Impact of Maternal Depression and Anxiety on Fetal Development

The Impact of Maternal Depression and Anxiety on Fetal Development

Abstract

The purpose of this review paper is to briefly review past and present literature on the impact of maternal depression and anxiety during pregnancy to the developing fetus.  We will be reviewing the prenatal risks involved in untreated depression during pregnancy.  We will be looking at depression and anxiety during pregnancy as risk factors for adverse outcomes to both mothers and fetal development.  As well as depression and anxiety being an insult to both neurological and neurobehavioral development of fetuses exposed during pregnancy.

Keywords: Fetal Development, Depression, Anxiety, Pregnancy, Prenatal, Insult, Neurological, Neurobehavioral

Introduction

This paper will be reviewing the current and past research on maternal depression, anxiety and its impact on fetal development. (Schetter, Tanner, 2012)  We will be looking at the prevalence and associated factors of depression, and anxiety during pregnancy. (Nasreen, et. al., 2011)  Links between increased uterine artery resistance and maternal anxiety and depression during pregnancy.

(Teixeira, et. al., 1999)

Newborn neurobehavioral patterns related to prenatal major depressive disorder. (Kinsella, Monk., 2009)  Stillbirths and other outside variables that are risk factors for depression and anxiety in subsequent pregnancies. (Hughes, et. al., 1999)  The prenatal, perinatal and postnatal risks of untreated depression. (Bonari,et. al., 2004)

Antenatal maternal anxiety as related to HPA-axis dysregulation. (Bergh, et. al, 2007)

We will not be discussing medications, treatments or care plans outside of those that were mentioned in the study.

Discussion

Pregnancy can be one of the most wonderful and breathtaking experiences in a women’s life, a time of great fulfillment.  However, it can also be a time of great stress, worry and anxiety.  At any given moment there are roughly 12.4 births per 1,000 population in the Unites States alone.  Which in 2015 came to a total of 3,978,497 births for that year . (CDC, 2015)].  Suffices to say that this is an area of some importance and needs to be researched and explored in some depth.  Particularly the maternal state of wellbeing.  The World Health Organization (WHO) estimates that by 2020 depressive disorders will be the second leading cause in global disease burden.  Already it is the leading cause of death for 15-29-year-olds. (WHO, 2018).  It was not listed as to how many of those 15-29-year-olds are pregnant women, but it would be in interesting question for future research and one worth considering.

For some time, psychologists, psychiatrist and other related disciplines and experts have expressed concern about pregnant women experiencing the telltale signs of anxiety, depression and stress during pregnancy and in postpartum. (Schetter et. al., 2012).  This is especially true for vulnerable populations of women such as those that live in rural or impoverish conditions with little to no help or support.  A study done in rural Bangladesh showed a prevalence of antepartum depressive (ADS) 18% and anxiety symptoms (AAS) was 29% with a total ending N=671. [See figure 1. (Nasreen, et. al., 2011)].

Recent studies have shown that anxiety and depression in pregnancy have had adverse implications for embryonic and fetal development.  Ranging from the neurological/neurobehavioral (Salisbury, e.t al. 2011), to the physiological (Teixeira et. al., 1999), and well after birth. (Schetter, et. al., 2012)  A study done by Salisbury, et. al. found evidence that suggests  women with depression and infants’ exposure to maternal depression during pregnancy have higher levels of norepinephrine and cortisol metabolites with decreased dopamine compared to nondepressed pregnant women and their infants.  To drive the point further their research, suggest newborns prenatally exposed to maternal depression showed low muscle tone, irritability, reactivity and more difficulty with behavioral state regulation. [See figure 2 (Salisbury, e.t al. 2011)].

