Mechanisms of Regeneration and Fibrosis in the Endometrium.

The uterine lining (endometrium) regenerates repeatedly over the life span as part of its normal physiology. Substantial portions of the endometrium are shed during childbirth (parturition) and, in some species, menstruation, but the tissue is rapidly rebuilt without scarring, rendering it a powerful model of regeneration in mammals. Nonetheless, following some assaults, including medical procedures and infections, the endometrium fails to regenerate and instead forms scars that may interfere with normal endometrial function and contribute to infertility. Thus, the endometrium provides an exceptional platform to answer a central question of regenerative medicine: Why do some systems regenerate while others scar? Here, we review our current understanding of diverse endometrial disruption events in humans, nonhuman primates, and rodents, and the associated mechanisms of regenerative success and failure. Elucidating the determinants of these disparate repair processes promises insights into fundamental mechanisms of mammalian regeneration with substantial implications for reproductive health.

Circumvention of luteolysis reveals parturition pathways in mice dependent upon innate type 2 immunity.

Although mice normally enter labor when their ovaries stop producing progesterone (luteolysis), parturition can also be triggered in this species through uterus-intrinsic pathways potentially analogous to the ones that trigger parturition in humans. Such pathways, however, remain largely undefined in both species. Here, we report that mice deficient in innate type 2 immunity experienced profound parturition delays when manipulated endocrinologically to circumvent luteolysis, thus obliging them to enter labor through uterus-intrinsic pathways. We found that these pathways were in part driven by the alarmin IL-33 produced by uterine interstitial fibroblasts. We also implicated important roles for uterine group 2 innate lymphoid cells, which demonstrated IL-33-dependent activation prior to labor onset, and eosinophils, which displayed evidence of elevated turnover in the prepartum uterus. These findings reveal a role for innate type 2 immunity in controlling the timing of labor onset through a cascade potentially relevant to human parturition.

The hormonal control of parturition.

Parturition is a complex physiological process that must occur in a reliable manner and at an appropriate gestation stage to ensure a healthy newborn and mother. To this end, hormones that affect the function of the gravid uterus, especially progesterone (P4), 17ß-estradiol (E2), oxytocin (OT), and prostaglandins (PGs), play pivotal roles. P4 via the nuclear P4 receptor (PR) promotes uterine quiescence and for most of pregnancy exerts a dominant block to labor. Loss of the P4 block to parturition in association with a gain in prolabor actions of E2 are key transitions in the hormonal cascade leading to parturition. P4 withdrawal can occur through various mechanisms depending on species and physiological context. Parturition in most species involves inflammation within the uterine tissues and especially at the maternal-fetal interface. Local PGs and other inflammatory mediators may initiate parturition by inducing P4 withdrawal. Withdrawal of the P4 block is coordinated with increased E2 actions to enhance uterotonic signals mediated by OT and PGs to promote uterine contractions, cervix softening, and membrane rupture, i.e., labor. This review examines recent advances in research to understand the hormonal control of parturition, with focus on the roles of P4, E2, PGs, OT, inflammatory cytokines, and placental peptide hormones together with evolutionary biology of and implications for clinical management of human parturition.

Progesterone inactivation in decidual stromal cells: A mechanism for inflammation-induced parturition.

The process of human parturition involves inflammation at the interface where fetal chorion trophoblast cells interact with maternal decidual stromal (DS) cells and maternal immune cells in the decidua (endometrium of pregnancy). This study tested the hypothesis that inflammation at the chorion-decidua interface (CDI) induces labor by negating the capacity for progesterone (P4) to block labor and that this is mediated by inactivation of P4 in DS cells by aldo-keto reductase family 1 member C1 (AKR1C1). In human, Rhesus macaque, and mouse CDI, AKR1C1 expression increased in association with term and preterm labor. In a human DS cell line and in explant cultures of term human fetal membranes containing the CDI, the prolabor inflammatory cytokine, interleukin-1ß (IL-1ß), and media conditioned by LPS-stimulated macrophages increased AKR1C1 expression and coordinately reduced nuclear P4 levels and P4 responsiveness. Loss of P4 responsiveness was overcome by inhibition of AKR1C1 activity, inhibition of AKR1C1 expression, and bypassing AKR1C1 activity with a P4 analog that is not metabolized by AKR1C1. Increased P4 activity in response to AKR1C1 inhibition was prevented by the P4 receptor antagonist RU486. Pharmacologic inhibition of AKR1C1 activity prevented parturition in a mouse model of inflammation-induced preterm parturition. The data suggest that inflammatory stimuli at the CDI drive labor by inducing AKR1C1-mediated P4 inactivation in DS cells and that inhibiting and/or bypassing of AKR1C1-mediated P4 inactivation is a plausible therapeutic strategy to mitigate the risk of inflammation-associated preterm birth.

