Assessment of Fetal Neurobehavior in Special Cases

INTRODUCTION

In utero life and particularly fetal brain development and fetal behavior and more specifically assessment and imaging of the fetal nervous system, is a field of great interest in perinatal medicine, with many unanswered questions.^1–4 Human brain development is a very complex, but also extremely structured process commencing the first weeks after conception and continuing for a very long time, even throughout adult life. Establishing the anatomical integrity of the CNS is of utmost importance in fetal medicine to verify the wellbeing of the fetus, but it is not always enough.^5–9 Motoric disabilities, mental impairment, and behavioral problems can occur even with an anatomical intact CNS, without the presence of any anatomical anomalies.^10–12 So whenever any of these functional problems occur, it is always a challenge to identify—if possible—when and how this problem could have happened, especially in cases when suspected to be responsible are antenatal, intrapartum, or postnatal incidents.^13–16 If a specific incident is not identified environmental factors should also be considered, as it happens, e.g., in cases of prematurity when the conditions of in utero life are imitated to protect the premature neonate, mainly regarding feeding and nurturing, but still the risk of morbidity and complication remains high, especially regarding the brain development and nerve function.^17–22 The degree that the fetus may be affected and the degree of neurological compromises in such cases, most of the times cannot be estimated, with the clinical pictures varying significantly, ranging from mild behavioral and learning disabilities to the most severe form of neurological impairment which is cerebral palsy (CP). But even when an anatomical abnormality or variation is detected antenatally, as it happens in the case of fetal ventriculomegaly, e.g., we cannot be certain to what extend the fetus will be affected, be able to offer complete counseling to the parents regarding the prognosis. In neonates, children, or adults certain clinical examinations can show the severity of the neurological damage that may have been caused by an injury, a tumor, or an infection.^23–26 Until recently, there were no structured methods of assessing the neurological integrity of the fetus during in utero life and therefore we could not be certain or even distinguish normal from abnormal fetal neurological behavior. As mentioned above, the development and maturation of the fetal nervous system is an extremely structured process and this neuronal development is reflected by certain neurobehavioral patterns of the fetus that correspond to each trimester, or even week of pregnancy.^27–29 The study of this developmental process and mainly being able to recognize the normal fetal neurobehavior that should be expected for each period of pregnancy, can help us understand firstly the normal state for in utero life. By understanding the normal fetal neurobehavior, we could then identify abnormal patterns and if possible link them to different anatomical and chromosomal abnormalities or even various insults that may affect fetal CNS and neurobehavioral integrity.^30–32 Ultrasound technology offered the unique possibility to examine the fetus in utero and detect various anatomical and chromosomal abnormalities. Further evolution of ultrasound technology and particularly 3D ultrasound allowed us to view the fetus in explicit detail, being able to view fetal parts and characteristics in a similar way that a neonate is looked at, and even further technological advance, 4D ultrasound, offered the possibility to view all these explicit details in real-time. Characteristics such as hand and feet movements, facial alterations and eye blinking can be assessed prenatally with 4D ultrasound technology, as one would observe and examine a newborn. The first test that succeeded to combine all the parameters and form a scoring system that would assess the fetus in a comprehensive and systematic approach, in the same way, that neonatologists perform a neurological assessment in newborns, to determine their neurological status during the first days of their life, is the Kurjak antenatal neurodevelopmental test (KANET). Kurjak antenatal neurodevelopmental test has already been shown to be useful in the standardization of neurobehavioral assessment with the potential for antenatal detection of fetuses with severe neurobehavioral impairment. Kurjak antenatal neurodevelopmental test has also succeeded to verify the good neurological outcomes of fetuses that had normal KANET scores, showing a great positive predictive value and offering reassurance for the neurological outcome of these pregnancies.^29–34 The first results prove that the prenatal neurological findings as estimated by the KANET test, are in concordance with their postnatal outcome. As already mentioned, fetal neurobehavior can be affected by many parameters and can be altered by environmental, racial, and maternal factors, by maternal disease, administration of drugs and neurotrophic agents, and many other factors.