In most societies it is accepted that psychological states during pregnancy can influence the developing fetus. Some studies have showed infants of depressed and anxious mothers are born with a significantly lower weight and born earlier when compared with those whose mothers were not depressed.  One large study even showed that depression, stress, and anxiety had the same low birth weight effect as those who were born from mothers who smoked. (Teixeira, et. al., 1999).  Animal studies have shown that when the mother is stressed during pregnancy, birth weight is reduced, and behavior is permanently affected. (Teixeira, et. al., 1999).  Two mechanisms have been shown to stress or cause anxiety that potentially will affect the fetus. Increased hormone concentration from the mother that is then transported through the placenta to the fetus. And blood flow becoming impaired through the uterine arteries.  These arteries may develop a resistance to blood flow as demonstrated by the presence of notches in waveform patterns seen by using a color doppler. [See figure 3 (Teixeira, et. al., 1999)].  These notches are associated with abnormal blood flow and denotes a high resistance to blood flow.  This effect has been demonstrated in primates but has not been studied in humans. (Teixeira, et. al., 1999) This had previously been seen in cases of gestational diabetes and pre-eclampsia. (Kinsella, Monk, 2009)

Some inferentially projected estimates place the prevalence of depression during pregnancy as high as 16% with 5% of those women displaying symptoms of major depressive disorder. (Schetter, et. al., 2012).  That said, there is a small caveat, and some have pointed to this. Experts have questioned the ability to appropriately diagnoses the depressive disorders using standard diagnostic criteria.  This is because the symptoms of the criteria are typical symptoms of pregnancy such as sleep disturbance, appetite changes, and fatigue. (Schetter, et. al., 2012).  But even with that being taken into consideration there is still an overwhelming amount of supporting research on the negative impact for pregnant mothers and teratogenic effects on fetal development from maternal depression and anxiety (Nasreen, et. al., 2011).

A study done in 1999 by P. M. Hughes, P. Turton, and C. D. H. Evans which focused on factors for depression and anxiety in pregnant women.  Looked at factors preluding pregnancy, in this case stillbirths were the choice topic of study.  Still births are, as defined by the Oxford English Dictionary, “The birth of an infant that has died in the womb – strictly, after having survived though at least the first 28 weeks of pregnancy.” (Oxford Dictionary, 2018).  Stillbirths create a vulnerability to depression and anxiety in any following pregnancies. (Hughes, et. al., 1999).  With this we can deduce that women who have had stillbirths are starting off with a  predisposition for depression and anxiety for the next pregnancy.  Depression from the lost pregnancy and the anxiety of what could happen with the next pregnancy could create an unfavorable combustible mixture. In fact, in the afore mentioned study it was noted that conception within a year of a stillbirth is associated with higher levels of depression and anxiety in that pregnancy than compared to conceptions much later.  This suggests that new pregnancies interfere with the normal mourning process. [See figure 4. (Hughes, et. al., 1999)].

It is lamentable the treatment of maternal depression has not received the appropriate level of attention: outside of medical studies in which they have attempted to determine potential but unproven risks of antidepressants. (Bonari, et. al., 2004).  Lifetime depression  risks from community-derived samples have estimated between 10%-25% of pregnant women will develop depression. (Bonari, et. al., 2004).  In one study 20% of obstetrics patients were randomly screened met the diagnosable criteria for depression. (Bonari, et. al., 2004).  With depression having such prevalence some researchers have suggested and believe pregnancy to be a risk factor for mood disorder to those who have a history of mood disorders. (Bonari, et. al., 2004).  In a study done by (Marcus et. al.,2003), they found 1 in 5 pregnant women experience depression during their pregnancy, but few seek treatment.  This study had an N=3,472 and showed both an undertreatment and underdiagnosis of depression.  Of those, 20% were found to have scored high on the Centre for Epidemiological Studies Depression Scale or CESD for short.  While this is not technically a clinical diagnosis only 13.8% of these pregnant women were receiving and kind of care.  The 86.2% remaining women were not receiving any form of treatment. [See figures 5,6,7 for summary depression studies, (Marcus et. al.,2003)].  The conclusion of the study stated that stigma attached with having depression during pregnancy has and may continue to prevent women from seeking help or reaching out to family and friends.  A pregnant woman might feel guilty for doing so because pregnancy is supposed to be a time of happiness and joy. (Bonari, et. al., 2004).

