Cesarean Myomectomy: Reflections on Clinical and Surgical Controversies between a New Trans-Decidual Technique vs. Traditional Method.

Up to 70-80% of women of reproductive age may be affected with the most common uterine tumors, known as fibroids or myomas. These benign tumors are the second most prevalent cause of surgery among premenopausal women. Predictions show that the occurrence of myomas in pregnancy will increase, and that the risk of having myomas during pregnancy increases with advanced maternal age. Although most women with fibroids do not experience any symptoms during pregnancy, up to 30% of women experience problems during pregnancy, childbirth, and the puerperium. The viability of myoma excision during cesarean surgery (CS) is a contentious issue raised by the rising incidence of myomas in pregnancy and CS rates. A new surgical procedure for removing fibroids using a trans-endometrial approach, which involves making an incision through the decidua itself, has put into doubt the long-standing practice of cesarean myomectomy (CM) with a trans-serosal approach. Some authors have recently advocated for this last approach, highlighting its advantages and potential uses in real-world situations. The purpose of this paper is to critique the present approach to cesarean myomectomy by analyzing the clinical and surgical distinctions between the two approaches and providing illustrations of the CM methods.

Reflections on Postpartum Hysterectomy as a Possible Complication of Cesarean Myomectomy: A Long Debate.

Uterine fibroids are common benign tumors found in fertile women. Numerous obstetrical issues, such as dystocia during labor, fetal hypotrophy, a ruptured amniotic sac, early labor, low-birth-weight newborns, etc., are associated with fibrous pregnant uteri. Cesarean myomectomy is not a common procedure because of the possibility of postpartum hysterectomy or a potentially lethal hemorrhage. For the chosen topic, we present two instances of emergency postpartum hysterectomies following cesarean myomectomy. After a cesarean myomectomy, two women experienced a perioperative hemorrhage that required a postpartum hysterectomy without a salpingo-oophorectomy. A postpartum hysterectomy was required in every instance due to the failure of additional hemostatic techniques to control the bleeding after the cesarean myomectomy. In every case, the location and number of fibroids-rather than their size-were the primary factors leading to the postpartum hysterectomy. In order to ensure that the patient is safe and that the advantages outweigh the dangers, the current trends in cesarean myomectomy include aiming to conduct the procedure either electively or when it offers an opportunity. The treatment is still up for debate because it is unknown how dangerous a second hysterectomy is for people who have had a cesarean myomectomy.

Adenomyosis and fertility-sparing surgery: A literature appraisal.

Adenomyosis is an intricate pathological condition that negatively impacts the uterus. It is closely related to the more well-known endometriosis, with which it shares parallels in terms of diagnosis, therapy, and both microscopic and macroscopic features. The purpose of this narrative review is to give a clear univocal definition and outlook on the different, patient-adapted, surgical treatments. MEDLINE and PubMed searches on these topics were conducted from 1990 to 2022 using a mix of selected keywords. Papers and articles were identified and included in this narrative review after authors' revision and evaluation. From the literature analysis, authors reported the following surgical techniques: laparoscopic double/triple-flap method, laparotomic wedge resection of the uterine wall, laparotomic transverse H-incision of the uterine wall, laparotomic wedge-shaped excision, and laparotomic complete debulking excision by asymmetric dissection technique. Each of these techniques has strengths and weaknesses, but the literature data on the pregnancy rate are somewhat limited. The only certain information is the risk of uterine rupture up to 6.0% after surgical treatment for uterine adenomyosis. Over the years, the surgical approach continued to reach a positive result by minimally invasive treatment, with less hospitalization, less postoperative pain, and less blood loss. Over the years, the gynecological surgeon has gained the skills, training and increasingly sophisticated surgical techniques to target effective therapy. That's why a hysterectomy is no longer the only surgical resource to treat adenomyosis, but in patients who wish to preserve the fertility, there is a wide variety of surgical alternatives.

PCOS and vitamin D: a clinical appraisal.

