By Kathleen Kendall-Tackett, Ph.D., IBCLC, FAPA and Kerstin Uvnäs Moberg, MD, Ph.D.

A study, "Association of peripartum synthetic oxytocin administration and depressive and anxiety disorders within the first postpartum year," released January 30, 2017, made headlines internationally, when researchers shared that the results of a study on the intrapartum and postpartum administration of synthetic oxytocin (Pitocin) increased the risk of postpartum mood disorders. They had hypothesized that receiving Pitocin during or after labor would decrease the risk of PPMADs. Science & Sensibility is lucky enough to have regular contributor Katheleen Kendall-Tackett, Ph.D., IBCLC, FAPA and renowned oxytocin researcher and expert Kerstin Uvnäs Moberg, MD, Ph.D. examine and review this new study and help us to understand what the unexpected results mean. Do you discuss with your students, clients and patients the impact receiving Pitocin during or immediately after labor could have on their mental health? - Sharon Muza, Science & Sensibility Community Manager

Synthetic Oxytocin - What is the Impact?

A recent study examined whether administration of synthetic oxytocin during labor would lower the risk of postpartum depression and anxiety. The authors review recent studies that show that depression or anxiety are higher in women with lower oxytocin levels. They, therefore, hypothesized that higher oxytocin would protect women and lower their risk of depression and anxiety since it has been shown to stimulate social interaction and decrease anxiety in animal models. In human studies, oxytocin administered via nasal spray has similar effects. Oddly, they chose to test that hypothesis by studying the effects of synthetic oxytocin during or after labor. Their sample was women in the Massachusetts Integrated Clinical Academic Research Database and included retrospective data on women who were exposed (n=9,684) or not exposed (n=37,048) to peripartum synthetic oxytocin.

Depression and anxiety were defined by record of diagnosis or receipt of a prescription for either antidepressants or anti-anxiety medications, before, during, or after pregnancy. Using this definition of depression meant that the rates of women identified as depressed were substantially lower than in previous studies: 10% before pregnancy, 4.2% during pregnancy, and 6.9% in the first year postpartum.

The data did not support the authors' hypothesis. In fact, they found the opposite to be true. For women with a history of depression or anxiety, oxytocin exposure increased their risk of postpartum depression or anxiety by 36%. For women with no history, peripartum oxytocin increased the risk by 32%. This was true for women who had either cesarean or vaginal births.

Why might this be true? If oxytocin is the feel-good hormone, why did it increase the risk of depression or anxiety?

Some possible answers are found in the methodology of this study, and examining the results in relation to previous studies on the biology of oxytocin and psychological impact of birth interventions.

Concerns about the Hypothesis and Method

Women were included in the exposed group for "any peripartum clinical indication within 2 weeks of delivery date" (p. 139). This included women who had contraction stress tests. It was also used to augment or induce labor, or for postpartum hemorrhage prevention or treatment.

There are some significant problems with the methodology of this study. There is no mention of the dose of oxytocin. If there are side effects, we should expect some dose relationship. Further, the ways by which oxytocin is delivered in these two uses are very different. During labor, oxytocin is given as an intravenous drip with increasing concentration for several hours. In Sweden, for example, 5 IU in 500 ml NaCl would be given as an intravenous infusion during a period of about ten hours and sometimes an additional 5 IU is given. After birth, an intravenous or intramuscular injection of 5 IU is given to stop bleeding, and if postpartum bleeding exceeds 400 ml, 5 extra IU are given and in extreme cases even more. (Recommendations from the Swedish Board of National Medical Indications). In this way, a woman can receive anything from 5-50 IU of oxytocin in connection with labor, but the majority of women don't receive more than 10 IU. Note that the synthetic, or exogenous oxytocin has the same chemical structure as the oxytocin produced in the mothers themselves.

