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Fetal behaviour: a commentary
Neurobiology of Aging 24 (2003) S47–S49
Commentary
Fetal behaviour: a commentary夽 Gerard H.A. Visser∗ Department of Obstetrics, Neonatology and Gynaecology, University Medical Centre Utrecht, P.O. Box 85090, 3508 AB Utrecht, The Netherlands Received 24 January 2003; accepted 10 February 2003
Keywords: Neural function; Fetal movement; Brain functioning
1. Introduction Nijhuis has given a comprehensive review on fetal behaviour, that deserves support, some additions and only minor criticism. Forty-nine of the 76 references in his paper are from Dutch authors and that underlines the importance given to fetal behavioural research in The Netherlands. The latter is undoubtedly due to the presence of Heinz Prechtl, an Austrian developmental neurologist who started as a baby watcher, moved on to become a fetus watcher and has stimulated most of the Dutch research groups.
2. Continuity of neural functions from prenatal to postnatal life Nijhuis stresses in his introduction rightly that gestational age is an important variable (“the most important factor”) regarding fetal behaviour. The incidence of occurrence of most movement patterns and of fetal heart rate and its variation are indeed dependent on gestational age, so is the percentage of coincidence of the three fetal state variables and therefore of organisation of fetal behavioural states. This emphasises changes occurring with development. One may, however, also put it the other way around and focus on continuity, continuity of neural functions from prenatal to postnatal life [13]. Embryonic and fetal movement patterns emerge early, are from their beginning onwards specific and closely resemble movement patterns after birth. This continuity, this onset of highly organised specific movement patterns, long before birth, is surprising, especially when the minimal development of the nervous 夽
Comment to the paper ‘Fetal behaviour’ by J.G. Nijhuis. Tel.: +31-30-2506426; fax: +31-30-2505320. E-mail address: [email protected] (G.H.A. Visser).
∗
system at that early age is taken into account. There are few studies on the ultrastructure of the nervous system of the young fetus. The available data suggest that movements emerge as soon as the first connective structures are formed [5]. The reason why different movement patterns emerge so early is still not clear. Certain movement patterns have an adaptive effect on the survival or development of the fetus. Frequent and active changes of intra-uterine position may prevent adhesions and local stasis of the circulation in the skin. Individual movements may prevent the occurrence of contractures such as those that can be found after prolonged oligohydramnios following leakage of amniotic fluid. Sucking and swallowing movements are necessary for the regulation of the amount of amniotic fluid. Another reason for fetal movements to emerge early may be anticipation of postnatal function. Some motor patterns begin during early prenatal development and are regularly performed long before they fulfil a meaningful task as part of a complex adaptive function. For example, fetal breathing movements are already present at 10 weeks. These movements might also have an influence on lung growth, as in animal experiments spinal cord transection results in fetal lung hypoplasia [7,27]. This link is still unclear in the human. A second example of continuity from prenatal to postnatal life concerns to the incidence of occurrence of some movement patterns, the interval between movements (e.g. the hiccup-to-hiccup interval remains the same), but most of all the continuity in behavioural states. Fetal behavioural states are defined by a different set of variables, but are equivalent to the states in the newborn [11]. Studies on the newborn may, therefore, help us in the interpretation of findings in the fetus. The duration of a complete 1F/2F cycle (non-REM/REM cycle) even remains the same into adulthood (±90 min).