PURPOSE: Polycystic ovary syndrome (PCOS) is the most common endocrine-reproductive disease linked not just to infertility but also to serious comorbidities. There is a reported association between low vitamin D levels and multiple health conditions including PCOS. This narrative review aims to analyze the role of vitamin D in PCOS development, use of the vitamin D in the treatment of PCOS, and the molecular basis of these observations. METHODS: A Medline and PubMed research was performed, during the years 1990-2023, using a combination of keywords on such topic. According to the author's evaluation and target, papers were identified and included for a narrative review. RESULTS: There are associations between lower levels of vitamin D and PCOS, as well as with insulin resistance, metabolic syndrome, hyperandrogenemia, metabolic and endocrine disorders as well as the onset of oxidative stress and pro-inflammatory milieu, in PCOS women. CONCLUSION: Vitamin D has a role in pathologic changes linked to PCOS. Molecular and clinical investigations which give new information about the role of vitamin D in the development of PCOS and related endocrine and metabolic disturbance are further needed.

Insulin-sensitizing agents for infertility treatment in woman with polycystic ovary syndrome: a narrative review of current clinical practice.

PURPOSE: Polycystic ovary syndrome (PCOS) is an endocrine, metabolic, and reproductive disorder which, according to the Rotterdam criteria, affects up to 24% of women of childbearing age. Although the prevalence of infertility in this subpopulation of women is high, the optimal treatment has not been fully established yet. Insulin resistance is considered to be an important mechanism involved in the development of PCOS; hence, the aim of this narrative review is to present an overview of the current pharmacological insulin-sensitizing treatment modalities for infertile women with PCOS. METHODS: A MEDLINE and PubMed search for the years 1990-2023 was performed using a combination of keywords. Clinical trials with insulin sensitizers used for infertility treatment as well as analyses of systematic reviews and meta-analyses were evaluated. When deemed necessary, additional articles referenced in the retrieved papers were included in this narrative review. RESULTS: Several insulin-sensitizing compounds and various therapeutical protocols are available for infertility treatment of women with PCOS. Metformin is the most common adjuvant medication to induce ovulation in infertile women with PCOS and is more frequently administered in combination with clomiphene citrate than on its own. Recently, inositol and glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as possible options for infertility treatment in PCOS. CONCLUSION: The future of medical treatment of PCOS women with infertility lies in a personalized pharmacological approach, which involves various compounds with different mechanisms of action that could modify ovarian function and endometrial receptivity, ultimately leading to better overall reproductive outcomes in these women.

Myomectomy in adult women of reproductive age: a propensity score-matched study for pregnancy rates.

PURPOSE: To study whether it is better to perform or not a myomectomy, in terms of surgical and reproductive outcomes in patients of advanced reproductive age, by an observational prospective study in university-affiliated and Community Hospitals. MATERIALS AND METHODS: 40 years and older patients affected by non-submucous symptomatic uterine fibroids and desiring future fertility were enrolled and treated by laparoscopic intracapsular myomectomy by (LIM) or by open laparotomy (OIM), or by a non-surgical management as control group, while attempting to conceive. The primary outcome measures were fibroid characteristics, pre- and post-surgical parameters, pregnancy achievement; the secondary outcome measures were the spontaneous or ART pregnancy outcomes, eventual week of abortion and type of delivery. Propensity scores have been calculated with logistic regression for binary and continuous variables. RESULTS: 202 patients completed the study: 112 operated by LIM, 40 by OIM and 50 patients as control group. Patients undergoing OIM have a worse surgical outcome than LIM. No difference was seen in pregnancy either after myomectomy or control group during follow-up. In the LIM group, there were 44 pregnancies (39.2%), and in the OIM group, there were 9 (22.5%) and 16 in the control group (32%). The weeks of delivery were statistically greater for the control group versus the surgical groups, with no difference in Apgar score between the 3 groups. CONCLUSION: Patients aged over 40 years did not show substantial differences in reproductive outcome, whether operated or not. Myomectomy in over 40-year-old patients has no detrimental effect on future pregnancy rates and over when compared to expectant management.

Uterine Aging and Reproduction: Dealing with a Puzzle Biologic Topic.