Loss of function of the maternal membrane oestrogen receptor ERα alters expansion of trophoblast cells and impacts mouse fertility.

The binding of 17ß-oestradiol to oestrogen receptor alpha (ERα) plays a crucial role in the control of reproduction, acting through both nuclear and membrane-initiated signalling. To study the physiological role of membrane ERα in the reproductive system, we used the C451A-ERα mouse model with selective loss of function of membrane ERα. Despite C451A-ERα mice being described as sterile, daily weighing and ultrasound imaging revealed that homozygous females do become pregnant, allowing the investigation of the role of ERα during pregnancy for the first time. All neonatal deaths of the mutant offspring mice resulted from delayed parturition associated with failure in pre-term progesterone withdrawal. Moreover, pregnant C451A-ERα females exhibited partial intrauterine embryo arrest at about E9.5. The observed embryonic lethality resulted from altered expansion of Tpbpa-positive spiral artery-associated trophoblast giant cells into the utero-placental unit, which is associated with an imbalance in expression of angiogenic factors. Together, these processes control the trophoblast-mediated spiral arterial remodelling. Hence, loss of membrane ERα within maternal tissues clearly alters the activity of invasive trophoblast cells during placentogenesis. This previously unreported function of membrane ERα could open new avenues towards a better understanding of human pregnancy-associated pathologies.

Arginase 1 and L-arginine coordinate fetal lung development and the initiation of labor in mice.

Fetal development and parturition are precisely regulated processes that involve continuous crosstalk between the mother and the fetus. Our previous discovery that wild-type mice carrying steroid receptor coactivator (Src)-1 and Src-2 double-deficient fetuses exhibit impaired lung development and delayed labor, which indicates that the signals for parturition emanate from the fetus. In this study, we perform RNA sequencing and targeted metabolomics analyses of the lungs from fetal Src-1/-2 double-knockout mice and find that expression of arginase 1 (Arg1) is significantly decreased, accompanied by increased levels of the Arg1 substrate L-arginine. Knockdown of Arg1 in the lungs of fetal mice induces apoptosis of epithelial cells and dramatically delays initiation of labor. Moreover, treatment of human myometrial smooth muscle cells with L-arginine significantly inhibits spontaneous contractions by attenuating activation of NF-κB and downregulating expression of contraction-associated protein genes. Transcription factors GR and C/EBPß increase transcription of Arg1 in an Src-1/Src-2-dependent manner. These findings provide new evidence that fetus-derived factors may play dual roles in coordinating fetal lung development and the initiation of labor.

In the Murine and Bovine Maternal Mammary Gland Signal Transducer and Activator of Transcription 3 is Activated in Clusters of Epithelial Cells around the Day of Birth.

Signal transducers and activators of transcription (STAT) proteins regulate mammary development. Here we investigate the expression of phosphorylated STAT3 (pSTAT3) in the mouse and cow around the day of birth. We present localised colocation analysis, applicable to other mammary studies requiring identification of spatially congregated events. We demonstrate that pSTAT3-positive events are multifocally clustered in a non-random and statistically significant fashion. Arginase-1 expressing cells, consistent with macrophages, exhibit distinct clustering within the periparturient mammary gland. These findings represent a new facet of mammary STAT3 biology, and point to the presence of mammary sub-microenvironments.

Disruption of the SP-A/SP-R210L (MYO18Aα) pathway prolongs gestation and reduces fetal survival during lipopolysaccharide-induced parturition in late gestation.