0197-4580/03/$ – see front matter © 2003 Elsevier Science Inc. All rights reserved. doi:10.1016/S0197-4580(03)00055-1
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G.H.A. Visser / Neurobiology of Aging 24 (2003) S47–S49
3. Studying fetal behaviour By studying fetal behaviour: (1) insight is obtained in normal development of aspects of nervous system functioning; (2) situations may be identified with a negative impact on nervous system development; and (3) individual fetuses might be identified with abnormal brain functioning. Nijhuis has addressed the importance of knowledge of physiology in the interpretation of fetal heart rate patterns. This not only holds for the spontaneously occurring patterns, but also for (absence of) fetal reactions to stimuli. We now know that a flat fetal heart rate pattern, with reduced variation is a normal phenomenon during the third trimester, representing behavioural state 1F (or non-REM-sleep). Obstetricians have for long tried to stimulate the fetus during a flat heart rate pattern, to distinguish between quiet sleep and a poor condition. However, state 1F is not influenced by shaking the maternal abdomen, nor by transabdominal sound stimulation [16,26]. Such procedures have therefore resulted in unnecessary obstetrical actions. These findings are consistent with the fact that it is difficult to wake up a newborn baby when in state 1. The fetus may benefit from this inaccessibility as it guarantees a more or less undisturbed endogenous development. However, fetuses do react to vibro-acoustic stimulation using an electronic artificial larynx and during the past 10 years, numerous papers on the use of this device have been published. The most important rationale for stimulation is also to differentiate between poor and good fetal status in cases of possibly abnormal fetal heart rate patterns. This kind of stimulus induces excessive fetal movements, a prolonged tachycardia and a disorganisation of behavioural states [24]. It seems better not to use this device, especially when the intra-uterine sound produced exceeds 125 dB [12]. It is obvious that situations with a negative impact on fetal nervous system development may be identified easier than diagnosing abnormal brain functioning in the individual fetus, since the former concerns a (statistical) comparison between groups. Nijhuis has mentioned some situations resulting in behavioural changes, but I would like to go a bit more in detail. Disturbances in development may be induced by endogenous factors (such as chromosome abnormalities) and maternal diseases (for example diabetes), but also by exogenous behavioural teratogens. Abnormal movement patterns, indicative of altered brain or muscular development, have been described in fetuses with chromosome abnormalities [3], in anencephalic fetuses [23], in fetuses with other cerebral malformations [25], in growth-retarded fetuses [2,18] and in fetuses suffering from prolonged oligohydramnios [17]. Common features in all these cases are the qualitative changes in the execution of movement patterns, which are abrupt and forceful, with large amplitude in the majority of
fetuses with a chromosome or central nervous system defect; or slow, with small amplitude, in the others. Recently fetal seizures have been described in association with severe brain abnormalities [1]. It should be emphasised that movement abnormalities associated with central nervous system dysfunction are qualitative and not quantitative in nature. In preterm babies with brain lesions assessment of the quality of movements appears to be a much better predictor of neurological outcome than the number of the movements [6,14]. In anencephalic fetuses movements tend to be numerous, forceful, jerky in character and of a large amplitude [23]. This indicates that only minimal neural structures are necessary for movements to be generated. On the other hand, these data indicate that already in the first half of pregnancy a normal nervous system, although only partly developed, is necessary for movements to be executed normally. In women with type-1 diabetes embryonic movements emerge during the first trimester of pregnancy about one week later than in control fetuses, apart from fetal breathing that starts earlier [9]. During the third trimester fetal behavioural states are less well organised, indicating a delayed or disturbed development of nervous system functioning [10]. Also in growth retarded fetuses states development is delayed [21]. This occurs before the onset of fetal hypoxemia, which indicates that brain dysfunction in these fetuses is more likely the result of chronic malnutrition in utero than due to hypoxemia. Finally, some additional data regarding exogenous behavioural teratogens. In a carefully controlled study we found that two glasses of white wine temporarily suppress fetal breathing movements and disturb fetal state cycling, the latter being mainly due to suppression of fetal eye movements [8]. REM sleep is important for normal brain development and these data may shed some light on behavioural abnormalities observed in infants whose mother consumed more than two glasses of alcohol per day during pregnancy. A study like this one, demonstrating direct effects of alcohol on the fetus, may discourage pregnant women from drinking. Maternal caffeine intake causes considerable increases in fetal body movements, fetal heart rate variability and in the percentage of fetal heart rate variability pattern D, indicating that the fetus spends more time “awake” [19]. Induced maternal emotions do not affect fetal state cycling, but there is a positive correlation between the level of maternal stress and the incidence of fetal body movements [20]. Active fetuses also tend to have a high activity level after birth and one may speculate whether this is due to prenatal effects of high maternal anxiety or to genetic differences. The relationship between maternal stress and fetal and neonatal behaviour is complex, given the large variety of stressors and differences in “coping” with stress. Moreover, maternal stress and cortisol do not show a clear relationship. Exogenous corticosteroids induce a temporary reduction in fetal movements, and fetal activity is inversely correlated to the maternal diurnal cortisol rhythm [4,15,22]. Thus, this important topic still needs further exploration.
