[HD 201] E02-T04-Maternal Adaptation_ GI, Endocrine, and Immune Systems (1)_compressed

Introduction

• Pregnancy imposes physiological stress and bodily changes, which affect all bodily systems
• Hormones coordinate changes which initiate and govern changes and alterations imposed by pregnancy

The Alimentary System

• Several changes within the GI tract are observed during advanced pregnancy

Anatomical Adjustments

• The stomach and intestines are displaced cephalad by the enlarging uterus
• The appendix is displaced upward and laterally and at times, it may reach the right flank, which affects the presentation of pathologies
• Hemorrhoids are common due to elevated pressure in the rectal veins and may be due to constipation

Oral Cavity

• Appetite and thirst increase throughout pregnancy because of increased body fat, which is caused by central changes in energy balance relating to circulating progesterone and a fall in plasma levels of glucose and amino acids

Qualitative Changes in Food Habits during Pregnancy

• Aversions and avoidance of fatty foods happen during this time
• Preferences or cravings for salty and spicy food may be a result of dulling of sense of taste or increased threshold for all tastes
• Pica is uncommon
• Compulsive eating disorder to eat non-food items
• May be associated with nutritional deficiency (e.g. iron deficiency)
• Establish nutritional deficiencies via laboratory testing
• Gums are often swollen, ‘spongy’ and bleed easily, and there's an increased incidence of gingivitis and periodontal disease
• Can be due to gingival edema from circulating estrogen, and NOT due to the presence of debris or irritants

Ptyalism

• This involves excessive salivation of about 1-2 L per day
• Nauseated women may have difficulty swallowing their saliva
• Sometimes, may also lead to stimulation by starch ingestion associated with pica

Esophagus

• Pyrosis can occur
• This is heartburn in pregnancy or a painful retrosternal burning sensation
• Caused by reflux esophagitis
• Due to reduced mechanical competence of lower esophageal sphincter
• Decreased pressure sphincter response to raised intragastric pressure
• Altered stomach position may contribute to frequency of pyrosis

Stomach

• Reduced peptic activity and decreased motility in the stomach
• Gastric emptying time and the volume of gastric contents after 30 minutes remain unchanged
• Nausea occurs due to gastric relaxation and hypomotility from progesterone and is common in the 1st trimester
• Lack of stomach tone is consistent with generalized smooth-muscle relaxation because of decreased motilin secretion
• Sluggishness of the stomach is greatly accentuated during labor, which imposes a risk of aspiration of gastric contents due to anesthesia
• Patients are advised to not eat for 6 hours prior to delivery
• Analgesics may cause prolonged gastric emptying

Small Intestines

• Shares the same sluggishness with the stomach, this provides longer time for digestion and absorption

Colon

• Constipation is a common complaint because of the relaxation of smooth muscle and intensified water absorption in the colon
• Caused by increased amounts of angiotensin and aldosterone

Gallbladder

• Elevated levels of bilirubin may result in an increased incidence of pruritus
• The gallbladder becomes sluggish, empties poorly and appears distended
• Progesterone may impair contraction of the gallbladder through inhibition of CCK-mediated smooth muscle stimulation
• Impaired emptying and stasis (cholestasis) leads to greater cholesterol saturation of bile
• Bile generally thick, tarry and viscous, favoring stone formation
• Increased prevalence of cholesterol gallstones

Maternal Weight Gain

• Fetal weight increases with a concomitant increase in the weight of the maternal organs

General Weight Gain

• Maternal pre-pregnancy weight and weight gain is associated with neonatal birth weight
• Average total weight gain is 12.5 kg
• Greater weight gain may mean the baby is heavier

Immune System Overview

• Pregnancy is the most important period for the conservation of species
• The immune system protects the mother against foreign bodies and stress, while also preventing damage to the developing fetus

The Maternal Immune System

• It relies on a reinforced network of interrelated immunological activities of recognition, communication, tracking, and repair
• Raises alarms and triggers a cascade of responses to maintain the well-being of both the mother and the fetus

Fertilization & Immune System

• The genetic makeup consists of paternal and maternal halves
• The embryo and placenta express both paternal and fetal antigens

Recognition of Antigens

• Antigens are recognized as "non-self" (foreign or semi-allogeneic) entities by the maternal immune system
• The maternal immune system is challenged by fetal antigens and fetal MHC molecules
• If not recognized as "self," the developing fetus can be harmed
• Existing balances within the immune system prevent attacks on the fetus