Prolonged labor can lead to infection, fetal distress, asphyxia, and life-threatening harm to both the mother and the baby. Surfactant protein A (SP-A) was shown to contribute to the maintenance of pregnancy and timing of term labor. SP-A modulates the stoichiometric expression of the SP-R210L and SP-R210S isoforms of the SP-R210 receptor on alveolar macrophages (AMs). Lack of SP-R210L dysregulates macrophage inflammatory responses. We asked whether SP-A alters normal and inflammation-induced parturition through SP-R210 using SP-A- and SP-R210L-deficient mice. Labor and delivery of time-pregnant mice were monitored in real time using a time-lapse infrared camera. Intrauterine injection with either vehicle or Escherichia coli lipopolysaccharide (LPS) on embryonic (E) day 18.5 post coitus was used to assess the effect of gene disruption in chorioamnionitis-induced labor. We report that either lack of SP-A or disruption of SP-R210L delays parturition by 0.40 and 0.55 days compared with controls, respectively. LPS induced labor at 0.60, 1.01, 0.40, 1.00, and 1.31 days earlier than PBS controls in wild type (WT), SP-A-deficient, littermate controls, heterozygous, and homozygous SP-R210L-deficient mice, respectively. Lack of SP-A reduced litter size in PBS-treated mice, whereas the total number of pups delivered was similar in all LPS-treated mice. The number of live pups, however, was significantly reduced by 50%-70% in SP-A and SP-R210L-deficient mice compared with controls. Differences in gestational length were not associated with intrauterine growth restriction. The present findings support the novel concept that the SP-A/SP-R210 pathway modulates timely labor and delivery and supports fetal lung barrier integrity during fetal-to-neonatal transition in term pregnancy.NEW & NOTEWORTHY To our knowledge, this study is the first to report that SP-A prevents delay of labor and inflammation-induced stillbirth through the receptor SP-R210L.

Cyclical endometrial repair and regeneration.

Uniquely among adult tissues, the human endometrium undergoes cyclical shedding, scar-free repair and regeneration during a woman's reproductive life. Therefore, it presents an outstanding model for study of such processes. This Review examines what is known of endometrial repair and regeneration following menstruation and parturition, including comparisons with wound repair and the influence of menstrual fluid components. We also discuss the contribution of endometrial stem/progenitor cells to endometrial regeneration, including the importance of the stem cell niche and stem cell-derived extracellular vesicles. Finally, we comment on the value of endometrial epithelial organoids to extend our understanding of endometrial development and regeneration, as well as therapeutic applications.

PGE2 functions in ovoviviparous teleost black rockfish (Sebastes schlegelii): evolutionary status between parturition and ovulation†.

Fish have evolved various reproductive strategies including oviparity, viviparity, and ovoviviparity, which undoubtedly affect the survival of the whole species continuity. As the final step in reproduction, parturition in viviparous vertebrate and ovulation in oviparous teleost seem to share a similar mechanism, when prostaglandins (PGs) act as the trigger to launch the whole process. In the present study, ovoviviparous teleost black rockfish (Sebastes schlegelii) is employed as the research object. Intraperitoneal injection showed that PGE2 (500 µg/kg) could activate the delivery reactions in perinatal black rockfish. RNA-seq data of ovary in perinatal period revealed transcriptional change in cell junction, inflammation, and apoptosis, which is related to mammal parturition and teleost ovulation. Further results proved the positive correlation between ptger EP2 and previous mentioned pathways. Subsequent experiment proved that PGE2 was able to induce the ovulation and spawning in unfertilized individuals, which had a bilayer follicular structure compared to monolayer follicular in perinatal period black rockfish. Both unfertilized and perinatal ovary matrix could response to PGE2 stimulation. In conclusion, the function of PGE2 in activating both parturition and ovulation in a relatively different pathways conserved with viviparity or oviparity provided novel evidence of the evolutionary status of ovoviviparous vertebrates.

Obese mice have decreased uterine contractility and altered energy metabolism in the uterus at term gestation.

Over 35% of reproductive-age women in the US are obese, putting them at increased risk for numerous obstetric complications due to abnormal labor. While the association between maternal obesity and abnormal labor has been well documented, the mechanisms responsible for this remain understudied. The uterine smooth muscle, myometrium, has high energy needs in order to fuel regular uterine contractions during parturition. However, the precise mechanisms by which the myometrium meets its energy demands has not been defined. Here, our objective was to define the effects of obesity on energy utilization in the myometrium during labor. We generated a mouse model of maternal diet-induced obesity (DIO) and found that these mice had a higher rate of dystocia than control chow-fed (CON) mice. Moreover, compared to CON mice, DIO mice at term, both before and during labor had lower in vivo spontaneous uterine contractility. Untargeted transcriptomic and metabolomic analyses suggest that DIO is associated with elevated long-chain fatty acid uptake and utilization in the uterus, but also an accumulation of medium-chain fatty acids. DIO uteri also had an increase in the abundance of long chain-specific ß-oxidation enzymes, which may be responsible for the observed increase in long-chain fatty acid utilization. This altered energy substrate utilization may be a contributor to the observed contractile dysfunction.