This has devastating consequences for fetal development as depression has been associated with hypothalamo-pituitary-adrenal (HPA) axis hyperactivity. (Bonari, et. al., 2004).  Peptides from the activated HPA axis regulate maternal stress, anxiety and depression and are thought to affect birth outcomes as well.  It may even, in crossing into the placenta, directly affect fetal growth.  So, not only does maternal depression activate the mothers HPA axis, it may induce an increase in the release of corticotropin-releasing hormone (CRH) from the placenta through catecholamines and cortisol. (Bonari, et. al., 2004).  The timing of delivery may also be affected by the CRH which would explain why women with depression show higher rates of premature labor verses those women who do not have depression. (Bonari, et. al., 2004).  Recent research with animals in this field have found that the stress during pregnancy is associated with dysfunctions of the HPA axis and fetal tissue development. (Bonari, et. al., 2004).  Another hypothesis put forth is that the depression alters excretion of the vasoactive hormones and neuroendocrine transmitters, which then induce the vascular changes we see in pregnant women.  (Bonari, et. al., 2004).  We can see a picture begin to develop here of the risks for both the women and fetal development in untreated depression during pregnancy.

Conclusion

In conclusion we can see that maternal depression and anxiety during pregnancy is a field of research just getting started.  As we learn more about the brain, we are sure to discover more about this.  We have looked at and considered current and past research on maternal depression and anxiety and its impact of fetal development. (Schetter, Tanner, 2012).  But there is still more to be done. We would be doing a disservice to the millions of pregnant women around the world by not conducting more studies, more research and providing more assistance for them. Maternal depression and anxiety on fetal neurobehavioral development should become a larger focus as we begin to understand  and learn more about embryonic development. (Salisbury, et. al., 2011).  We have reviewed the biological impacts and teratogenic affects. (Teixeira, et. al., 1999).  We have looked at external contributing variables such as stillbirths that are risk factors for depression and anxiety in subsequent pregnancies. (Hughes, et. al., 1999).  We have reviewed the risks of untreated depression during pregnancy (Bonari, et. al., 2004).  And we have ended with antenatal maternal anxiety as related to HPA-axis dysregulation. (Bergh, et. al, 2007).

References

1. Bergh, Bea RH, V., Calster, Ben, V., Smits, Tim, et. al. (2007).  Antenatal Maternal Anxiety Is Related To HPA-Axis Dysregulation And Self-Reported Depressive Symptoms In Adolescence: A Prospective Study On The Fetal Origins Of Depressed Mood, Neuropsychopharmacology (2008) 33, 536-545
2. Bonari, Lori, MSc., Pinto, Natasha, MSc., et. al., (2004).  Perinatal Risks Of Untreated Depression During Pregnancy, Can J Psychiatry, Volume 49, No. 11, November 2004
3. Biaggi, Alessandra, Conroy, Susan, Pawlby, Susan, Parainte, Carmine, M., (2015).  Identifying The Women At Risk Of Antenatal Anxiety And Depression: A Systematic Review, Retrieved from URL
   
   http://dx.doi.org/10.1016/j.jad.2015.11.014
   
4. Hughes, P., M., Turton, P., Evans, C., D H., (1999).  Stillbirth As Risk Factor For Depression And Anxiety In The Subsequent Pregnancy: Cohort Study, BMJ Volume 318 26, June 1999
5. Kinsella, Michael, T., Monk, Catherine, (2009).  Impact Of Maternal Stress, Depression & Anxiety On Fetal Neurobehavioral Development, Clin Obstet Gynecol. 2009 September ; 52(3): 425-440. Doi:10.1097/GRF.0b013e3181b52dfl
6. Marcus SM, Flynn HA, et. al., (2003).  Depressive symptoms among pregnant women screened in obstetrics settings. J Womens Health (Larchmont);12:373-80
7. Martin, Joyce, A., et. al. (2015).  National Vital Statistics Reports, Volume 66, Number 1, Retrieved from URL
   
   https://www.cdc.gov/nchs/nvss/births.htm
   
8. Nasreen, Hashima, E., Kabir, Zarina, N., et. al. (2011).  Prevalence And Associated Factor Of Depressive And Anxiety Symptoms During Pregnancy: A Population Based Study In Rural Bangladesh, Retrieved from URL
   