ETHNICITY AND FETAL BEHAVIOR

Hanaoka et al. studied whether fetuses of different ethnical backgrounds behave differently in utero and alter the assessment of fetal neurobehavior as anthropometric characteristics in the different populations can give a different picture, and especially for the Asian population what has been noted is a shorter palpebral fissure, a wider soft nose within wide facial contours, a smaller mouth width, and a lower face smaller than the forehead height, parameters that can differentiate the result.^35–37 The authors applied KANET to Asian (Japanese) and Caucasian (Croatian) populations and noted the differences in their scores, and also to the particular parameters that can be different. They calculated the KANET scores for both groups and what they noticed was that although the total KANET scores of both groups were within normal ranges, there was a difference in some parameters that finally altered the score, but not to a statistically significant degree. The parameters of KANET that were noted to have some differences were mainly the following: isolated eye blinking and facial alteration or mouth opening. As mentioned by the authors part of these differences could be attributed to different anthropometric characteristics which were also mentioned above such as shorter, wider, and shallower noses for the Japanese population and also greater intercanthal width in relation to a shorter palpebral fissure, a smaller mouth width, a lower face, smaller than the forehead height, and a wider, shallower soft nose within wide facial contours. The characteristics of the Caucasian face are a high-bridged, long nose, deep-set eyes, and a sharply sculpted face. The authors conclude that even when considering these anthropometric differences ethnicity is a parameter that should be considered when evaluating fetal behavior. Regarding the remaining parameters of KANET isolated head anteflexion, and isolated leg movement was noted to also differ between the two populations, but not to a statistically significant degree. So, there may be some expected ethnic differences in fetal behavior and they should be kept in mind when assessing fetal neurobehavior, but overall these differences do not affect the final total KANET score (normal, abnormal, borderline) and the assessment of the fetus, but especially in borderline cases this should be taken into consideration and close follow-up should be continued in these cases (Figs 1 to 3).

FETAL SEX AND FETAL BEHAVIOR

While assessing specific characteristics of newborns differences have been noted between newborns of different sex and this has been attributed to the different maturational process of the neurobehavior between the two sexes. Differences in newborns have been noted in startle movements (male newborns are thought to have more frequent movements), in reflex smiles and bursts of rhythmic mouthing (female newborns present them earlier and more frequently), prone head reaction, and grip strength.^38–40 There have been some studies on sex difference in fetal behavior assessed by two-dimensional (2D) sonography^41–43 or fetal actocardiography using a single wide array Doppler transducer.^44,45 Studies have shown that there may be differences in fetal behavior according to fetal sex and especially mouthing movements (they are increased in female fetuses), while female fetuses appear to require significantly fewer stimuli than males to habituate, suggesting that habituation in the human fetus is affected by fetal sex, and these differences have to do with “central type” developmental differences in the nervous system of the fetuses.⁴⁶ Taste stimuli of the mother also seem to affect fetuses of different sex differently. When pregnant women ingested dark chocolate there was an increase in fetal response and fetal movements, which was more apparent in female fetuses.⁴⁷ Hata et al. by using 4D ultrasound and applying KANET for the evaluation of neurobehavior in both male and female fetuses showed that there was no significant difference in the total KANET score between male and female fetuses, and when they further analyzed each parameter of KANET they found no significant difference in none of the eight parameters, concluding that fetal neurobehavioral and developmental process of the fetal nervous system has no apparent difference between male and female fetuses.³⁸ There are studies particularly on neonates^39,40,44 that have shown differences in some parameters of neurobehavior (e.g., general movement, smiling, and mouthing) between males and females, and most of these parameters are parts of the KANET test, but as far as fetuses are concerned these studies used 2D ultrasound to assess fetuses and what is more that could not be confirmed by the only study that assessed fetuses with 4D ultrasound and the complete KANET.

DIABETES AND FETAL BEHAVIOR

It has been well established that different maternal or environmental factors can affect fetal development and fetal neurobehavior. Especially gestational diabetes is a well-known risk factor for both maternal and fetal complications so that it could affect the fetus either directly or indirectly, by affecting the condition of the mother.^48–50 Gestational diabetes is a condition that is increasing through the years and is a known risk factor for maternal and fetal complications and affects fetal behavior.⁵¹ In a hyperglycemic environment, there is a decrease in the number of fetal movements, and the effect of diabetes on fetal activity could be attributed to the immaturity of the development of the sensory-motor response system that characterizes fetuses of diabetic pregnancies, rather than solely a direct effect of glucose levels on the fetus.^52,53 Studies have also shown that fetal breathing and body movements of diabetic pregnancies are decreased and are altered due to poor behavioral organization, even when glycemic control is adequate and often fetuses of diabetic women had higher numbers of fetal breathing movement and fetal heart rate rhythms, but the fetal movements were lower. Studies show that in diabetic pregnancies hypoglycemia rather than hyperglycemia increases fetal activity and that in these pregnancies hyperglycemia is related to a decrease in the frequency of fetal movements.^53–56 However, in most of these studies, a structured and homogeneous method of assessing fetal activity was lacking. Antsaklis et al. attempted to assess the fetal behavior of fetuses in conditions of diabetes by applying KANET to fetuses of diabetic mothers.⁴⁸ What they showed was that there are identifiable differences in the fetal behavior between diabetic and non-diabetic fetuses with the non-diabetic group having overall higher KANET scores. They also identified which specific parameters—movements differ between the two groups, with the biggest difference between the two groups being for isolated eye blinking, facial alterations, and finger movements, while there was also a small difference for isolated hand movements, but this was not statistically significant, concluding that glycemic control affects fetal neurobehavior and possibly early identification of undiagnosed diabetes in pregnancy and good glycemic control, may be crucial for fetal neurodevelopment.