Only about 1 per mille of a dose of oxytocin given into the circulation passes into the central nervous system because of the blood-brain barrier (Jones & Robinsson 1982, Neuroendocrinology). Oxytocin given as infusions will not reach levels that allow passage of oxytocin into the brain. Oxytocin given as a bolus injection gives rise to high, but short-lasting peaks, that might allow some passage of small amounts of oxytocin into the brain.

In other words, an infusion of synthetic or exogenous oxytocin given in labor is unlikely to cross the blood-brain barrier and will, therefore, not exert any direct effects on the central nervous system, including influencing postpartum mood. So we shouldn't expect that it would lower the risk of depression/anxiety. An injection given to stop hemorrhage might because it is the same amount of medication given over a much shorter amount of time. Still, this transfer of oxytocin to the brain should be minute because of the short duration of the oxytocin peak caused by the infusion.

In contrast, administration of oxytocin spray exerts some actions in the brain, because the nasal mucosa has a weak blood-brain barrier. It cannot be compared with IV. Therefore, we would not expect that a study that showed positive results of oxytocin delivered via nasal spray would be the same as oxytocin delivered during IV infusion during labor. One crosses the blood-brain barrier and has central nervous system effects. The other does not.

Still, there is an indirect way by which infused oxytocin might influence brain function. During normal birth oxytocin is released, when the head of the fetus presses against the cervix of the uterus and the vaginal wall. This is because nerves are activated which via the spinal cord stimulates the release of oxytocin from the brain (The Fergusson reflex). In this way, oxytocin is released into the circulation to further activate uterine contractions. But some oxytocin is also released within the brain where it decreases feelings of fear and pain and promotes maternal social behaviors. At the end of labor, when oxytocin levels are at its highest oxytocin in the brain may also stimulate the reward system and increase the levels of dopamine.

It is, therefore, possible that infusion of oxytocin increases the activity in the Fergusson reflex and thereby induces some central effects. Indeed, some data indicate that such effects may occur (Jonas et al 2008, Velandia 2012). But in the case of the present study, this indirect effect was not enough and did not lower mothers' risk.

Epidurals and Oxytocin

As birth professionals know, synthetic oxytocin as an intervention rarely happens alone, especially during labor. It is frequently accompanied by other birth interventions, especially epidurals. In fact, it's uncommon for someone to have a synthetic oxytocin drip without an epidural. In addition, synthetic oxytocin and epidurals often lead to a cascade of other interventions, including forceps deliveries and cesarean sections.

For this reason, use of synthetic oxytocin can also be a marker for a high-intervention birth. If a mother received oxytocin, chances are that she had other birth interventions, and higher numbers of birth interventions are associated with increased depressive, anxiety, and PTSD symptoms (Kendall-Tackett, 2017). Mothers may be more prone to depression and anxiety when they received oxytocin because their births had more interventions. In our study of 6,410 new mothers, we found that women who had epidurals had higher depressive symptoms even after controlling for all other birth interventions, history of depression and sexual assault, income, education, and parity (Kendall-Tackett, Cong, & Hale, 2015).

In addition, it is well known that epidurals per se influence maternal endocrinology after birth. Labor induced by oxytocin infusion causes increased stress reactions because the contractions do not follow the normal physiological curve, oxytocin levels are flat instead of spiky as during normal birth. The mother's body perceives these contractions as more painful-because they are. So mothers are offered epidurals.

Epidurals also inhibit the positive mental effects towards reduced fear and increased social behavior, as well as feelings of joy and happiness at birth, which can be observed after birth, that are normally induced by the Fergusson reflex, because epidurals do not only block nerves mediating pain, but also the nerves connected with the Fergusson reflex which result in oxytocin release. (Jonas et al 2008) The combination of oxytocin infusions and epidurals is also bad from another point of view because it lowers oxytocin levels and increases cortisol levels after breastfeeding and results in an overactive hypothalamic-pituitary-adrenal (HPA) axis. (Jonas et al 2009, Handlin et al 2009). This increase in the activity of the HPA axis is particularly interesting from the perspective of the theme of this article since anxiety and depression are often linked to an increased activity in the HPA axis.