   http://www.biomedcentral.com/1472-6874/11/22
   
9. Oberlander, Tim, F., Weinberg, Joanne, Papsdorf, Michael, et. al. (2008).  Prenatal Exposure to maternal Depression Neonatal methylation Of Human Glucocorticoid Receptor Gene (NR3C1) And Infant Cortisol Stress Responses, ISSN: 1559-2294 (Print) 1559-2308, doi: 10.4161/epi.3.2.6034
10. Oxford English Dictionary, Stillbirths, (2018), Retrieved from URL
    
    https://en.oxforddictionaries.com/definition/stillbirth
    
11. Rich-Edwards, J., W., Mohllajee, Kleinman, K., et. al. (2008).  Elevated Midpregnacy Corticotropin- Releasing Hormone Is Associated With Prenatal, But Not Postpartum, Maternal Depression, J Clin Endocrinal Metab. May 2008, 93(5):1946-1951
12. Salisbury, Amy, L., Wisner, Katherine, L., et. al. (2011).  Newborn Neurobehavioral Patterns Are Differentially Related To Prenatal Maternal Major Depressive Disorder And Serotonin Reuptake Inhibitor Treatment,  Depression and Anxiety 28: 1008-1019 (2011)
13. Schetter, Christine, D., Tanner, Lynlee, (2012).  Anxiety, Depression And Stress In Pregnancy: Implications For Mothers, Children, Research, And Practice
    
    ,
    
    Curr Opin Psychiatry. 2012 March; 25(2): 141-148. Doi:10.1097/YCO.0b013e3283503680
14. Teixeira, Jeronima, M A., Fisk, Nicholas, M., Glover, Vivette, (1999).  Association Between Maternal Anxiety In Pregnancy And Increased Uterine Artery Resistance Index: Cohort Based Study, BMJ Volume 318 16, January 1999
15. World Health Organization: WHO, multi-county study on women’s health and domestic violence against women: study protocol Geneva; 2004
16. World Health Organization: WHO, Depression, Retrieved from URL
    
    https://www/who.int/news-room/fact-sheets/detail/depression
    

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

The Impact of Maternal Depression and Anxiety on Fetal Development

Abstract

The purpose of this review paper is to briefly review past and present literature on the impact of maternal depression and anxiety during pregnancy to the developing fetus.  We will be reviewing the prenatal risks involved in untreated depression during pregnancy.  We will be looking at depression and anxiety during pregnancy as risk factors for adverse outcomes to both mothers and fetal development.  As well as depression and anxiety being an insult to both neurological and neurobehavioral development of fetuses exposed during pregnancy.

Keywords: Fetal Development, Depression, Anxiety, Pregnancy, Prenatal, Insult, Neurological, Neurobehavioral

Introduction

This paper will be reviewing the current and past research on maternal depression, anxiety and its impact on fetal development. (Schetter, Tanner, 2012)  We will be looking at the prevalence and associated factors of depression, and anxiety during pregnancy. (Nasreen, et. al., 2011)  Links between increased uterine artery resistance and maternal anxiety and depression during pregnancy.

(Teixeira, et. al., 1999)

Newborn neurobehavioral patterns related to prenatal major depressive disorder. (Kinsella, Monk., 2009)  Stillbirths and other outside variables that are risk factors for depression and anxiety in subsequent pregnancies. (Hughes, et. al., 1999)  The prenatal, perinatal and postnatal risks of untreated depression. (Bonari,et. al., 2004)

Antenatal maternal anxiety as related to HPA-axis dysregulation. (Bergh, et. al, 2007)

We will not be discussing medications, treatments or care plans outside of those that were mentioned in the study.

Discussion

Pregnancy can be one of the most wonderful and breathtaking experiences in a women’s life, a time of great fulfillment.  However, it can also be a time of great stress, worry and anxiety.  At any given moment there are roughly 12.4 births per 1,000 population in the Unites States alone.  Which in 2015 came to a total of 3,978,497 births for that year . (CDC, 2015)].  Suffices to say that this is an area of some importance and needs to be researched and explored in some depth.  Particularly the maternal state of wellbeing.  The World Health Organization (WHO) estimates that by 2020 depressive disorders will be the second leading cause in global disease burden.  Already it is the leading cause of death for 15-29-year-olds. (WHO, 2018).  It was not listed as to how many of those 15-29-year-olds are pregnant women, but it would be in interesting question for future research and one worth considering.