HYPOTHYROIDISM AND FETAL BEHAVIOR

Maternal thyroid function is directly related to the development and function of the fetal and neonatal neurological system. Thyroid hormones play an important role in the myelination and differentiation of neuronal cells of the fetus and as a result good control of maternal thyroid function, especially during the first weeks of pregnancy when the fetus is dependent entirely on the maternal thyroid, are important for the formation and development of fetal nervous system and neurobehavior.^57–61 Several studies have shown the significant effect that maternal hypothyroidism, whether overt or subclinical, has on the neurodevelopment and cognitive functions of neonates.⁶² Neurophysiological tests on neonates of pregnant women with overt hypothyroidism proved that these neonates are negatively affected and that they have a higher incidence of verbal and non-verbal cognitive delays, but also that motor and intellectual functions are also adversely affected. What is more maternal hypothyroidism may indirectly affect fetal brain development through pregnancy-related complications as preterm birth, IUGR, and CP with their possible detrimental effects on the future neurological development of the offspring?^63–65 Dieb et al. showed that fetuses of hypothyroid mothers had lower KANET scores, compared to fetuses of mothers with normal thyroid function.⁵⁷ They reported abnormal fetal neurological behavior in cases of overt maternal hypothyroidism, proving the importance of well-controlled thyroid function of pregnant women.

PSYCHOTROPIC DRUGS AND FETAL BEHAVIOR

The effect of psychotropic drugs on fetal behavior during pregnancy has been a great challenge in fetal neurology. Prenatal administration of selective serotonin reuptake inhibitors (SSRIs) and antidepressants has been related to neonatal psychiatric, anxiety, and withdrawal symptoms up to 3 years of life and even with cases of autism.⁶⁶ It has been reported that fetuses of pregnant women with depression showed differences in their behavior during the second and third trimester of pregnancy, as it happened for fetuses of pregnant women who were under treatment with anticonvulsants, with the effects of these drugs being evident even up to school age for these children.^67–72 Even regarding the activity of the fetuses of mothers who had depression there were some differences noted, even for different trimesters. However, all these studies used 2D ultrasonography to evaluate fetal behavior, a technique that limits the assessment of fetal neurobehavior, without structured methods of assessment for the duration of the examination and the parameters that were assessed. Hata et al. used 4D ultrasonography and KANET to assess the fetuses of pregnant women who were under treatment with psychotropic drugs for different conditions (schizophrenia, depression, anxiety, epilepsy, panic disorders, OCD, personality disorder) and found no significant difference in the total KANET score. There were also no significant differences in any of the eight parameters between the groups, suggesting that psychotropic drugs may not affect fetal behavioral development in utero. However their study population was limited (10 cases) and their study group was not homogeneous as it consisted of women with different conditions and under different treatment methods-medications, and these factors were suggested by the authors as a limitation for safe conclusions (Figs 4 to 6).

FETAL RESPONSE TO VIBROACOUSTIC STIMULATION

Vibroacoustic stimulation (VAS) has been routinely used in everyday obstetrical clinical practice to stimulate fetuses, to cause fetal heart rate acceleration during a non-stress test (NST) or biophysical profile, and to detect fetal response and therefore to evaluate fetal well-being, fetal hearing impairment, and neurobehavioral development.^73–76 Fetal responses to different stimuli throughout pregnancy and especially during the third trimester have been proposed as a method to assess functional neurodevelopment of the fetus and indirectly to assess the fetal condition and particularly brain maturation and CNS integrity.^76–79 Ogo et al. showed that for fetuses of gestational age <36 weeks VAS did not appear to have a diagnostic value as a significant response was not noted in these fetuses, whereas in fetuses after 36 weeks of gestation the response appeared to be notable, and with an application of KANET they identified specific changes after VAS, which was significant increases in the frequencies of eye blinking and also in startle movements, and what the authors mentioned was that these changes possible reflected the functional maturation of the auditory system of the fetus, which does not reach an adequate level before 37 weeks. The decreased maturation of the fetal auditory system appeared to be responsible for the decreased response after VAS to fetuses of gestational age 24–27 weeks, whose auditory system has not yet developed, whereas, for later gestational age, that is after 28 weeks, but before 36 weeks (at 28–31 and 32–35 weeks) also had decreased response to VAS as the fetal auditory system has not been completely formed. What is more, the authors managed to identify which specific fetal parameters increase in fetuses after 36 weeks after VAS, which was eye blinking and startle movements, and the attributed this to the fact that eye blinking is related to central dopamine system maturation, which occurs at about 36 weeks of gestation, while eye blinking and startle movement after 36 weeks of gestation, might represent an advanced stage of the fetal brain and CNS maturation and response to external stimulation, so that the other parameters of fetal behavior are not altered.