Active Interactions

• Fetal-maternal interface is the active hub of interactions during implantation and placental development
• It grants immunotolerance of the fetus
• Consists of immune adaptations and crosstalk among the maternal microbiome, uterine decidua, and trophoblast

Maternal microbiome

• Some areas of the uterus are colonized with commensal bacteria that play a tolerizing and protective role
• Pregnancy reduces various humoral and cell-mediated immunologic functions
• Permits the accommodation of the foreign semi-allogeneic growth that contains the paternal and maternal antigens

Fetal Trophoblasts

• Direct contact with maternal tissues and blood
• Consists of two subsets: Villous trophoblast and Invasive extravillous trophoblast

Villous Trophoblast

• Exchanges gases and nutrients between mother and fetus
• Does NOT have MHC Class I and II antigens
• Appears to be immunologically inert at all gestational stages
• A mechanism involves the pregnancy to continue by modulating immune cells

Invasive Extravillous Trophoblast

• Responsible for invading the uterine wall
• Anchors the chorionic villi into the uterus and expresses the MHC Class I molecules
• Allows them to bypass transplantation rejection or avoid rejection by the maternal immune system

Fetal syncytiotrophoblast

• Synthesizes and secretes factors to regulate the immune responses of maternal cells

Human leukocyte associated (HLA) complex

• A human analogue of the MHC
• The MHC is a group of antigens that occur in vertebrates
• HLA includes a series of 40-50 genes in the short arm of chromosome 6
• Has 17 HLA Class I genes
• Classical genes
• Encode the major Class 1a transplantation antigens
• Non-classical genes
• Encode Class 1b HLA antigens that are expressed in humans only
• Restricted to the fetal extravillous cytotrophoblasts that are contiguous with maternal tissues
• HLA recognition by natural killer (NK) cells in the decidua would inhibit their activity and promote immune quiescence

HLA-G

• Major MHC expressed in extravillous trophoblast
• Can act via multiple mechanisms to aid tolerance of the maternal-fetal antigen mismatch
• Involved in bypassing rejection and protecting the uterus from immune attack by modulating both the circulating and decidual natural killer (dNK) cells

Clinical Significance HLA-G

• The importance of HLA-G is highlighted by failure of IVF embryos to implant due to a lack of soluble HLA-G isoform
• Women with preeclampsia is associated with an abnormal HLA-G expression in extravillous trophoblasts
• Involves abnormal trophoblastic invasion of the uterine muscle and spiral arteries causing abnormal changes when pregnancy progresses

Immune Adaptations

• Major Histocompatibility Complex is found on the trophoblast
• One immune adaptation that promotes tolerance and protection at the maternal-fetal interface
• Involves the special MHC Class 1a, where any cell that expresses this complex is privileged against attack by maternal immune responses

Decidua and Immune Cells

• the human maternal-fetal interface including maternal immune cells
• in the decidua, the majority of early infiltrating immune cells consist of NK cells
• predominate in the mid-luteal phase of the endometrium up to the 1st trimester decidua
• numbers decline by term and kill cells under stress, recognize and lyse cells lacking self MHC-I or HLA-I
• Macrophages help regulate adaptive T cell responses, control dNK differentiation, activation, and cytotoxicity, and produce anti-inflammatory cytokines

Dendritic cells

• Cells present antigens to T-cells
• Play a role in the endometrium's development for implantation
• T cells are less common, but numbers increase and they function after meeting a specific antigen; respond later when encountering the antigen

Uterine natural killer (uNK) cells

• deciduas natural killer (dNK) cells in pregnant women, immune subset found in uterus
• permit and limit trophoblastic invasion, when combined with HLA class I genes in extravillous cytotrophoblasts
• they express different cell receptors, aren't cytotoxic, and allow immunotolerance;
• The expressions of HLA-E, HLA-G, HLA-F in fetal trophoblasts suppress cells
• Abnormal cell count and and impaired function are connected to pregnancy issues
• For example, recurrent miscarriage early 1st trimester resulted from problems around preeclampsia or pregnancy intolerance
• Tregs are made up of 20% of decidua T cells

Regulatory T cells (Treg)

• cells decrease CD4+ and CD8+ T cells, they create anti-inflammatory Cytokines which balance immune responses, autoimmunity prevention
• derived from the local blood or expansion caused by trophoblast derived IL-10 that expresses transcription factors, they can inhibit fetal responses
• shifts happen during the first trimester, peaks within 2nd, then dips prior to birth