For some time, psychologists, psychiatrist and other related disciplines and experts have expressed concern about pregnant women experiencing the telltale signs of anxiety, depression and stress during pregnancy and in postpartum. (Schetter et. al., 2012).  This is especially true for vulnerable populations of women such as those that live in rural or impoverish conditions with little to no help or support.  A study done in rural Bangladesh showed a prevalence of antepartum depressive (ADS) 18% and anxiety symptoms (AAS) was 29% with a total ending N=671. [See figure 1. (Nasreen, et. al., 2011)].

Recent studies have shown that anxiety and depression in pregnancy have had adverse implications for embryonic and fetal development.  Ranging from the neurological/neurobehavioral (Salisbury, e.t al. 2011), to the physiological (Teixeira et. al., 1999), and well after birth. (Schetter, et. al., 2012)  A study done by Salisbury, et. al. found evidence that suggests  women with depression and infants’ exposure to maternal depression during pregnancy have higher levels of norepinephrine and cortisol metabolites with decreased dopamine compared to nondepressed pregnant women and their infants.  To drive the point further their research, suggest newborns prenatally exposed to maternal depression showed low muscle tone, irritability, reactivity and more difficulty with behavioral state regulation. [See figure 2 (Salisbury, e.t al. 2011)].

In most societies it is accepted that psychological states during pregnancy can influence the developing fetus. Some studies have showed infants of depressed and anxious mothers are born with a significantly lower weight and born earlier when compared with those whose mothers were not depressed.  One large study even showed that depression, stress, and anxiety had the same low birth weight effect as those who were born from mothers who smoked. (Teixeira, et. al., 1999).  Animal studies have shown that when the mother is stressed during pregnancy, birth weight is reduced, and behavior is permanently affected. (Teixeira, et. al., 1999).  Two mechanisms have been shown to stress or cause anxiety that potentially will affect the fetus. Increased hormone concentration from the mother that is then transported through the placenta to the fetus. And blood flow becoming impaired through the uterine arteries.  These arteries may develop a resistance to blood flow as demonstrated by the presence of notches in waveform patterns seen by using a color doppler. [See figure 3 (Teixeira, et. al., 1999)].  These notches are associated with abnormal blood flow and denotes a high resistance to blood flow.  This effect has been demonstrated in primates but has not been studied in humans. (Teixeira, et. al., 1999) This had previously been seen in cases of gestational diabetes and pre-eclampsia. (Kinsella, Monk, 2009)

Some inferentially projected estimates place the prevalence of depression during pregnancy as high as 16% with 5% of those women displaying symptoms of major depressive disorder. (Schetter, et. al., 2012).  That said, there is a small caveat, and some have pointed to this. Experts have questioned the ability to appropriately diagnoses the depressive disorders using standard diagnostic criteria.  This is because the symptoms of the criteria are typical symptoms of pregnancy such as sleep disturbance, appetite changes, and fatigue. (Schetter, et. al., 2012).  But even with that being taken into consideration there is still an overwhelming amount of supporting research on the negative impact for pregnant mothers and teratogenic effects on fetal development from maternal depression and anxiety (Nasreen, et. al., 2011).

A study done in 1999 by P. M. Hughes, P. Turton, and C. D. H. Evans which focused on factors for depression and anxiety in pregnant women.  Looked at factors preluding pregnancy, in this case stillbirths were the choice topic of study.  Still births are, as defined by the Oxford English Dictionary, “The birth of an infant that has died in the womb – strictly, after having survived though at least the first 28 weeks of pregnancy.” (Oxford Dictionary, 2018).  Stillbirths create a vulnerability to depression and anxiety in any following pregnancies. (Hughes, et. al., 1999).  With this we can deduce that women who have had stillbirths are starting off with a  predisposition for depression and anxiety for the next pregnancy.  Depression from the lost pregnancy and the anxiety of what could happen with the next pregnancy could create an unfavorable combustible mixture. In fact, in the afore mentioned study it was noted that conception within a year of a stillbirth is associated with higher levels of depression and anxiety in that pregnancy than compared to conceptions much later.  This suggests that new pregnancies interfere with the normal mourning process. [See figure 4. (Hughes, et. al., 1999)].