ANTENATAL CORTICOSTEROID ADMINISTRATION AND FETAL BEHAVIOR

Antenatal administration of corticosteroids has been related to a reduction of fetal activity, mainly of body and respiratory movements.⁸⁰ It is also well documented that these changes in fetal behavior are not permanent and that they last on average about 1–2 days, with a maximum duration reaching up to 4 days.⁸¹ Changes have also been documented regarding the Doppler studies of the fetus, mainly ductus venosus, and umbilical Doppler but without affecting the overall uteroplacental circulation.⁸² Also, a decrease of the biophysical profile score has been documented after administration of corticosteroids antenatally.^83,84 Betamethasone is a stronger risk factor for reduction of fetal movements compared to dexamethasone, although this effect appears to be transient in both cases.^82–85 What is more, the effect of corticosteroids on fetal behavior and neurological development has been proved by studies about direct administration of corticosteroids intrauterine, which caused the fetus vasoconstriction and hypoxemia, located especially in the area of thalamus, diencephalon, and pons. However, the effect of corticosteroid administration as already mentioned is transient and does not appear to alter the overall perinatal outcome, so that decisions regarding the management of pregnancy and delivery, should be carefully taken when corticosteroids are administered in pregnancy and their effect may be obvious in the cardiotocograph or the biophysical profile of the fetus, to which corticosteroids were administered. Antsaklis et al. studied the effect of corticosteroids on fetal neurobehavior by applying KANET to 65 singleton pregnancies after 28 weeks, who were administered corticosteroids. Compared to the control group there was an overall decrease of 2 at the KANET scores when performed 24–48 hours after corticosteroid administration. These reductions of KANET were not reported in the follow-up examination 2 weeks later for the same fetuses. While comparing betamethasone to dexamethasone, dexamethasone appeared to have a smaller effect on the KANET score, but this difference was not statistically significant. It is really important therefore when applying KANET to have a good knowledge of the maternal history and drug administration that could potentially affect fetal behavior, to avoid misinterpretations.

CONCLUSION

Verifying the integrity of the fetal nervous system is a very difficult and at the same time very complex procedure. Assessment of fetal anatomy has reached a very high level via 2D, but especially through 3D ultrasound, as has an assessment of chromosomal abnormalities of the fetus with molecular genetics, who could affect the nervous motoric, behavioral and mental status of the fetus. Assessment of fetal neurobehavior has up to a level been standardized with 4D ultrasound and with KANET, a method that by applying 4D ultrasound to the fetus assesses its neurobehavior in real-time in a similar way that neonatologists assess the newborn in real life. Many multicentric studies have examined and confirmed the validity of KANET on different populations, both low and high risk. However, in this new field of fetal medicine, fetal neurology, and fetal neurobehavior there is still a lot to be discovered and to be learned. Fetal behavior is a very complex situation, susceptible to many genetic, epigenetic, environmental, and anatomical parameters. Common maternal conditions such as maternal diabetes and thyroid disease, administration of medications that are used frequently in pregnancy such as antenatal corticosteroids and psychotropic drugs, or even ethnic and fetal sex differences can alter the way a fetus is behaving. All these parameters should be taken into consideration when fetal neurobehavior is assessed, as we should take into consideration the full maternal medical history. Assessment of fetal neurobehavior opens a new era in fetal medicine, as many of the so thought routine techniques that we apply in obstetrics could be proved that could be further improved by assessing the fetal neurobehavior at the same time.

This paper will be published in Kurjak A. Fetal Brain Function (in preparation). New Delhi: Jaypee Brothers Medical Publishers, 2021.

REFERENCES

1. Yigiter AB, Kavak ZN. Normal standards of fetal behavior assessed by four-dimensional sonography. J Matern Fetal Neonatal Med 2006;19(11):707–721. DOI: 10.1080/14767050600924129.

2. Rees S, Harding R. Brain development during fetal life: influences of the intra-uterine environment. Neurosci Lett 2004;361(1-3):111–114. DOI: 10.1016/j.neulet.2004.02.002.

3. Joseph R. Fetal brain and cognitive development. Dev Rev 1999;20(1):81–98. DOI: 10.1006/drev.1999.0486.

4. Antsaklis P, Antsaklis A. The assessment of fetal neurobehavior with four-dimensional ultrasound: the Kurjak antenatal neurodevelopmental test. Donald School J Ultrasound in Obstet Gynecol 2012;6(4):362–375. DOI: 10.5005/jp-journals-10009-1259.

5. Eidelman AI. The living fetus–dilemmas in treatment at the edge of viability. In: ed. S, Blazer EZ, Zimmer ed. The embryo: Scientific Discovery and Medical Ethics.. Basel: Karger; 2005. 351–370.

6. Stanojevic M, Zaputovic S, Bosnjak AP. Continuity between fetal and neonatal neurobehavior. Semin Fetal Neonatal Med 2012;17(6):324–329. DOI: 10.1016/j.siny.2012.06.006.