Uterine aging is the process of the senescence of uterine tissue, observed in all middle-aged mammals. Since the aging-related changes in the uterus are associated with infertility and poor pregnancy outcomes, with a lack of studies discussing uterine aging, authors reviewed uterine aging and its consequences on reproduction. MEDLINE, Scopus, and PubMed searches during the years 1990-2023 were performed using a combination of keywords and terms on such topics. According to the author's evaluation, articles were identified, selected, and included in this narrative review. The aging process has an unfavorable impact on the uterus of mammals. There are different and selected molecular pathways related to uterine aging in humans and animals. Uterine aging impairs the function of the uterine myometrium, neurofibers of the human uterus, and human endometrium. These biological pathways modulate oxidative stress, anti-inflammatory response, inflammation, mitochondrial function, DNA damage repair, etc. All these dysregulations have a role in poorer reproductive performance and pregnancy outcomes in older mammals. The most recent data suggest that uterine aging is accompanied by genetic, epigenetic, metabolic, and immunological changes. Uterine aging has a negative impact on the reproductive performance in mammalian species, but it could be potentially modulated by pharmacological agents, such as quercetin and dasatinib.

Unraveling the Puzzle: Oocyte Maturation Abnormalities (OMAS).

Oocyte maturation abnormalities (OMAS) are a poorly understood area of reproductive medicine. Much remains to be understood about how OMAS occur. However, current knowledge has provided some insight into the mechanistic and genetic origins of this syndrome. In this study, current classifications of OMAS syndromes are discussed and areas of inadequacy are highlighted. We explain why empty follicle syndrome, dysmorphic oocytes, some types of premature ovarian insufficiency and resistant ovary syndrome can cause OMAS. We discuss live births in different types of OMAS and when subjects can be offered treatment with autologous oocytes. As such, we present this review of the mechanism and understanding of OMAS to better lead the clinician in understanding this difficult-to-treat diagnosis.

Fibroid Removal after Myomectomy: An Overview on the Problems of Power Morcellation.

The authors reviewed uterine fibroid (UF) morcellation and its potential consequences, notably a hypothetical spread and dissemination of occult uterine leiomyosarcoma (LMS) tissue, evaluating the effect of laparoscopic versus open myomectomies with and without morcellation on patients' outcomes, as well as related medical-legal issues. MEDLINE and PubMed search was performed for the years 1990-2021, using a combination of keywords on this topic. Relevant articles were identified and included in this narrative review. There is an individual risk, for all patients, for LMS diagnosis after myomectomy. However, the risk for occult LMS diagnosis during a laparoscopic myomectomy is generally reduced when the guidelines of scientific societies are followed, with an overall benefit from the laparoscopic approach with morcellation in appropriate cases. Gynecological societies do not ban morcellation and laparoscopic hysterectomy/myomectomy per se, but recommend their use on the basis of the patients' clinical characteristics. It is suggested for gynecologists to provide detailed information to patients when obtaining an informed consent for open or laparoscopic hysterectomy/myomectomy. A detailed preoperative assessment of patients and the risk benefit ratio of laparoscopic morcellation of uterine mass could overcome the "a priori" banning of the morcellation technique.

Molecular Insights in Uterine Leiomyosarcoma: A Systematic Review.

Uterine fibroids (UFs) are the most common benign tumors of female genital diseases, unlike uterine leiomyosarcoma (LMS), a rare and aggressive uterine cancer. This narrative review aims to discuss the biology and diagnosis of LMS and, at the same time, their differential diagnosis, in order to distinguish the biological and molecular origins. The authors performed a Medline and PubMed search for the years 1990-2022 using a combination of keywords on the topics to highlight the many genes and proteins involved in the pathogenesis of LMS. The mutation of these genes, in addition to the altered expression and functions of their enzymes, are potentially biomarkers of uterine LMS. Thus, the use of this molecular and protein information could favor differential diagnosis and personalized therapy based on the molecular characteristics of LMS tissue, leading to timely diagnoses and potential better outcomes for patients.

Long-term quality of life assessment after excisional treatment for cervical dysplasia.