Epidurals combined with oxytocin infusions create a mutually maintaining bidirectional system: epidurals decrease the release of natural oxytocin during birth, and therefore synthetic oxytocin is given. In turn, synthetic oxytocin infusion causes painful contractions and therefore epidurals are given so mothers can cope with the additional pain.

Don't Mix Up Synthetic Oxytocin with the Real Thing

The authors describe a few studies finding that low oxytocin levels seem to be related to postpartum depression, but then suggest that Pitocin (exogenous or synthetic oxytocin) could be used to treat it. As we have described, synthetic oxytocin infusions do not cross the blood-brain barrier and have central nervous system effects, and therefore would be a choice for treating depression. But let's not mix this up with the real thing (i.e., naturally generated oxytocin). Naturally occurring oxytocin has all the good effects these authors were hoping for and more. It specifically downregulates the stress system, increases bonding and affiliation, and increases positive mood.

So what helps increase oxytocin in new mothers? Many positive things increase oxytocin levels, but two are especially relevant: skin-to-skin contact and breastfeeding. There are more studies on this than we can review here, but here is one example. A 2009 study of 63 primips at two days postpartum found that both breastfeeding and skin-to-skin contact were related to lower stress levels (Handlin et al. 2009). Breastfeeding lowered the stress hormones ACTH and cortisol (both part of the HPA axis), and skin-to-skin contact contributed to this effect. ACTH was negatively correlated with suckling, and longer skin-to-skin was related to lower cortisol. Oxytocin lowered both ACTH and cortisol. Downregulation of the HPA axis is related to lower risk of depression and anxiety.

Breastfeeding has consistently been related to a lower risk of depression. These findings get tricky to interpret because depressed mothers are less likely to breastfeeding. Could it be that the mothers who breastfeed are the ones who are healthier, to begin with? How do we know that breastfeeding itself is having an influence? One way to address this concern is to look at the results of prospective studies, in which you know the mothers' mental state before they breastfeed. These studies support the hypothesis that breastfeeding exerts an independent effect, lowering risk of depression by upregulating oxytocin and downregulating the stress response and that this effect is still found even when taking into account the effect of depression on breastfeeding cessation (Ahn & Corwin, 2015; Hahn-Holbrook et al., 2013).

The bottom line is this: if oxytocin is generated naturally, i.e. released during birth, skin-to-skin contact and breastfeeding, it does seem to have the effect hypothesized, and lowers mothers' risk of depression and anxiety. However, administration of synthetic oxytocin does not create this kind of effect and may lead to the type of high-intervention birth that increases the risk of depression.

Conclusion

Mothers' risk of depression and anxiety increased if they were exposed to synthetic oxytocin during or after labor. This effect was not caused by an "intoxication" of the brain by oxytocin. It is likely to be due to other factors such as synthetic oxytocin's alteration of the pattern of contractions and consequent information to the brain by nerve fibers, which increases the activity in the HPA axis. This is more likely to occur in mothers who receive both oxytocin infusion and epidurals. Further, the mothers' depression and stress may have been due to other medical interventions, or combinations of them. Or depression or anxiety may have been simply due to a complicated birth, which gives rise to anxiety.