G.H.A. Visser / Neurobiology of Aging 24 (2003) S47–S49
Data on abnormal behaviour in individual fetuses with abnormal brain functioning are more numerous than indicated by Nijhuis. However, I do agree that prenatal prediction of neurological outcome will remain difficult and requires different approaches.
4. Conclusion Fetal movements appear early, are from their start specific and closely resemble movements after birth. This makes them candidates for diagnostic purposes. Disturbances in embryonic and fetal central nervous system development can be investigated by studying the timetable of appearance of movement patterns, the quality of specific movements and the development of fetal behavioural states. Abnormal development can be found in many endogenous malfunctions and in disturbances caused by maternal diseases and exogenous behavioural teratogens. It remains questionable if fetal behavioural studies will prove to be specific enough to identify the individual fetus with an impaired brain functioning, except for isolated cases. References [1] Abrams LA, Balducci J. Fetal seizures: a case study. Obstet Gynecol 1996;88:661–3. [2] Bekedam DJ, Visser GH, De Vries JJ, Prechtl HF. Motor behaviour in the growth retarded fetus. Early Hum Dev 1985;12:155–65. [3] Boué J, Vignal P, Aubry MC, Alees JM. Ultrasound movement patterns of fetuses with chromosome anomalies. Prenat Diagn 1982;2:61–5. [4] Derks JB, Mulder EJ, Visser GH. The effects of maternal betamethasone administration on the fetus. Br J Obstet Gynaecol 1995;102:40–6. [5] De Vries JI, Visser GH, Prechtl HF. The emergence of fetal behaviour. I. Qualitative aspects. Early Hum Dev 1982;7:301–22. [6] Ferrari F, Cioni G, Prechtl HF. Qualitative changes of general movements in preterm infants with brain lesions. Early Hum Dev 1990;23:193–231. [7] Liggins GC, Vilos GA, Kitterman JA, Lee CH. The effect of spinal cord transection on lung development in fetal sheep. J Dev Physiol 1981;3:267–74. [8] Mulder EJ, Morssink LP, Benschop T, Visser GH. Acute maternal alcohol consumption disrupts behavioral state organization in the near-term fetus. Pediatr Res 1998;44:774–9.
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[9] Mulder EJ, Visser GH. Growth and motor development in fetuses of women with type-1 diabetes. II. Emergence of specific movement patterns. Early Hum Dev 1991;25:107–15. [10] Mulder EJ, Visser GH, Bekedam DJ, Prechtl HF. Emergence of behavioural states in fetuses of type-1 diabetic women. Early Hum Dev 1987;15:231–52. [11] Nijhuis JG, Prechtl HF, Martin Jr CB, Bots RS. Are there behavioural states in the human fetus? Early Hum Dev 1982;6:177–95. [12] Nyman M, Arulkumaran S, Hsu TS, Ratman SS, Till O, Westgren M. Vibroacoustic stimulation and intrauterine sound pressure levels. Obstet Gynecol 1991;78:803–6. [13] Prechtl HFR, editor. Continuity of neural functions from prenatal to postnatal life. Oxford: Blackwell Publishers; 1984. [14] Prechtl HF. Qualitative changes of spontaneous movements in fetus and preterm infant are a marker of neurological dysfunction. Early Hum Dev 1990;23:151–8. [15] Roberts AB, Little D, Cooper D, Campbell S. Normal patterns of fetal activity in the third trimester. Br J Obstet Gynaecol 1979;86:4–9. [16] Schmidt W, Boos R, Gnirs J, Auer L, Schulze S. Fetal behavioural states and controlled sound stimulation. Early Hum Dev 1985;12:145–53. [17] Sival DA, Visser GH, Prechtl HF. Does reduction of amniotic fluid affect fetal movements? Early Hum Dev 1990;23:233–46. [18] Sival DA, Visser GH, Prechtl HF. The effect of