We evaluated factors influencing long-term health-related quality of life (HRQoL) after excisional treatments of low- and high grade squamous intraepithelial cervical lesions (SIL) in three groups of women (n = 160): nulliparas interested in reproduction (A), parous women interested in reproduction (B) and women without pregnancy desire (C). The HRQoL was assessed using the disease-specific FACIT-CD and the generic SF36v2 questionnaires. Anxiety and depression were evaluated by Beck's inventories. After median follow-up of 5 (2-18) years, FACIT-CD total score and the score for Emotional Well-Being (EWB) were significantly lower in group A. The total, EWB and REL (Relationships) scores of FACIT-CD were the highest in group B. Women operated for HSIL demonstrated lower REL quality in comparison to those with LSIL. Neither SF36v2 nor FACIT-CD total scores differed in relation to SIL grade or type of excision. 'SF36v2 Mental Component Summary Score' and 'being parous and interested in fertility' were independent predictors of disease-specific FACIT-CD score.Impact StatementWhat is already known on this subject? Long-term consequences of excisional treatments for cervical dysplasia on health-related quality of life (HRQoL) are not well reported.What do the results of this study add? Our study provides data on HRQoL in women treated with large loop excision of the transformation zone (LLETZ) or cold knife conization (CKC) obtained during the longest (median 5 years) follow-up as reported to date. We were able to show that having children and planning further pregnancies positively influenced HRQoL in these patients. In addition, we identified nulliparas with pregnancy desire as psychologically the most vulnerable group within the studied cohort.What are the implications of these findings for clinical practice and/or further research? Even several years after LLETZ or CKC, women may suffer from impaired Emotional Well-Being and reduced HRQoL. Awareness and assessment of these long-term consequences should be part of surveillance after excisional treatments for cervical dysplasia.

Do Changes in Body Shape Due to Pregnancy Lead to Cosmetic Surgery? A Cross-Sectional Study.

OBJECTIVE: Pregnants and puerperas show different perceptions of their body image and appearance, so authors investigated their perceptions related to pregnancy and puerperium, evaluating their views on cosmetic surgery, by a cross-sectional study. MATERIALS AND METHODS: 5-item questionnaires were administrated to women at first pregnancy and puerperas. Patients were submitted also to Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI) and Body Image Inventory (BII) analysis, indicating the level of anxiety, depression and body dissatisfaction for somatic changes during pregnancy and after childbirth. RESULTS: 186 healthy women, aged between 25-35 years, equally divided in pregnancy and puerperium, were compared in terms of body image, with no significant difference between groups. Analyzing the item "cosmetic surgery is required after all pregnancies", there was a significant difference in puerperas and the item "cosmetic surgery is necessary for postpartum" was the principal. The comparison of BII, BDI, BAI values between pregnants and puerperas showed a significant difference between groups (p<0.00), with higher scores in postpartum patients. CONCLUSION: Body shape and physical dissatisfaction during pregnancy is linked with increased risk of depression in pregnancy and puerperium, pushing women to opt for cosmetic surgery, especially in puerperium.

Uterine rupture during pregnancy: The URIDA (uterine rupture international data acquisition) study.

OBJECTIVE: To describe the characteristics and peripartum outcomes of patients diagnosed with uterine rupture (UR) by an observational cohort retrospective study on 270 patients. METHODS: Demographic information, surgical history, symptoms, and postoperative outcome of women and neonates after UR were collected in a large database. The statistical analysis searched for correlation between UR, previous uterine interventions, fibroids, and the successive perinatal outcomes in women with previous UR. RESULTS: Uterine rupture was significantly associated with previous uterine surgery, occurring, on average, at 36 weeks of pregnancy in women also without previous uterine surgery. UR did not rise exponentially with an increasing number of uterine operations. Fibroids were related to UR. The earliest UR occurred at 159 days after hysteroscopic myomectomy, followed by laparoscopic myomectomy (251 days) and laparotomic myomectomy (253 days). Fertility preservation was feasible in several women. Gestational age and birth weight seemed not to be affected in the subsequent pregnancy. CONCLUSION: Data analysis showed that previous laparoscopic and abdominal myomectomies were associated with UR in pregnancy, and hysteroscopic myomectomy was associated at earlier gestational ages. UR did not increase exponentially with an increasing number of previous scars. UR should not be considered a contraindication to future pregnancies.

Gestational Diabetes Mellitus and Antenatal Corticosteroid Therapy-A Narrative Review of Fetal and Neonatal Outcomes.

BACKGROUND: There, we review the pathogenesis of gestational diabetes mellitus (GDM), its influence on fetal physiology, and neonatal outcomes, as well as the usage of antenatal corticosteroid therapy (ACST) in pregnancies complicated by GDM. METHODS: MEDLINE and PubMed search was performed for the years 1990-2022, using a combination of keywords on such topics. According to the aim of the investigation, appropriate articles were identified and included in this narrative review. RESULTS: GDM is a multifactorial disease related to unwanted pregnancy course and outcomes. Although GDM has an influence on the fetal cardiovascular and nervous system, especially in preterm neonates, the usage of ACST in pregnancy must be considered taking into account maternal and fetal characteristics. CONCLUSIONS: GDM has no influence on neonatal outcomes after ACST introduction. The ACST usage must be personalized and considered according to its gestational age-specific effects on the developing fetus.