Local vaginal bioelectrical impedance can predict preterm delivery in mice.

Preterm birth is a serious pregnancy complication that affects neonatal mortality, morbidity, and long-term neurological prognosis. Predicting spontaneous preterm delivery (PTD) is important for its management. While excluding the risk of PTD is important, identifying women at high risk of PTD is imperative for medical intervention. Currently used PTD prediction parameters in clinical practice have shown high negative predictive values, but low positive predictive values. We focused on sulfated and sialylated glycocalyx changes in the uterus and vagina prior to the onset of parturition and explored the potential of electrophysiological detection of these changes as a PTD prediction parameter with a high positive predictive value. In vivo local vaginal bioelectrical impedance (VZ) was measured using two different mouse PTD models. PTD was induced in ICR mice through the subcutaneous injection of mifepristone or local intrauterine injection of lipopolysaccharide (LPS). The PTD rates were 100% and 60% post-administration of mifepristone (16-20 h, n = 4) and LPS (12-24 h, n = 20), respectively. The local VZ values (15 and 10 h after mifepristone or LPS treatment, respectively) were significantly lower in the PTD group than in the non-PTD group. Receiver operator characteristic (ROC) curve analysis of VZ at 125 kHz as a predictor of PTD showed an area under the ROC curve of 1.00 and 0.77 and positive predictive values of 1.00 and 0.86, for the mifepristone and LPS models, respectively, suggesting that local VZ value can predict PTD. Histological examination of the LPS-treated model 6 h post-treatment revealed increased expression of sulfomucins and/or sulfated proteoglycans and sialomucins in the cervical epithelium, cervical stroma and vaginal stroma. In conclusion, local VZ values can determine sulfated and sialylated glycocalyx alterations within the uterus and vagina and might be a useful PTD prediction parameter.

Breeding phenology drives variation in reproductive output, reproductive costs and offspring fitness in a viviparous ectotherm.

Phenological advances are a widespread response to global warming and can contribute to determine the climate vulnerability of organisms, particularly in ectothermic species which are highly dependent on ambient temperatures to complete their life cycle. Yet, the relative contribution of breeding dates and temperature conditions during gestation on fitness of females and their offspring is poorly documented in reptiles. Here, we exposed females of the common lizard Zootoca vivipara to contrasting thermal scenarios (cold versus hot treatment) during gestation and quantified effects of parturition dates and thermal treatment on life-history traits of females and their offspring for one year. Overall, our results suggest that parturition date has a greater impact than thermal conditions during gestation on life history strategies. In particular, we found positive effects of an earlier parturition date on juvenile survival, growth and recruitment suggesting that environmental dependent selection and/or differences in parental quality between early and late breeders underlie seasonal changes in offspring fitness. Yet, an earlier parturition date compromised the energetic condition of gravid females, which suggests the existence of a mother-offspring conflict regarding the optimisation of parturition dates. While numerous studies focused on the direct effects of alterations in incubation temperatures on reptile life-history traits, our results highlight the importance of considering the role of breeding phenology in assessing the short- and long-term effects of thermal developmental plasticity.

The inflammatory response to birth requires MyD88 and is driven by both mother and offspring.

Birth is an inflammatory event for the newborn, characterized by elevations in interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α peripherally and/or centrally, as well as changes in brain microglia. However, the mechanism(s) underlying these responses is unknown. Toll-like receptors (TLRs) play crucial roles in innate immunity and initiate inflammatory cascades upon recognition of endogenous or exogenous antigens. Most TLR signaling depends on the adaptor molecule myeloid differentiation primary response 88 (MyD88). We independently varied MyD88 gene status in mouse dams and their offspring to determine whether the inflammatory response to birth depends on MyD88 signaling and, if so, whether that signaling occurs in the offspring, the mother, or both. We find that the perinatal surges in plasma IL-6 and brain expression of TNF-α depend solely on MyD88 gene status of the offspring, whereas postnatal increases in plasma IL-10 and TNF-α depend on MyD88 in both the pup and dam. Interestingly, MyD88 genotype of the dam primarily drives differences in offspring brain microglial density and has robust effects on developmental neuronal cell death. Milk cytokines were evaluated as a possible source of postnatal maternal influence; although we found high levels of CXCL1/GROα and several other cytokines in ingested post-partum milk, their presence did not require MyD88. Thus, the inflammatory response previously described in the late-term fetus and newborn depends on MyD88 (and, by extension, TLRs), with signaling in both the dam and offspring contributing. Unexpectedly, naturally-occuring neuronal cell death in the newborn is modulated primarily by maternal MyD88 gene status.