intra-uterine growth retardation on the quality of general movements in the human fetus. Early Hum Dev 1992;28:119–32. [19] Tegaldo L, Mulder EJ, Visser GH, Bruschettini PL. The effects of maternal caffeine intake on the near-term human fetus. Pren Neon Med 1998;3:S30 [abstract]. [20] Van den Bergh BR, Mulder EJ, Visser GH, Poelmann-Weesjes G, Bekedam DJ, Prechtl HF. The effect of (induced) maternal emotions on fetal behaviour: a controlled study. Early Hum Dev 1989;19: 9–19. [21] Van Vliet MA, Martin CB, Nijhuis JG, Prechtl HF. Behavioural states in growth retarded human fetuses. Early Hum Dev 1985;12:183–97. [22] Visser GH, Goodman JD, Levine DH, Dawes GH. Diurnal and other cyclic variations in human fetal heart rate near term. Am J Obstet Gynecol 1982;142:535–44. [23] Visser GH, Laurini RN, De Vries JI, Bekedam DJ, Prechtl HF. Abnormal motor behaviour in anencephalic fetuses. Early Hum Dev 1985;12:173–83. [24] Visser GH, Mulder HH, Wit HP, Mulder EJ, Prechtl HF. Vibro-acoustic stimulation of the human fetus: effect on behavioural state organization. Early Hum Dev 1989;19:285–96. [25] Visser GH, Prechtl HF. Movements and behavioural states in the human fetus. In: Jones CJ, editor. Fetal and neonatal development. New York: Perinatology Press; 1988. p. 581–90. [26] Visser GH, Zeelenberg HJ, De Vries JI, Dawes GS. External physical stimulation of the human fetus during episodes of low heart rate variation. Am J Obstet Gynecol 1983;145:579–84. [27] Wigglesworth JS, Desat R. Effects of lung growth on cervical cord section in the rabbit fetus. Early Hum Dev 1979;3:51–65.
Commentary
Fetal behaviour: a commentary夽 Gerard H.A. Visser∗ Department of Obstetrics, Neonatology and Gynaecology, University Medical Centre Utrecht, P.O. Box 85090, 3508 AB Utrecht, The Netherlands Received 24 January 2003; accepted 10 February 2003
Keywords: Neural function; Fetal movement; Brain functioning
1. Introduction Nijhuis has given a comprehensive review on fetal behaviour, that deserves support, some additions and only minor criticism. Forty-nine of the 76 references in his paper are from Dutch authors and that underlines the importance given to fetal behavioural research in The Netherlands. The latter is undoubtedly due to the presence of Heinz Prechtl, an Austrian developmental neurologist who started as a baby watcher, moved on to become a fetus watcher and has stimulated most of the Dutch research groups.
2. Continuity of neural functions from prenatal to postnatal life Nijhuis stresses in his introduction rightly that gestational age is an important variable (“the most important factor”) regarding fetal behaviour. The incidence of occurrence of most movement patterns and of fetal heart rate and its variation are indeed dependent on gestational age, so is the percentage of coincidence of the three fetal state variables and therefore of organisation of fetal behavioural states. This emphasises changes occurring with development. One may, however, also put it the other way around and focus on continuity, continuity of neural functions from prenatal to postnatal life [13]. Embryonic and fetal movement patterns emerge early, are from their beginning onwards specific and closely resemble movement patterns after birth. This continuity, this onset of highly organised specific movement patterns, long before birth, is surprising, especially when the minimal development of the nervous 夽
Comment to the paper ‘Fetal behaviour’ by J.G. Nijhuis. Tel.: +31-30-2506426; fax: +31-30-2505320. E-mail address: [email protected] (G.H.A. Visser).