It is lamentable the treatment of maternal depression has not received the appropriate level of attention: outside of medical studies in which they have attempted to determine potential but unproven risks of antidepressants. (Bonari, et. al., 2004).  Lifetime depression  risks from community-derived samples have estimated between 10%-25% of pregnant women will develop depression. (Bonari, et. al., 2004).  In one study 20% of obstetrics patients were randomly screened met the diagnosable criteria for depression. (Bonari, et. al., 2004).  With depression having such prevalence some researchers have suggested and believe pregnancy to be a risk factor for mood disorder to those who have a history of mood disorders. (Bonari, et. al., 2004).  In a study done by (Marcus et. al.,2003), they found 1 in 5 pregnant women experience depression during their pregnancy, but few seek treatment.  This study had an N=3,472 and showed both an undertreatment and underdiagnosis of depression.  Of those, 20% were found to have scored high on the Centre for Epidemiological Studies Depression Scale or CESD for short.  While this is not technically a clinical diagnosis only 13.8% of these pregnant women were receiving and kind of care.  The 86.2% remaining women were not receiving any form of treatment. [See figures 5,6,7 for summary depression studies, (Marcus et. al.,2003)].  The conclusion of the study stated that stigma attached with having depression during pregnancy has and may continue to prevent women from seeking help or reaching out to family and friends.  A pregnant woman might feel guilty for doing so because pregnancy is supposed to be a time of happiness and joy. (Bonari, et. al., 2004).

This has devastating consequences for fetal development as depression has been associated with hypothalamo-pituitary-adrenal (HPA) axis hyperactivity. (Bonari, et. al., 2004).  Peptides from the activated HPA axis regulate maternal stress, anxiety and depression and are thought to affect birth outcomes as well.  It may even, in crossing into the placenta, directly affect fetal growth.  So, not only does maternal depression activate the mothers HPA axis, it may induce an increase in the release of corticotropin-releasing hormone (CRH) from the placenta through catecholamines and cortisol. (Bonari, et. al., 2004).  The timing of delivery may also be affected by the CRH which would explain why women with depression show higher rates of premature labor verses those women who do not have depression. (Bonari, et. al., 2004).  Recent research with animals in this field have found that the stress during pregnancy is associated with dysfunctions of the HPA axis and fetal tissue development. (Bonari, et. al., 2004).  Another hypothesis put forth is that the depression alters excretion of the vasoactive hormones and neuroendocrine transmitters, which then induce the vascular changes we see in pregnant women.  (Bonari, et. al., 2004).  We can see a picture begin to develop here of the risks for both the women and fetal development in untreated depression during pregnancy.

Conclusion

In conclusion we can see that maternal depression and anxiety during pregnancy is a field of research just getting started.  As we learn more about the brain, we are sure to discover more about this.  We have looked at and considered current and past research on maternal depression and anxiety and its impact of fetal development. (Schetter, Tanner, 2012).  But there is still more to be done. We would be doing a disservice to the millions of pregnant women around the world by not conducting more studies, more research and providing more assistance for them. Maternal depression and anxiety on fetal neurobehavioral development should become a larger focus as we begin to understand  and learn more about embryonic development. (Salisbury, et. al., 2011).  We have reviewed the biological impacts and teratogenic affects. (Teixeira, et. al., 1999).  We have looked at external contributing variables such as stillbirths that are risk factors for depression and anxiety in subsequent pregnancies. (Hughes, et. al., 1999).  We have reviewed the risks of untreated depression during pregnancy (Bonari, et. al., 2004).  And we have ended with antenatal maternal anxiety as related to HPA-axis dysregulation. (Bergh, et. al, 2007).

