternal circulation. As gestation advances, hiccups may become less frequent due to development of inhibitory neural inputs, such as the GABAergic pathways which have been shown to inhibit hiccup generation in the medulla of adult cats [17]. Tentative circumstantial evidence exists for this function of hiccups. In an ultrasonographic study of the foetal oesophagus between weeks 19 and 25 of gestation, the most common motility pattern was a ‘simultaneous, synchronised opening of the oesophageal lumen from the oropharynx to the lower oesophageal sphincter’ lasting around 3 s; the authors speculate that this could be associated with hiccups [18]. Interestingly, hiccups also cause a transient drop in flow through the umbilical vein [19], which could augment the regulatory action of hiccups by reducing blood flow to the foetus and the movement of fluid into the extravascular and amniotic compartments. Alternatively, this could increase umbilical vein pressure and promote loss of fluid to the maternal circulation. However, it is uncertain whether this change in umbilical vein flow is physiologically important. One caveat is that studies of hiccups in pathological settings have demonstrated an initial brief displacement of air towards the mouth, followed by abrupt decrease as the glottis closes [7], suggesting that hiccups would cause negligible fluid influx. Presumably, the high resting pressure of the upper oesophageal sphincter impedes the movement of air into the oesophagus during post-natal hiccups. The resting pressure of this sphincter is lower in premature infants aged 31–32 weeks compared to 35–36 weeks corrected age (gestational age plus postnatal age) [20]. It might be hypothesised that it is lower still in the first half of gestation, and that hiccups would lead to amniotic fluid flow in the absence of this impediment. This is supported by the observation that hiccups generate much higher inspiratory air flow in intubated compared to unintubated infants [15]. Investigation of the development of upper oesophageal sphincter pressure in early pregnancy might prove a useful test of the viability of the hypothesis that hiccups contribute to amniotic fluid ingestion. Conclusions The factors contributing to amniotic fluid production and resorption in the first half of pregnancy are poorly defined. Hiccups are very common between weeks 9 and 24 of human gestation; the sharp drop in intra-thoracic and intra-oesophageal pressure produced could lead to amniotic fluid ingestion. Furthermore, hiccups may be stimulated by an increase in amniotic fluid pressure, thereby providing a method of regulating volume. At present, only circumstantial evidence exists to support this role for hiccups. Ultrasound studies assessing correlation between oesophageal flow, foetal movements and amniotic fluid volume in the first half of gestation would provide a useful test of this hypothesis. Conflict of interest statement None declared. Acknowledgement None declared. References [1] Lewis JH. Hiccups: causes and cures. J Clin Gastroenterol 2007:539–52. [2] Howes D. Hiccups: a new explanation for the mysterious reflex. BioEssays 2012;34:451–3.
450
A.G. Murchison / Medical Hypotheses 84 (2015) 448–450
[3] Straus C, Vasilakos K, Wilson RJA, et al. A phylogenetic hypothesis for the origin of hiccough. BioEssays 2003;25:182–8. [4] Kondo T, Toyooka H, Arita H. Hiccups reflex is mediated by pharyngeal branch of glossopharyngeal nerve in cats. Neuroscience 2003;47:317–21. [5] Fass R, Higa L, Kodner A, et al. Stimulus and site specific induction of hiccups in the oesophagus of normal subjects. Gut 1997;41:590–3. [6] Arita H, Oshima T, Kita I, et al. Generation of hiccup by electrical stimulation in medulla of cats. Neurosci Lett 1994;175:67–70. [7] Davis JN. An experimental study of hiccup. Brain 1970;93:851–72. [8] Graham D. Esophageal motor abnormality during hiccup. Gastroenterol 1986;90:2039–44. [9] Underwood MA, Gilbert WM, Sherman PM. Amniotic fluid: not just fetal urine anymore. J Perinatol 2005;25:341–8. [10] Beall MH, Van den Wijngaard JPHM, Van Gemert MJC, et al. Amniotic fluid water dynamics. Placenta 2007;28:816–23. [11] Beall MH, van den Wijngaard JPMH, van Gemert MJC, et al. Regulation of amniotic fluid volume. Placenta 2007;28:824–32. [12] Matsumoto LC, Cheung CY, Brace RA. Effect of esophageal ligation on amniotic fluid volume and urinary flow rate in fetal sheep. Am J Obstet Gynecol 2000;182:699–705.
[13] Pillai M, James D. Hiccups and breathing in human fetuses. Arch Dis Child 1990;65:1072–5. [14] Liberty G, Boldes R, Shen O, et al. The fetal larynx and pharynx: structure and development on two- and three-dimensional ultrasound. Ultrasound Obstet Gynecol 2013;42:140–8. [15] Brouillette RT, Thatch BT, Abu-Osba YK, et al. Hiccups in infants: characteristics and effects on ventilation. J Pediatr 1980;96:219–25. [16] Brownbill P, Sibley CP. Regulation of transplacental water transfer: the role of fetoplacental venous tone. Placenta 2006;27:560–7. [17] Oshima T, Sakamoto M, Tatsuta H, et al. GABAergic inhibition of hiccup-like reflex induced by electrical stimulation of medulla in cats. Neurosci Res 1998;30:287–93. [18] Malinger G, Levine A, Rotmensch S. The fetal esophagus: anatomical and physiological ultrasonographic characterization using a high-resolution linear transducer. Ultrasound Obstet Gynecol 2004;24:500–5. [19] Zheng YT, Sampson MB, Soper R. The significance of umbilical vein Doppler changes during fetal hiccups. J Matern Fetal Invest 1998;8:89–91. [20] Rommel N, Van Wijk M, Boets B, et al. Development of pharyngo-esophageal physiology during swallowing in the preterm infant. Neurogastroenterol Motil 2011;23:e401–8.