7. Kurjak A, Carrera J, Stanojevic M, et al. The role of 4D sonography in the neurological assessment of early human development. Ultrasound Rev Obstet Gynecol 2004;4(3):148–159. DOI: 10.3109/14722240400017075.

8. Strijbis EM, Oudman I, van Essen P, et al. Cerebral palsy and the application of the international criteria for acute intrapartum hypoxia. Obstet Gynecol 2006;107(6):1357–1365. DOI: 10.1097/01.AOG.0000220544.21316.80.

9. de Vries JI, Fong BF. Changes in fetal motility as a result of congenital disorders: an overview. Ultrasound Obstet Gynecol 2007;29(5):590–599. DOI: 10.1002/uog.3917.

10. de Vries JI, Fong BF. Normal fetal motility: an overview. Ultrasound Obstet Gynecol 2006;27(6):701–711. DOI: 10.1002/uog.2740.

11. Kurjak A, Abo-Yaqoub S, Stanojevic M, et al. The potential of 4D sonography in the assessment of fetal neurobehavior—multicentric study in high-risk pregnancies. J Perinat Med 2010;38(1):77–82. DOI: 10.1515/jpm.2010.012.

12. DiPietro JA, Bornstein MH, Costigan KA, et al. What does fetal movement predict about behavior during the first two years of life? Dev Phych 2002;40(4):358–371. DOI: 10.1002/dev.10025.

13. Rosier-van Dunné FM, van Wezel-Meijler G, Bakker MP, et al. General movements in the perinatal period and its relation to echogenicity changes in the brain. Early Hum Dev 2010;86(2):83–86. DOI: 10.1016/j.earlhumdev.2010.01.023.

14. Hata T, Kanenishi K, Akiyama M, et al. Realtime 3-D sonographic observation of fetal facial expression. J Obstet Gynaecol Res 2005;31(4):337–340. DOI: 10.1111/j.1447-0756.2005.00298.x.

15. Kozuma S, Baba K, Okai T, et al. Dynamic observation of the fetal face by three-dimensional ultrasound. Ultrasound Obstet Gynecol 1999;13(4):283–284.

16. Kurjak A, Azumendi G, Andonotopo W, et al. Three- and four-dimensional ultrasonography for the structural and functional evaluation of the fetal face. Am J Obstet Gynecol 2007;196(1):16–28. DOI: 10.1016/j.ajog.2006.06.090.

17. Kurjak A, Tikvica A, Stanojevic M, et al. The assessment of fetal neurobehavior by three-dimensional and four-dimensional ultrasound. J Matern Fetal Neonatal Med 2008;21(10):675–684. DOI: 10.1080/14767050802212166.

18. Kurjak A, Pooh R, Tikvica A, et al. Assessment of neurobehavior by 3D/4D ultrasound. In: Fetal Neurology. Pooh RK, Kurjak A, ch. 7 1st ed., 2009. pp.222–285.

19. Kurjak A, Stanojevic M, Andonotopo W, et al. Behavioral pattern continuity from prenatal to postnatal life—a study by four-dimensional (4D) ultrasonography. J Perinat Med 2004;32(4):346–353. DOI: 10.1515/JPM.2004.065.

20. Andonotopo W, Kurjak A, Kosuta MI. Behavior of an anencephalic fetus studied by 4D sonography. J Matern Fetal Neonatal Med 2005 Feb;17(2):165–168. DOI: 10.1080/jmf.17.2.165.168.

21. Nijhuis JG, Prechtl HF, Martin CB, et al. Are there behavioral states in the human fetus? Early Hum Dev 1982;6(2):177–195. DOI: 10.1016/0378-3782(82)90106-2.

22. Lebit DF, Vladareanu PD. The role of 4D ultrasound in the assessment of fetal behaviour. Maedica (Buchar) 2011;6(2):120–127.

23. Salihagic-Kadic A, Kurjak A, Medic M, et al. New data about embryonic and fetal neurodevelopment and behaviour obtained by 3D and 4D sonography. J Perinat Med 2005;33(6):478–490. DOI: 10.1515/JPM.2005.086.

24. Kurjak A, Azumendi G, Vecek N, et al. Fetal hand movements and facial expression in normal pregnancy studied by four-dimensional sonography. J Perinat Med 2003;31(6):496–508. DOI: 10.1515/JPM.2003.076.

25. Andonotopo W, Stanojevic M, Kurjak A, et al. Assessment of fetal behavior and general movements by four-dimensional sonography. Ultrasound Rev Obstet Gynecol 2004;4(2):103–114. DOI: 10.3109/14722240400016895.

26. Kurjak A, Stanojevic M, Azumendi G, et al. The potential of four-dimensional (4D) ultrasonography in the assessment of fetal awareness. J Perinat Med 2005;33(1):4653. DOI: 10.1515/JPM.2005.008.