Neurological outcomes of antenatal corticosteroid therapy.

AIM OF THE STUDY: The aim of the study was to investigate whether antenatal corticosteroid therapy (ACST) could impact neurological condition, as assessed through muscular tone, of prematurely born infants. METHODS: All 82 patients at risk of preterm delivery treated and delivered over 12 months were divided into two equal groups regarding the use of ACST. The investigated parameters were pregnancy complications, biophysical profile, Apgar score, gestational age of delivery and all postpartum complications. Neurological development and muscular tone were evaluated at the 1st, 3rd, 6th and 12th months of life using Vojta's method, which classifies muscular tone as good, hypotonic or hypertonic. RESULTS: After therapy, infants from the treated and control groups differed in biophysical profile, Apgar score, length of intensive care, occurrence of respiratory distress syndrome and intraventricular haemorrhage. During the follow-up, significantly more infants from the ACST group had good muscular tone when compared with those from the control group. Regression analysis showed that ASCT can significantly impact an infant's muscular tone. Still, the week of delivery and the complications such as diabetes mellitus, intrauterine growth restriction and respiratory distress syndrome, could change the association of ACST and infants' muscular tone. CONCLUSION: ACST was associated with the positive neurological outcomes of prematurely born infants when assessed through their muscular tone.

Laparoscopic Intracapsular Myomectomy in Women 40 Years Old and Over with Symptomatic Uterine Fibroids. A Pilot Study.

Authors evaluated the impact of laparoscopic intracapsular myomectomy (LIM) in women 40 years of age and over with desire of future fertility compared with medical management of symptomatic fibroids, by a prospective cohort study in University affiliated Hospitals. This study includes a cohort of women 40 years of age and older with symptomatic intramural fibroids with desire of future fertility. Women with symptomatic fibroid uterus were offered to undergo LIM or medical management. They were encouraged to attempt conception either spontaneously or by assisted reproductive technology (ART) according to their individual preference. All women were followed for 2 years. Fibroid characteristics, pre- and post-surgical variables, including surgical complications, days of hospitalization, pregnancy rate, and obstetrical outcomes were collected. A total of 100 patient were included in the analysis. Fifty patients were assigned to the LIM group and 50 to the medical treatment group (MT). Groups were similar regarding age (43.5 ± 2.4 and 43.5 ± 2.4, p = 0.99), body mass index (23.8 ± 3.1 and 24.2 ± 3.1, p = 0.54), parity (0.46 ± 0.09 and 0.58 ± 0.09, p = 0.37), fibroid number (1.38 ± 0.6 and 1.46 ± 0.6, p = 0.53), and fibroid size (5.92 ± 1.62 cm vs. 5.94 ± 1.49 cm, p = 0.949). Of the patients who underwent LIM, 62% conceived within the study period compared with 56% in the control group ( p = 0.54). Pregnancy was achieved by ART in 44% of the patients of the LIM group and 30% in control group. There was no significant difference in pregnancy rates among the two groups regarding spontaneous pregnancy rate ( p = 0.332), nor in pregnancies obtained by ART with own eggs ( p = 0.146) and oocyte or embryo donation ( p = 0.821). The take home baby rate was 65% (20/31) in the LIM group and 61% (17/28) in the control group ( p = 0.7851). Both groups had similar rate of miscarriage ( p = 0.748). Patients 40 years old and over with symptomatic fibroid uterus who undergo LIM have similar subsequent fertility and obstetrical outcomes than women treated with medical management. LIM has no detrimental impact on future fertility in women 40 years old and over.

Uterine Fibroids and Diet.