About Kathleen Kendall-Tackett and Kerstin Uvnäs Moberg

Kathleen Kendall-Tackett, Ph.D., IBCLC, FAPA

Kathleen Kendall-Tackett, Ph.D., IBCLC, FAPA, is a health psychologist and International Board Certified Lactation Consultant, and the Owner and Editor-in-Chief of Praeclarus Press, a small press specializing in women's health. Dr. Kendall-Tackett is Editor-in-Chief of two peer-reviewed journals: Clinical Lactation and Psychological Trauma. She is Fellow of the American Psychological Association in Health and Trauma Psychology, Past President of the APA Division of Trauma Psychology, and a member of the Board for the Advancement of Psychology in the Public Interest. Dr. Kendall-Tackett specializes in women's health research including breastfeeding, depression, trauma, and health psychology, and has won many awards for her work including the 2016 Outstanding Service to the Field of Trauma Psychology from the American Psychological Association's Division 56. Dr. Kendall-Tackett has authored more than 400 articles or chapters and is currently completing her 35^th book, The Phantom of the Opera: A Social History of the World's Most Popular Musical. Her most recent books include: Depression in New Mothers, 3^rd Edition (2017, Routledge UK), Women's Mental Health Across the Lifespan (2017, Routledge US, with Lesia Ruglass), Psychology of Trauma 101 (2015, Springer, with Lesia Ruglass) and The Science of Mother-Infant Sleep (2014, Praeclarus, with Wendy Middlemiss). Her websites are UppityScienceChick.com, BreastfeedingMadeSimple.com, KathleenKendall-Tackett.com, and PraeclarusPress.com. Google Scholar link: http://bit.ly/1nSwWIW

Kerstin Uvnäs Moberg, MD, PhD

Kerstin Uvnäs Moberg, MD, Ph.D., is a physician and professor of physiology with a research focus on the healing aspects of oxytocin. Her vision is to help in creating healthier and happier women by expanding the knowledge about female physiology and by creating medical interventions based on oxytocin.

The wish to understand the biology of women emerged, when she had children herself. At that time, she left a promising research career within the field of gastrointestinal physiology in order to study the positive and health promoting effects of oxytocin.

Kerstin Uvnäs Moberg found among other things that oxytocin reduces pain and anxiety, decreases blood pressure and reduces the levels of stress hormones in both sexes. She also found that the speed, by which wounds and other types of physical damage heal, increases, and that atrophic (thin) mucosal membranes become rejuvenated. The latter research findings form the basis for patents and clinical studies with the aim to create a pharmaceutical drug for relief of menopausal symptoms. You can learn more about Dr. Uvnäs Moberg on her website. You can find her books on Amazon.

References

Ahn, S., & Corwin, E.J. (2015). The association between breastfeeding, the stress response, inflammation, and postpartum depression during postpartum period: Prospective cohort study. International Journal of Nursing Studies, 52, 1582-1590.

Hahn-Holbrook, J., Haselton, M.G., Schetter, C.D., & Glynn, L.M. (2013). Does breastfeeding offer protection against maternal depressive symptomatology? A prospective study from pregnancy to 2 years after birth. Archives of Women's Mental Health, 16, 411-422.

Handlin L, Jonas W, Ransjö Arvidsson AB, Petersson M, Uvnäs Moberg K and Nissen E. Effect of Sucking and Skin-to-Skin contact on Maternal ACTH and Cortisol Levels during the second day postpartum. Influence of Epidural analgesia and Oxytocin in the Perinatal period. Breastfeeding medicine 4 (4), 207-220

Jonas W, Johansson L.M., Nissen E, Ejdebäck M, Ransjö Arvidsson AB Uvnäs Moberg K (2009). Effects of intrapartum oxytocin administration and epidural analgesia on the concentration of plasma oxytocin and prolactin in response to suckling during the second day postpartum, Breastfeeding medicine 4(2) 71-82

Jonas W, Wiklund I, Nissen E, Ransjö Arvidsson A.B., Uvnäs Moberg K. Influence of oxytocin or epidural analgesia on personality profile in breastfeeding women: a comparative study, Archives of Women's Mental Health 2008, 11, 335-445

Kendall-Tackett, K.A. (2017). Depression in new mothers, 3^rd Ed. Abington, UK: Routledge.

Kroll-Desrosiers, A.R., Nephew, B.C., Babb, J.A., Guilarte-Walker, Y., Moore Simas, T., Deligiannidis, K.M. (2017). Association of peripartum synthetic oxytocin administration and depressive and anxiety disorders within the first postpartum year. Depression & Anxiety, 34, 137-146.

Velandia Marianne, Theses for doctoral degree, 2012, Parent-infant Skin-to-skin Contact Studies

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