Selective serotonin reuptake inhibitors (SSRI) are the most common antidepressant used by pregnant women; however, they have been associated with adverse pregnancy outcomes and perinatal morbidity in pregnant women and animal models. We investigated the effects of two SSRI, fluoxetine and sertraline, on pregnancy and neonatal outcomes in mice. Wild-type mice were treated daily with low and high doses of fluoxetine (2 and 20 mg/kg) and sertraline (10 and 20 mg/kg) from the day of detection of a vaginal plug until the end of lactation (21 days postpartum). Pregnancy rate was decreased only in the high dose of fluoxetine group. Maternal weight gain was reduced in the groups receiving the high dose of each drug. Number of pups born was decreased in the high dose of fluoxetine and low and high doses of sertraline while the number of pups weaned was decreased in all SSRI-treated groups corresponding to increased neonatal mortality in all SSRI-treated groups. In conclusion, there was a dose-dependent effect of SSRI on pregnancy and neonatal outcomes in a non-depressed mouse model. However, the distinct placental transfer of each drug suggests that the effects of SSRI on pup mortality may be mediated by SSRI-induced placental insufficiency rather than a direct toxic effect on neonatal development and mortality.

Lactation is a physiological adaptation of the class Mammalia and is a product of over 200 million years of evolution. During lactation, the mammary gland orchestrates bone metabolism via serotonin signaling in order to provide sufficient calcium for the offspring in milk. The role of serotonin in bone remodeling was first discovered over two decades ago, and the interplay between serotonin, lactation, and bone metabolism has been explored in the years following. It is estimated that postpartum depression affects 10–15% of the population, and selective serotonin reuptake inhibitors (SSRI) are often used as the first-line treatment. Studies conducted in humans, nonhuman primates, sheep, and rodents have provided evidence that there are consequences on both parent and offspring when serotonin signaling is disrupted during the peripartal period; however, the long-term consequences of disruption of serotonin signaling via SSRIs during the peripartal period on the maternal and offspring skeleton are not fully known. This review will focus on the relationship between the mammary gland, serotonin, and bone remodeling during the peripartal period and the skeletal consequences of the dysregulation of the serotonergic system in both human and animal studies.

Perinatal mood disorders are a tremendous burden to childbearing families and treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants is increasingly common. Exposure to SSRIs may affect serotonin signaling and ultimately, microbes that live in the gut. Health of the gut microbiome during pregnancy, lactation, and early infancy is critical, yet there is limited evidence to describe the relationship between SSRI exposure and gut microbiome status in this population. The purpose of this Preferred Reporting Items for Systematic reviews and Meta‐Analyses (PRISMA)‐compliant scoping review is to assess evidence and describe key concepts regarding whether SSRI exposure affects the maternal and infant gut microbiome. Sources were collected from PubMed, Web of Science, and Scopus databases, and an additional gray literature search was performed. Our search criteria returned only three sources, two rodent models and one human subjects research study. Results suggest that fluoxetine (SSRI) exposure may affect maternal gut microbiome dynamics during pregnancy and lactation. There were no available sources to describe the relationship between perinatal SSRI exposure and the infant gut microbiome. There is a significant gap in the literature regarding whether SSRI antidepressants affect the maternal and infant gut microbiome. Future studies are required to better understand how SSRI antidepressant exposure affects perinatal health.

The transition to lactation demands a substantial amount of calcium (Ca) to support colostrum and milk production. Extensive research has been focused on elucidating the interplay between the traditional Ca-parathyroid hormone-vitamin D axis and mammary- derived factors, such as serotonin (5-HT) and parathyroid-hormone-like hormone (PTHLH), in regulating Ca metabolism during the transition period. Here, we investigate the impact of induced subclinical hypocalcemia (SCH) on 5-HT and parathyroid hormone (PTH) concentrations in early-lactation dairy cows under conditions of 24-h milk stasis. Twelve multiparous Holstein cows in early lactation received either continuous intravenous infusion of saline solution or 5% ethylene glycol tetraacetic acid (EGTA) to maintain blood ionized calcium (iCa) below 1 mM(n = 6/treatment). Blood samples were collected hourly during infusion and 4, 8, 12, 24, and 48 h post- infusion. Urine samples were collected every 4 h during infusion and at 12, 24, and 48 h post-infusion, and milk samples were collected daily from 2 d pre-infusion to 4 d post-infusion. Infusion of EGTA resulted in decreased blood iCa during the infusion period, with iCa concentrations rebounding 24 h post-infusion. No significant treatment effects were observed on 5-HT and PTH blood concentrations. These findings underscore the importance of considering physiological distinctions in studies of Ca metabolism during the transition period.

Inducing a transient state of hypocalcemia prepartum mobilizes stored calcium (Ca) before the abrupt demand for Ca at parturition thus more tightly regulating postpartum hypocalcemia. Prepartum transient hypocalcemia can be achieved through intravenous infusions of either the precursor to serotonin, 5-hydroxy-tryptophan (5HTP) or a Ca chelating agent, ethylene-glycol-tetraacetic acid (EGTA). This study aimed to compare the ability of 5HTP and EGTA treatments to prevent postpartum hypocalcemia. We hypothesized that the 2 methods would be similarly effective compared with the control. Cows received either 5HTP, EGTA, 5HTP+EGTA, or control saline (n = 6/treatment) beginning 7 d before expected calving date through parturition (range 4-13 d). The 5HTP treatment was administered daily as a single 1 L dose at 1 mg/kg body weight (BW). Saline and EGTA were infused for 6 h/d. Infusion rates of EGTA were adjusted to maintain blood ionized Ca (iCa) between 0.7 and 0.8 mM inducing subclinical hypocalcemia, which occurs when iCa is 0.61-0.9 mM. Mammary biopsies were collected from rear quarters at 6, 30, 54, and 78 h postpartum. Cows in the 5HTP+EGTA group required less EGTA to maintain low iCa during infusions and had the lowest total Ca concentrations during infusions. Therefore, 5HTP and EGTA likely utilize different mechanisms to reduce blood Ca that can occur simultaneously resulting in an additive effect in blood Ca reduction. Control cows were subclinically hypocalcemic through 48 h postpartum, and 2 became clinically hypocalcemic. All other treatments were normocalcemic through 96 h postpartum and had significantly greater iCa than the control from 12 to 24 h postpartum. Administering 5HTP increased blood serotonin concentrations from the start of infusions through 72 h postpartum. Cows receiving EGTA or 5HTP+EGTA had decreased mammary Ca compared with the control at 54 and 78 h after calving. Mammary tissue qPCR and Western blot analysis revealed increased gene and protein expression of Ca release-activated Ca modulator 1 on the day of parturition compared with 30 and 78 h postpartum. Mammary gland gene expression of the calcium sensing receptor was decreased 78 h postpartum compared with 6 and 30 h postpartum. While 5HTP and EGTA both prevented postpartum hypocalcemia, EGTA significantly increased iCa through 48 h post-calving rather than 24 h in the 5HTP group. The 5HTP+EGTA and EGTA treatments were equally effective at regulating periparturient calcemic status indicating that the additive effect of 5HTP and EGTA did not persist beyond parturition.