∗
system at that early age is taken into account. There are few studies on the ultrastructure of the nervous system of the young fetus. The available data suggest that movements emerge as soon as the first connective structures are formed [5]. The reason why different movement patterns emerge so early is still not clear. Certain movement patterns have an adaptive effect on the survival or development of the fetus. Frequent and active changes of intra-uterine position may prevent adhesions and local stasis of the circulation in the skin. Individual movements may prevent the occurrence of contractures such as those that can be found after prolonged oligohydramnios following leakage of amniotic fluid. Sucking and swallowing movements are necessary for the regulation of the amount of amniotic fluid. Another reason for fetal movements to emerge early may be anticipation of postnatal function. Some motor patterns begin during early prenatal development and are regularly performed long before they fulfil a meaningful task as part of a complex adaptive function. For example, fetal breathing movements are already present at 10 weeks. These movements might also have an influence on lung growth, as in animal experiments spinal cord transection results in fetal lung hypoplasia [7,27]. This link is still unclear in the human. A second example of continuity from prenatal to postnatal life concerns to the incidence of occurrence of some movement patterns, the interval between movements (e.g. the hiccup-to-hiccup interval remains the same), but most of all the continuity in behavioural states. Fetal behavioural states are defined by a different set of variables, but are equivalent to the states in the newborn [11]. Studies on the newborn may, therefore, help us in the interpretation of findings in the fetus. The duration of a complete 1F/2F cycle (non-REM/REM cycle) even remains the same into adulthood (±90 min).
0197-4580/03/$ – see front matter © 2003 Elsevier Science Inc. All rights reserved. doi:10.1016/S0197-4580(03)00055-1
S48
G.H.A. Visser / Neurobiology of Aging 24 (2003) S47–S49
3. Studying fetal behaviour By studying fetal behaviour: (1) insight is obtained in normal development of aspects of nervous system functioning; (2) situations may be identified with a negative impact on nervous system development; and (3) individual fetuses might be identified with abnormal brain functioning. Nijhuis has addressed the importance of knowledge of physiology in the interpretation of fetal heart rate patterns. This not only holds for the spontaneously occurring patterns, but also for (absence of) fetal reactions to stimuli. We now know that a flat fetal heart rate pattern, with reduced variation is a normal phenomenon during the third trimester, representing behavioural state 1F (or non-REM-sleep). Obstetricians have for long tried to stimulate the fetus during a flat heart rate pattern, to distinguish between quiet sleep and a poor condition. However, state 1F is not influenced by shaking the maternal abdomen, nor by transabdominal sound stimulation [16,26]. Such procedures have therefore resulted in unnecessary obstetrical actions. These findings are consistent with the fact that it is difficult to wake up a newborn baby when in state 1. The fetus may benefit from this inaccessibility as it guarantees a more or less undisturbed endogenous development. However, fetuses do react to vibro-acoustic stimulation using an electronic artificial larynx and during the past 10 years, numerous papers on the use of this device have been published. The most important rationale for stimulation is also to differentiate between poor and good fetal status in cases of possibly abnormal fetal heart rate patterns. This kind of stimulus induces excessive fetal movements, a prolonged tachycardia and a disorganisation of behavioural states [24]. It seems better not to use this device, especially when the intra-uterine sound produced exceeds 125 dB [12]. It is obvious that situations with a negative impact on fetal nervous system development may be identified easier than diagnosing abnormal brain functioning in the individual fetus, since the former concerns a (statistical) comparison between groups. Nijhuis has mentioned some situations resulting in behavioural changes, but I would like to go a bit more in detail. Disturbances in development may be induced by endogenous factors (such as chromosome abnormalities) and maternal diseases (for example diabetes), but also by exogenous behavioural teratogens. Abnormal movement patterns, indicative of altered brain or muscular development, have been described in fetuses with chromosome abnormalities [3], in anencephalic fetuses [23], in fetuses with other cerebral malformations [25], in growth-retarded fetuses [2,18] and in fetuses suffering from prolonged oligohydramnios [17]. Common features in all these cases are the qualitative changes in the execution of movement patterns, which are abrupt and forceful, with large amplitude in the majority of