27. Kurjak A, Pooh RK, Carrera JM, et al. Structural and functional early human development assessed by three-dimensional (3D) and four dimensional (4D) sonography. Fertil Steril 2005;84(5):1285–1299. DOI: 10.1016/j.fertnstert.2005.03.084.

28. Kurjak A, Miskovic B, Andonotopo W, et al. How useful is 3D and 4D ultrasound in perinatal medicine. J Perinat Med 2007;35(1):10–27. DOI: 10.1515/JPM.2007.002.

29. Andonotopo W, Medic M, Salihagic-Kadic A, et al. The assessment of embryonic and fetal neurodevelopment in early pregnancy: comparison between 2D and 4D sonographic scanning. J Perinat Med 2005;33(5):406–414. DOI: 10.1515/JPM.2005.073.

30. Kurjak A, Stanojevic M, Andonotopo W, et al. Fetal behavior assessed in all three trimesters of normal pregnancy by four-dimensional ultrasonography. Croat Med J 2005;46(5):772–780.

31. Pooh RK, Ogura T. Normal and abnormal fetal hand positioning and movement in early pregnancy detected by three- and four-dimensional ultrasound. Ultrasound Rev Obset Gynecol 2004;4:46–51.

32. Andonopo W, Kurjak A. The assessment of fetal behavior of growth restricted fetuses by 4D sonography. J Perinat Med 2006;34:471–478.

33. Kurjak A, Andonotopo W, Hafner T, et al. Normal standards for fetal neurobehavioural developments-longitudinal quantification by four-dimensional sonography. J Perinat Med 2006;34(1):56–65. DOI: 10.1515/JPM.2006.007.

34. Walusinski O, Kurjak A, Andonotopo W, et al. Fetal yawning assessed by 3D and 4D sonography. Ultrasound Rev Obstet Gynecol 2005;5(3):210–217. DOI: 10.3109/14722240500284070.

35. Hanaoka U, Hata T, Kanenishi K, et al. Does ethnicity have an effect on fetal behavior? a comparison of Asian and Caucasian populations. J Perinat Med 2016;44(2):217–221. DOI: 10.1515/jpm-2015-0036.

36. Farkas LG, Katic MJ, Forrest CR. International anthropometric study of facial morphology in various ethnic groups/races. J Craniofac Surg 2005;16(4):615–646. DOI: 10.1097/01.scs.0000171847.58031.9e.

37. Le TT, Farkas LG, Ngim RCK, et al. Proportionality in Asian and North American Caucasian faces using neoclassical facial canons as criteria. Aesth Plast Surg 2002;26:64–69.

38. Hata T, Hanaoka U, Mostafa AboEllail MA, et al. Is there a sex difference in fetal behavior? A comparison of the KANET test between male and female fetuses. J Perinat Med 2016;44(5):585–588. DOI: 10.1515/jpm-2015-0387.

39. Korner AF. Neonatal startles, smiles, erections, and reflex sucks as related to state, sex, and individuality. Child Dev 1969;40(4):1039–1053. DOI: 10.2307/1127010.

40. Jacklin CN, Snow ME, Maccoby EE. Tactile sensitivity and muscle strength in newborn boys and girls. Infant Behav Dev 1981;4:261–268. DOI: 10.1016/S0163-6383(81)80028-8.

41. de Vries JIP, Visser GHA, Prechtl HFR. The emergence of fetal behaviour. III. Individual differences and consistencies. Early Hum Dev 1988;16(1):85–103. DOI: 10.1016/0378-3782(88)90089-8.

42. Hepper PG, Shannon EA, Dornan JC. Sex differences in fetal mouth movements. Lancet 1997;350(9094):1820. DOI: 10.1016/S0140-6736(05)63635-5.

43. Robles de Medina PG, Visser GHA, Huizink AC, et al. Fetal behaviour does not differ between boys and girls. Early Hum Dev 2003;73(1-2):17–26. DOI: 10.1016/s0378-3782(03)00047-1.

44. DiPietro JA, Hodgson DM, Costigan KA, et al. Fetal neurobehavioral development. Child Dev 1996;67(5):2553–2567. DOI: 10.2307/1131640.

45. Pressman EK, DiPietro JA, Costigan KA, et al. Fetal neurobehavioral development: associations with socioeconomic class and fetal sex. Dev Psychobiol 1998;33(1):79–91. DOI: 10.1002/(SICI)1098-2302(199807)33:1andlt;79::AID-DEV7andgt;3.0.CO;2-P.

46. Hepper PG, Dornan JC, Lynch C. Sex differences in fetal habituation. Dev Sci 2012;15(3):373–383. DOI: 10.1111/j.1467-7687.2011.01132.x.

47. Tranquilli AL, Lorenzi S, Buscicchio G, et al. Female fetuses are more reactive when mother eats chocolate. J Matern Fetal Neonatal Med 2014;27(1):72–74. DOI: 10.3109/14767058.2013.804053.