High rates of placental inflammation among samples collected by the Multi-Omics for Mothers and Infants consortium.

BACKGROUND: The Multi-Omics for Mothers and Infants consortium aims to improve birth outcomes. Preterm birth is a major obstetrical complication globally and causes significant infant and childhood morbidity and mortality. OBJECTIVE: We analyzed placental samples (basal plate, placenta or chorionic villi, and the chorionic plate) collected by the 5 Multi-Omics for Mothers and Infants sites, namely The Alliance for Maternal and Newborn Health Improvement Bangladesh, The Alliance for Maternal and Newborn Health Improvement Pakistan, The Alliance for Maternal and Newborn Health Improvement Tanzania, The Global Alliance to Prevent Prematurity and Stillbirth Bangladesh, and The Global Alliance to Prevent Prematurity and Stillbirth Zambia. The goal was to analyze the morphology and gene expression of samples collected from preterm and uncomplicated term births. STUDY DESIGN: The teams provided biopsies from 166 singleton preterm (<37 weeks' gestation) and 175 term (≥37 weeks' gestation) deliveries. The samples were fixed in formalin and paraffin embedded. Tissue sections from these samples were stained with hematoxylin and eosin and subjected to morphologic analyses. Other placental biopsies (n=35 preterm, 21 term) were flash frozen, which enabled RNA purification for bulk transcriptomics. RESULTS: The morphologic analyses revealed a surprisingly high rate of inflammation that involved the basal plate, placenta or chorionic villi, and the chorionic plate. The rate of inflammation in chorionic villus samples, likely attributable to chronic villitis, ranged from 25% (Pakistan site) to 60% (Zambia site) of cases. Leukocyte infiltration in this location vs in the basal plate or chorionic plate correlated with preterm birth. Our transcriptomic analyses identified 267 genes that were differentially expressed between placentas from preterm vs those from term births (123 upregulated, 144 downregulated). Mapping the differentially expressed genes onto single-cell RNA sequencing data from human placentas suggested that all the component cell types, either singly or in subsets, contributed to the observed dysregulation. Consistent with the histopathologic findings, gene ontology analyses highlighted the presence of leukocyte infiltration or activation and inflammatory responses in both the fetal and maternal compartments. CONCLUSION: The relationship between placental inflammation and preterm birth is appreciated in developed countries. In this study, we showed that this link also exists in developing geographies. In addition, among the participating sites, we found geographic- and population-based differences in placental inflammation and preterm birth, suggesting the importance of local factors.

Soft-tissue dystocia due to paradoxical contraction of the levator ani as a cause of prolonged second stage: concept, diagnosis, and potential treatment.

Smaller pelvic floor dimensions seem to have been an evolutionary need to provide adequate support for the pelvic organs and the fetal head. Pelvic floor dimension and shape contributed to the complexity of human birth. Maternal pushing associated with pelvic floor muscle relaxation is key to vaginal birth. Using transperineal ultrasound, pelvic floor dimensions can be objectively measured in both static and dynamic conditions, such as pelvic floor muscle contraction and pushing. Several studies have evaluated the role of the pelvic floor in labor outcomes. Smaller levator hiatal dimensions seem to be associated with a longer duration of the second stage of labor and a higher risk of cesarean and operative deliveries. Furthermore, smaller levator hiatal dimensions are associated with a higher fetal head station at term of pregnancy, as assessed by transperineal ultrasound. With maternal pushing, most women can relax their pelvic floor, thus increasing their pelvic floor dimensions. Some women contract rather than relax their pelvic floor muscles under pushing, which is associated with a reduction in the anteroposterior diameter of the levator hiatus. This phenomenon is called levator ani muscle coactivation. Coactivation in nulliparous women at term of pregnancy before the onset of labor is associated with a higher fetal head station at term of pregnancy and a longer duration of the second stage of labor. In addition, levator ani muscle coactivation in nulliparous women undergoing induction of labor is associated with a longer duration of the active second stage of labor. Whether we can improve maternal pelvic floor relaxation with consequent improvement in labor outcomes remains a matter of debate. Maternal education, physiotherapy, and visual feedback are promising interventions. In particular, ultrasound visual feedback before the onset of labor can help women increase their levator hiatal dimensions and correct levator ani muscle coactivation in some cases. Ultrasound visual feedback in the second stage of labor was found to help women push more efficiently, thus obtaining a lower fetal head station at ultrasound and a shorter duration of the second stage of labor. The available evidence on the role of any intervention aimed to aid women to better relax their pelvic floor remains limited, and more studies are needed before considering its routine clinical application.