fetuses with a chromosome or central nervous system defect; or slow, with small amplitude, in the others. Recently fetal seizures have been described in association with severe brain abnormalities [1]. It should be emphasised that movement abnormalities associated with central nervous system dysfunction are qualitative and not quantitative in nature. In preterm babies with brain lesions assessment of the quality of movements appears to be a much better predictor of neurological outcome than the number of the movements [6,14]. In anencephalic fetuses movements tend to be numerous, forceful, jerky in character and of a large amplitude [23]. This indicates that only minimal neural structures are necessary for movements to be generated. On the other hand, these data indicate that already in the first half of pregnancy a normal nervous system, although only partly developed, is necessary for movements to be executed normally. In women with type-1 diabetes embryonic movements emerge during the first trimester of pregnancy about one week later than in control fetuses, apart from fetal breathing that starts earlier [9]. During the third trimester fetal behavioural states are less well organised, indicating a delayed or disturbed development of nervous system functioning [10]. Also in growth retarded fetuses states development is delayed [21]. This occurs before the onset of fetal hypoxemia, which indicates that brain dysfunction in these fetuses is more likely the result of chronic malnutrition in utero than due to hypoxemia. Finally, some additional data regarding exogenous behavioural teratogens. In a carefully controlled study we found that two glasses of white wine temporarily suppress fetal breathing movements and disturb fetal state cycling, the latter being mainly due to suppression of fetal eye movements [8]. REM sleep is important for normal brain development and these data may shed some light on behavioural abnormalities observed in infants whose mother consumed more than two glasses of alcohol per day during pregnancy. A study like this one, demonstrating direct effects of alcohol on the fetus, may discourage pregnant women from drinking. Maternal caffeine intake causes considerable increases in fetal body movements, fetal heart rate variability and in the percentage of fetal heart rate variability pattern D, indicating that the fetus spends more time “awake” [19]. Induced maternal emotions do not affect fetal state cycling, but there is a positive correlation between the level of maternal stress and the incidence of fetal body movements [20]. Active fetuses also tend to have a high activity level after birth and one may speculate whether this is due to prenatal effects of high maternal anxiety or to genetic differences. The relationship between maternal stress and fetal and neonatal behaviour is complex, given the large variety of stressors and differences in “coping” with stress. Moreover, maternal stress and cortisol do not show a clear relationship. Exogenous corticosteroids induce a temporary reduction in fetal movements, and fetal activity is inversely correlated to the maternal diurnal cortisol rhythm [4,15,22]. Thus, this important topic still needs further exploration.
G.H.A. Visser / Neurobiology of Aging 24 (2003) S47–S49
Data on abnormal behaviour in individual fetuses with abnormal brain functioning are more numerous than indicated by Nijhuis. However, I do agree that prenatal prediction of neurological outcome will remain difficult and requires different approaches.
4. Conclusion Fetal movements appear early, are from their start specific and closely resemble movements after birth. This makes them candidates for diagnostic purposes. Disturbances in embryonic and fetal central nervous system development can be investigated by studying the timetable of appearance of movement patterns, the quality of specific movements and the development of fetal behavioural states. Abnormal development can be found in many endogenous malfunctions and in disturbances caused by maternal diseases and exogenous behavioural teratogens. It remains questionable if fetal behavioural studies will prove to be specific enough to identify the individual fetus with an impaired brain functioning, except for isolated cases. References [1] Abrams LA, Balducci J. Fetal seizures: a case study. Obstet Gynecol 1996;88:661–3. [2] Bekedam DJ, Visser GH, De Vries JJ, Prechtl HF. Motor behaviour in the growth retarded fetus. Early Hum Dev 1985;12:155–65. [3] Boué J, Vignal P, Aubry MC, Alees JM. Ultrasound movement patterns of fetuses with chromosome anomalies. Prenat Diagn 1982;2:61–5. [4] Derks JB, Mulder EJ, Visser GH. The effects of maternal betamethasone administration on the fetus. Br J Obstet Gynaecol 1995;102:40–6. [5] De Vries JI, Visser GH, Prechtl HF. The emergence of fetal behaviour. I. Qualitative aspects. Early Hum Dev 1982;7:301–22. [6] Ferrari F, Cioni G, Prechtl HF. Qualitative changes of general movements in preterm infants with brain lesions. Early Hum Dev 1990;23:193–231. [7] Liggins GC, Vilos GA, Kitterman JA, Lee CH. The effect of spinal cord transection on lung development in fetal sheep. J Dev Physiol 1981;3:267–74. [8] Mulder EJ, Morssink LP, Benschop T, Visser GH. Acute maternal alcohol consumption disrupts behavioral state organization in the near-term fetus. Pediatr Res 1998;44:774–9.