48. Antsaklis P, Porovic S, Daskalakis G, et al. 4D assessment of fetal brain function in diabetic patients. J Perinat Med 2017;45(6):711–715. DOI: 10.1515/jpm-2016-0394.

49. Edelberg SC, Dierker L, Kalhan S, et al. Decreased fetal movements with sustained maternal hyperglycemia using the glucose clamp technique. Am J Obstet Gynecol 1987;156(5):1101–1105. DOI: 10.1016/0002-9378(87)90118-9.

50. Cosmi EV, Anceschi MM, Cosmi E, et al. Ultrasonographic patterns of fetal breathing movements in normal pregnancy. Int J Gynaecol Obstet 2003;80(3):285–290. DOI: 10.1016/s0020-7292(02)00384-3.

51. Allen CL, Kisilevsky BS. Fetal behavior in diabetic and nondiabetic pregnant women: an exploratory study. Dev Psychobiol 1999;35(1):69–80. DOI: 10.1002/(SICI)1098-2302(199907)35:1andlt;69::AID-DEV9andgt;3.0.CO;2-W.

52. Mulder EJ, O’Brien MJ, Lems YL, et al. Body and breathing movements in near-term fetuses and newborn infants of type-1 diabetic women. Early Hum Dev 1990;24(2):131–152. DOI: 10.1016/0378-3782(90)90143-7.

53. Devoe LD, Youssef AA, Castillo RA, et al. Fetal biophysical activities in third-trimester pregnancies complicated by diabetes mellitus. Am J Obstet Gynecol 1994;171(2):298–303. DOI: 10.1016/s0002-9378(94)70026-5.

54. Kainer F, Prechtl HF, Engele H, et al. Assessment of the quality of general movements in fetuses and infants of women with type-I diabetes mellitus. Early Hum Dev 1997;50(1):13–25. DOI: 10.1016/s0378-3782(97)00089-3.

55. Holden KP, Jovanovic L, Druzin ML, et al. Increased fetal activity with low maternal blood glucose levels in pregnancies complicated by diabetes. Am J Perinatol 1984;1(2):161–164. DOI: 10.1055/s-2007-999994.

56. Yeoshoua E, Goldstein I, Zlozover M, et al. Sonographic study of the relationship between gestational diabetes mellitus and fetal activity. J Matern Fetal Neonatal Med 2012;25(6):623–626. DOI: 10.3109/14767058.2011.597897.

57. Dieb A, Salam R, Shaheen D, et al. Evaluation of foetal neurological behaviour in hypothyroid pregnant females - a pilot study. J Matern Fetal Neonatal Med 2019;32(16):2617–2621. DOI: 10.1080/14767058.2018.1442428.

58. Bernal J. Thyroid hormones and brain development. Vitam Horm 2005;71:95–122. DOI: 10.1016/S0083-6729(05)71004-9.

59. Kooistra L, Crawford S, van Baar AL, et al. Neonatal effects of maternal hypothyroxinemia during early pregnancy. Pediatrics 2006;117(1):161–167. DOI: 10.1542/peds.2005-0227.

60. Henrichs J, Bongers-Schokking JJ, Schenk JJ, et al. Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab 2010;95(9):4227–4234. DOI: 10.1210/jc.2010-0415.

61. Li Y, Shan Z, Teng W, et al. Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25–30 months. Clin Endocrinol (Oxf) 2010;72(6):825–829. DOI: 10.1111/j.1365-2265.2009.03743.x.

62. Gyamfi C, Wapner RJ, D’Alton ME. Thyroid dysfunction in pregnancy: the basic science and clinical evidence surrounding the controversy in management. Obstet Gynecol 2009;113(3):702–707. DOI: 10.1097/AOG.0b013e3181996fe5.

63. Chevrier J, Harley KG, Kogut K, et al. Maternal thyroid function during the second half of pregnancy and child neurodevelopment at 6, 12, 24, and 60 months of age. J Thyroid Res 2011;2011:426427. DOI: 10.4061/2011/426427.

64. Pop VJ, Brouwers EP, Vader HL, et al. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol (Oxf) 2003;59(3):282–288. DOI: 10.1046/j.1365-2265.2003.01822.x.

65. Nazarpour S, Ramezani Tehrani F, Simbar M, et al. Thyroid dysfunction and pregnancy outcomes. Iran J Reprod Med 2015;13(7):387–396.

66. Hata T, Kanenishi K, AboEllail MAM, et al. Effect of psychotropic drugs on fetal behavior in the third trimester of pregnancy. J Perinat Med 2019;47(2):207–211. DOI: 10.1515/jpm-2018-0114.

67. Sanz EJ, De-las-Cuevas C, Kiuru A, et al. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet 2005;365(9458):482–487. DOI: 10.1016/S0140-6736(05)17865-9.