References

1. Bergh, Bea RH, V., Calster, Ben, V., Smits, Tim, et. al. (2007).  Antenatal Maternal Anxiety Is Related To HPA-Axis Dysregulation And Self-Reported Depressive Symptoms In Adolescence: A Prospective Study On The Fetal Origins Of Depressed Mood, Neuropsychopharmacology (2008) 33, 536-545
2. Bonari, Lori, MSc., Pinto, Natasha, MSc., et. al., (2004).  Perinatal Risks Of Untreated Depression During Pregnancy, Can J Psychiatry, Volume 49, No. 11, November 2004
3. Biaggi, Alessandra, Conroy, Susan, Pawlby, Susan, Parainte, Carmine, M., (2015).  Identifying The Women At Risk Of Antenatal Anxiety And Depression: A Systematic Review, Retrieved from URL
   
   http://dx.doi.org/10.1016/j.jad.2015.11.014
   
4. Hughes, P., M., Turton, P., Evans, C., D H., (1999).  Stillbirth As Risk Factor For Depression And Anxiety In The Subsequent Pregnancy: Cohort Study, BMJ Volume 318 26, June 1999
5. Kinsella, Michael, T., Monk, Catherine, (2009).  Impact Of Maternal Stress, Depression & Anxiety On Fetal Neurobehavioral Development, Clin Obstet Gynecol. 2009 September ; 52(3): 425-440. Doi:10.1097/GRF.0b013e3181b52dfl
6. Marcus SM, Flynn HA, et. al., (2003).  Depressive symptoms among pregnant women screened in obstetrics settings. J Womens Health (Larchmont);12:373-80
7. Martin, Joyce, A., et. al. (2015).  National Vital Statistics Reports, Volume 66, Number 1, Retrieved from URL
   
   https://www.cdc.gov/nchs/nvss/births.htm
   
8. Nasreen, Hashima, E., Kabir, Zarina, N., et. al. (2011).  Prevalence And Associated Factor Of Depressive And Anxiety Symptoms During Pregnancy: A Population Based Study In Rural Bangladesh, Retrieved from URL
   
   http://www.biomedcentral.com/1472-6874/11/22
   
9. Oberlander, Tim, F., Weinberg, Joanne, Papsdorf, Michael, et. al. (2008).  Prenatal Exposure to maternal Depression Neonatal methylation Of Human Glucocorticoid Receptor Gene (NR3C1) And Infant Cortisol Stress Responses, ISSN: 1559-2294 (Print) 1559-2308, doi: 10.4161/epi.3.2.6034
10. Oxford English Dictionary, Stillbirths, (2018), Retrieved from URL
    
    https://en.oxforddictionaries.com/definition/stillbirth
    
11. Rich-Edwards, J., W., Mohllajee, Kleinman, K., et. al. (2008).  Elevated Midpregnacy Corticotropin- Releasing Hormone Is Associated With Prenatal, But Not Postpartum, Maternal Depression, J Clin Endocrinal Metab. May 2008, 93(5):1946-1951
12. Salisbury, Amy, L., Wisner, Katherine, L., et. al. (2011).  Newborn Neurobehavioral Patterns Are Differentially Related To Prenatal Maternal Major Depressive Disorder And Serotonin Reuptake Inhibitor Treatment,  Depression and Anxiety 28: 1008-1019 (2011)
13. Schetter, Christine, D., Tanner, Lynlee, (2012).  Anxiety, Depression And Stress In Pregnancy: Implications For Mothers, Children, Research, And Practice
    
    ,
    
    Curr Opin Psychiatry. 2012 March; 25(2): 141-148. Doi:10.1097/YCO.0b013e3283503680
14. Teixeira, Jeronima, M A., Fisk, Nicholas, M., Glover, Vivette, (1999).  Association Between Maternal Anxiety In Pregnancy And Increased Uterine Artery Resistance Index: Cohort Based Study, BMJ Volume 318 16, January 1999
15. World Health Organization: WHO, multi-county study on women’s health and domestic violence against women: study protocol Geneva; 2004
16. World Health Organization: WHO, Depression, Retrieved from URL
    
    https://www/who.int/news-room/fact-sheets/detail/depression
    

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.