Assisted vaginal birth in 21st century: current practice and new innovations.

Assisted vaginal birth rates are falling globally with rising cesarean delivery rates. Cesarean delivery is not without consequence, particularly when carried out in the second stage of labor. Cesarean delivery in the second stage is not entirely protective against pelvic floor morbidity and can lead to serious complications in a subsequent pregnancy. It should be acknowledged that the likelihood of morbidity for mother and baby associated with cesarean delivery increases with advancing labor and is greater than spontaneous vaginal birth, irrespective of the method of operative birth in the second stage of labor. In this article, we argue that assisted vaginal birth is a skilled and safe option that should always be considered and be available as an option for women who need assistance in the second stage of labor. Selecting the most appropriate mode of birth at full dilatation requires accurate clinical assessment, supported decision-making, and personalized care with consideration for the woman's preferences. Achieving vaginal birth with the primary instrument is more likely with forceps than with vacuum extraction (risk ratio, 0.58; 95% confidence interval, 0.39-0.88). Midcavity forceps are associated with a greater incidence of obstetric anal sphincter injury (odds ratio, 1.83; 95% confidence interval, 1.32-2.55) but no difference in neonatal Apgar score or umbilical artery pH. The risk for adverse outcomes is minimized when the procedure is conducted by a skilled accoucheur who selects the most appropriate instrument likely to achieve vaginal birth with the primary instrument. Anticipation of potential complications and dynamic decision-making are just as important as the technique for safe instrument use. Good communication with the woman and the birthing partner is vital and there are various recommendations on how to achieve this. There have been recent developments (such as OdonAssist) in device innovation, training, and strategies for implementation at a scale that can provide opportunities for both improved outcomes and reinvigoration of an essential skill that can save mothers' and babies' lives across the world.

Labor of a free-living buffy-tufted marmoset (Callithrix aurita) at a Wildlife Rehabilitation Center in southeastern Brazil.

Callithrix aurita is an endangered small primate endemic to the Atlantic Forest. The present work reports the labor of a free-living C. aurita, through observation of its length and offspring viability. A conservative treatment was used to maintain fetal viability, in view of the species conservation importance.

Safety of dermatologic medications in pregnancy and lactation: An Update - Part I: Pregnancy.

The breadth of therapeutic options for the management of dermatologic skin conditions continues to expand rapidly as exemplified by biologics and small molecule drug development. While dermatologists and healthcare providers are aware of the underlying mechanisms and indications for these therapeutics, there is a recognized practice gap due to an incomplete understanding of the safety of these medications in women of childbearing age during the prepartum, antepartum and postpartum phases. Although a two-part continuing medical education review was published regarding the prescribing practices and safety profiles of these new therapeutics in women of childbearing age while pregnant or lactating in 20141,2, many new medications have been approved since then. Herein, we will update the safety of dermatologic therapies during pregnancy and Part II will review the safety of medications during lactation.

Impact of parental leave system on the childbirth plan among working married women: a three-year follow-up study of the Korean longitudinal survey of women and families.

BACKGROUND: The Korean government seeks to balance work and family and alleviate low fertility by implementing a parental leave system. This study aimed to identify the impact of the parental leave system on childbirth among married working women in South Korea. METHODS: This study used three-year follow-up data from the Korean Longitudinal Survey of Women and Families (2016, 2018, and 2020). The number of participants was 324 at baseline. Logistic regressions using a generalized estimating equation model were performed to examine the impact of parental leave on childbirth. Sub-analyses of covariates, childbirth support, and parental leave systems were conducted. RESULTS: Of workers covered by the parental leave system, 31.7% considered childbirth. Women covered by parental leave were 3.63 times more likely to plan childbirth (95% confidence interval [CI], 1.32-9.99). The tendency to plan childbirth was pronounced among those in their early 30s (adjusted odds ratio [AOR], 7.20) and those who thought that having children was necessary (AOR, 4.30). Child planning was more influenced by leave support (AOR, 6.61) than subsidies. CONCLUSIONS: Parental leave systems can have a positive impact on working married women's childbirth plans. Although this system was effective in a group interested in childbirth, it did not create a fundamental child plan. Time support is more important than money concerning childbirth plans. The parental leave system had an impact on childbirth plan. Appropriate parenting policies can effectively increase the fertility rate.