68. Brandlistuen RE, Ystrom E, Eberhard-Gran M, et al. Behavioural effects of fetal antidepressant exposure in a Norwegian cohort of discordant siblings. Int J Epidemiol 2015;44(4):1397–1407. DOI: 10.1093/ije/dyv030.

69. Boukhris T, Sheehy O, Mottron L, et al. Antidepressant use during pregnancy and the risk of autism spectrum disorder in children. JAMA Pediatr 2016;170(2):117–124. DOI: 10.1001/jamapediatrics.2015.3356.

70. Mezzacappa A, Lasica PA, Gianfagna F, et al. Risk for autism spectrum disorders according to period of prenatal antedepressant exposure. JAMA Pediatr 2017;171(6):555–563. DOI: 10.1001/jamapediatrics.2017.0124.

71. Rihtman T, Parush S, Ornoy A. Developmental outcomes at preschool age after fetal exposure to valproic acid and lamotrigine: cognitive, motor, sensory and behavioral function. Reprod Toxicol 2013;41:115–125. DOI: 10.1016/j.reprotox.2013.06.001.

72. Deshmukh U, Adams J, Macklin EA, et al. Behavioral outcomes in children exposed prenatally to lamotrigine, valproate, or carbamazepine. Neurotoxicol Teratol 2016;54:5–14. DOI: 10.1016/j.ntt.2016.01.001.

73. Ogo Κ, Kanenishi Κ, Mori Ν, et al. Change in fetal behavior in response to vibroacoustic stimulation. J Perinat Med 2019;47(5):558–563. DOI: 10.1515/jpm-2018-0344.

74. Spencer JAD, Deans A, Nicolaidis P, et al. Fetal heart rate response to vibroacoustic stimulation during low and high heart rate variability episodes in late pregnancy. Am J Obstet Gynecol 1991;165(1):86–90. DOI: 10.1016/0002-9378(91)90230-o.

75. D’Elia A, Pighetti M, Vanacore F, et al. Vibroacoustic stimulation in normal term human pregnancy. Early Hum Dev 2005;81(5):449–453. DOI: 10.1016/j.earlhumdev.2004.04.017.

76. Umstad M, Bailey C, Permezel M. Intrapartum fetal stimulation testing. Aust N Z J Obstet Gynaecol 1992;32(3):222–224. DOI: 10.1111/j.1479-828X.1992.tb01951.x.

77. East CE, Smyth R, Leader LR, et al. Vibroacoustic stimulation for fetal assessment in labour in the presence of a nonreassuring fetal heart rate trace. Cochrane Database Syst Rev 2005(2):CD004664. DOI: 10.1002/14651858.CD004664.pub2.

78. Arulkumaran S, Talbert D, Hsu TS, et al. In-utero sound levels when vibroacoustic stimulation is applied to the maternal abdomen: an assessment of the possibility of cochlea damage in the fetus. Br J Obstet Gynaecol 1992;99(1):43–45. DOI: 10.1111/j.1471-0528.1992.tb14390.x.

79. Arulkumaran S, Skurr B, Tong H, et al. No evidence of hearing loss due to fetal acoustic stimulation test. Obstet Gynecol 1991;78(2):283–285.

80. Mulder EJ, Koenen SV, Blom I, et al. The effects of antenatal betamethasone administration on fetal heart rate and behaviour depend on gestational age. Early Hum Dev 2004;76(1):65–67. DOI: 10.1016/j.earlhumdev.2003.10.007.

81. Mushkat Y, Ascher-Landsberg J, Keidar R, et al. The effect of betamethasone versus dexamethasone on fetal biophysical parameters. Eur J Obstet Gynecol Reprod Biol 2001;97(1):50–52. DOI: 10.1016/s0301-2115(00)00498-x.

82. Kelly MK, Schneider EP, Petrikovsky BM, et al. Effect of antenatal steroid administration on the fetal biophysical profile. J Clin Ultrasound 2000;28(5):224–226. DOI: 10.1002/(sici)1097-0096(200006)28:53.0.co;2-g.

83. Rotmensch S, Liberati M, Vishne TH, et al. The effect of betamethasone and dexamethasone on fetal heart rate patterns and biophysical activities. A prospective randomized trial. Acta Obstet Gynecol Scand 1999;78(6):493–500. DOI: 10.1080/j.1600-0412.1999.780604.x.

84. Derks JB, Mulder EJ, Visser GH. The effects of maternal betamethasone administration on the fetus. Br J Obstet Gynaecol 1995;;102(1):40–46. DOI: 10.1111/j.1471-0528.1995.tb09024.x.

85. Mulder EJ, Derks JB, Visser GH. Antenatal corticosteroid therapy and fetal behaviour: a randomised study of the effects of betamethasone and dexamethasone. Br J Obstet Gynaecol 1997;104(11):1239–1247. DOI: 10.1111/j.1471-0528.1997.tb10969.x.