S49
[9] Mulder EJ, Visser GH. Growth and motor development in fetuses of women with type-1 diabetes. II. Emergence of specific movement patterns. Early Hum Dev 1991;25:107–15. [10] Mulder EJ, Visser GH, Bekedam DJ, Prechtl HF. Emergence of behavioural states in fetuses of type-1 diabetic women. Early Hum Dev 1987;15:231–52. [11] Nijhuis JG, Prechtl HF, Martin Jr CB, Bots RS. Are there behavioural states in the human fetus? Early Hum Dev 1982;6:177–95. [12] Nyman M, Arulkumaran S, Hsu TS, Ratman SS, Till O, Westgren M. Vibroacoustic stimulation and intrauterine sound pressure levels. Obstet Gynecol 1991;78:803–6. [13] Prechtl HFR, editor. Continuity of neural functions from prenatal to postnatal life. Oxford: Blackwell Publishers; 1984. [14] Prechtl HF. Qualitative changes of spontaneous movements in fetus and preterm infant are a marker of neurological dysfunction. Early Hum Dev 1990;23:151–8. [15] Roberts AB, Little D, Cooper D, Campbell S. Normal patterns of fetal activity in the third trimester. Br J Obstet Gynaecol 1979;86:4–9. [16] Schmidt W, Boos R, Gnirs J, Auer L, Schulze S. Fetal behavioural states and controlled sound stimulation. Early Hum Dev 1985;12:145–53. [17] Sival DA, Visser GH, Prechtl HF. Does reduction of amniotic fluid affect fetal movements? Early Hum Dev 1990;23:233–46. [18] Sival DA, Visser GH, Prechtl HF. The effect of intra-uterine growth retardation on the quality of general movements in the human fetus. Early Hum Dev 1992;28:119–32. [19] Tegaldo L, Mulder EJ, Visser GH, Bruschettini PL. The effects of maternal caffeine intake on the near-term human fetus. Pren Neon Med 1998;3:S30 [abstract]. [20] Van den Bergh BR, Mulder EJ, Visser GH, Poelmann-Weesjes G, Bekedam DJ, Prechtl HF. The effect of (induced) maternal emotions on fetal behaviour: a controlled study. Early Hum Dev 1989;19: 9–19. [21] Van Vliet MA, Martin CB, Nijhuis JG, Prechtl HF. Behavioural states in growth retarded human fetuses. Early Hum Dev 1985;12:183–97. [22] Visser GH, Goodman JD, Levine DH, Dawes GH. Diurnal and other cyclic variations in human fetal heart rate near term. Am J Obstet Gynecol 1982;142:535–44. [23] Visser GH, Laurini RN, De Vries JI, Bekedam DJ, Prechtl HF. Abnormal motor behaviour in anencephalic fetuses. Early Hum Dev 1985;12:173–83. [24] Visser GH, Mulder HH, Wit HP, Mulder EJ, Prechtl HF. Vibro-acoustic stimulation of the human fetus: effect on behavioural state organization. Early Hum Dev 1989;19:285–96. [25] Visser GH, Prechtl HF. Movements and behavioural states in the human fetus. In: Jones CJ, editor. Fetal and neonatal development. New York: Perinatology Press; 1988. p. 581–90. [26] Visser GH, Zeelenberg HJ, De Vries JI, Dawes GS. External physical stimulation of the human fetus during episodes of low heart rate variation. Am J Obstet Gynecol 1983;145:579–84. [27] Wigglesworth JS, Desat R. Effects of lung growth on cervical cord section in the rabbit fetus. Early Hum Dev 1979;3:51–65.