Uterine myomas or fibroids are the most common benign female tumors of the reproductive organs, associated with significant morbidity and quality of life impairment. Several epidemiological risk factors for their occurrence have been identified so far, including nutrition and dietary habits. In this investigation, authors reviewed, as a narrative review, the data about diet and uterine myoma development in order to homogenize the current data. A PubMed search was conducted for the years 1990-2020, using a combination of keywords of interest for the selected topic. The authors searched the databases, selecting the randomized clinical studies, the observational studies, and the basic (experimental), clinical, and epidemiological researches. Once they collected the articles, they analyzed them according to the number of citations of each article, starting from the most cited to the least cited articles. Subsequently, authors collected the data of each article and inserted them in the various research paragraphs, summarizing the data collected. In this way, they crossed the available data regarding the association between nutrition habits and dietary components and myoma onset and growth. Many nutrients and dietary habits are associated with myoma development risk. These factors include low intakes of fruit, vegetables, and vitamin D, as well as pollutants in food. Despite the available data on the influence of some foods on the development of fibroids, further research is mandatory to understand all the nutrition risk factors which contribute to myoma growth and how exactly these risk factors influence myoma pathogenesis.

A Comparative Multicentric Study on Serosal and Endometrial Myomectomy During Cesarean Section: Surgical Outcomes.

OBJECTIVE: This multi-center study aims to determine the efficiency and safety of endometrial myomectomy (EM) for the removal of uterine fibroids during cesarean section (CS). METHODS: Retrospective review of 360 women diagnosed for fibroids during pregnancy. They all delivered by CS between 2014 and 2019. The study groups included 118 women who only underwent EM, 120 women who only had subserosal myomectomy by traditional technique and 122 women with fibroids who decided to avoid cesarean myomectomy, as control group. They were analyzed and compared the surgical outcomes. RESULTS: The EM, subserosal myomectomy and control groups were statistically (p > 0.05) similar for to age, body mass index (BMI), gravidity, parity, gestational age at delivery, indications for CS, number of excised fibroids, size of the largest myoma. Postoperative hemoglobin values and ? (?) hemoglobin concentrations were lower in SM group (10.39gr/dl vs 9.98 gr/dl vs 10.19 - 1.44 gr/dl vs 1.90 gr/dl vs 1.35; p = 0.047, p = 0.021; respectively) Hybrid fibroids were significantly more frequent in the EM group than subserosal myomectomy and control groups (respectively, 33.1% vs 23.3% vs 27.0%, p = 0.002). Surgery time was significantly longer in the subserosal myomectomy group than EM and control groups (respectively, 46.53 min vs 37.88 min vs 33.86 min, p = 0.001). Myomectomy took significantly longer time in the subserosal myomectomy than EM group (13.75 min vs 8.17 min, p = 0.001). CONCLUSIONS: Endometrial myomectomy is a feasible choice for treatment of fibroids during CS, and, basing on our results could be an alternative to traditional cesarean subserosal myomectomy.

Adrenergic and Cholinergic Uterine Innervation and the Impact on Reproduction in Aged Women.

In recent years, the development of Assisted Reproductive Technique, the egg and embryo donation changed substantially the role of the uterus in recent years. It provided a higher chance for a pregnancy even in women over 45 years or post-menopause. In fact, the number of aged patients and in peri/post-menopause in pregnancy is nowadays increasing, but it increases obstetrical and neonatal related problems. The human uterus is richly innervated and modified especially during pregnancy and labor, and it is endowed with different sensory, parasympathetic, sympathetic and peptidergic neurofibers. They are differently distributed in uterine fundus, body and cervix, and they are mainly observed in the stroma and around arterial vessel walls in the myometrial and endometrial layers. Many neurotransmitters playing important roles in reproductive physiology are released after stimulation by adrenergic or cholinergic nerve fibers (the so called sympathetic/parasympathetic co-transmission). Immunohistochemical study demonstrated the localization and quantitative distribution of neurofibers in the fundus, the body and cervix of young women of childbearing age. Adrenergic and cholinergic effects of the autonomous nervous system are the most implicated in the uterine functionality. In such aged women, the Adrenergic and AChE neurofibers distribution in the fundus, body and cervix is progressively reduced by increasing age. Adrenergic and AChE neurotransmitters were closely associated with the uterine arteries and myometrial smooth muscles, and they reduced markedly by ageing. The Adrenergic and AChE neurofibers decreasing has a dramatical and negative impact on uterine physiology, as the reduction of pregnancy chance and uterine growth, and the increase of abortion risk and prematurity.