Innate Immunology

• Two types of cells responsible for innate immunology involve T-cells and B-cells
• The adaptive mechanisms use Th cells
• In cases of implantation, it accompanies localized Inflammation; pregnancy promotes shift toward 2 cytokines and pregnancy tolerance
• In these scenarios, T2 cells over express T1 so that body can tolerate the fetus; during labor T1 cells are over expressed

Th1-mediated Immunity

• Suppressing Th1-mediated immunity maintains pregnancy
• Decreased production of cytokines results: interleukin-2 (IL-2), interferon α, and tumor necrosis factor
• Th1 suppression can result in the remission of rheumatoid arthritis, multiple sclerosis, & Hashimoto thyroiditis

Th2-mediated Immunity

• The maternal immune cells rely on shifting towards T2 Immunity to accept fetus
• If T1s decrease, humoral and auto immune responses cause increase in cytokine production (i.e. IL-4, IL-10, and IL-13)
• Autoimmune conditions may arise if T2s are upregulated, namely systemic lupus erythematosus; this mostly happens in the earlier periods of pregnancy

B Regulatory cells

• Bregs are tolerogenic and responsible for tolerating pregnancy
• Capable of inhibiting T-cell response through the production of cytokines to mainting equilibrium between T1 and T2, they are highly relevant in pregnancy
• Deficiencies stem from fetal restriction, resorption, and mortality, can restrict excessive inflammatory response caused by infections

Inflammatory Markers

• Typically inflammatory markers will likely rise should the body be contracted with an infection
• Inflammation in pregnancy is naturally high; Tests to diagnose this are unreliable like Leukocyte, alkaline phosphatase, C-reactive protien, Erythrocyte sedimentation rate (ESR), Complement factors C3 and C4

Endocrine System: Hypothalamus and Pituitary Gland

• During pregnancy, gland cells such as lactotrophs rise that expands size to 135% original capacity, the pituitary gland is still able to regulate hyperplasia
• With tumor growth, pituitary gland grows quickly which causes compression symptoms such as headaches, visual defects, cavernous sinus syndrom

Sheehan Syndrome

• Rare condition of pituitary during pregnancy occurs due to the loss of volume and severe post partum hemorrhaging
• Common background usually involves pregnant mothers in their first trimester who don't show any periods post delivery

The Anterior Pituitary Hormones & Prolactin

• Lactation that initiates milk secretion, triggered by estrogen that affects salt balance, maternal calcium levels, and breast stimulation
• It initiates replication of glandular & presecretory alveolar cells

Lactation

• It is linked to hormones and begins prior to delivery
• Hormones play a role in the preparation of the breast and the growth of milk stimulation
• While pregnant Prolactin levels increase;
• Later, levels will drop, then begin their cycle of release with the suckling baby
• Estrogen, Progesterone, hormones help the breast production

Hormonal Control

• During birth the hormones activate and sensitize the nipple
• It activates ovulation (prolactin)
• Delivery and Prolactin production are linked: Breast stimulation with suckling causes hormones to stimulate
• Stimuli and sensation from child will block fertility

Hormonal Release Blockers

• Antiostrogens, inhibit prolactin with suckling; Clomiphene, used to stimulate the ovaries Tamoxifen for breast cancer patients
• Dopamine inhibits these transmissions to manage prolactinoma; inhibits vasal releases which control gonadotrophs causing inhibitions of pregnancy
• The lack of stimulation controls pregnancy during corticoptropin, these mostly occur under normal pregnancy

ACTH Hormone Level

• Hormone activation and increases in cortisol are increased
• Higher concentrations are linked to the inflammation to protect the fetus

Thyroid Gland

• Hormones have increased function of the gland to benefit from mother to child

Thyroid Hormone and Pregnancy

• A thyroxine increase of 20-50% is needed to maintain state, may need supplements so they are ready for proper hormone intake
• Hormones are helpful for development of brain, somatic, and bones during various functions
• Hormonal disfunction in early years can lead to abortion/ reduction and preterm births
• lodine intake with pregnancy is needed and women should consume 150 - 250ug per day from supplements

Parathyroid

• Bone growth and calcium is crucial during the period of bone transformation and women are recommended calcium supplements

Calcium Levels

• Bone turn over creates the yields from fetal skeletal formations, calcium and magnesium stimulate secretions which results from fetal skeletons
• Calcitriol, Vitamin D are consumed and transferred with absorption

Mineralization

• A process that requires 30g of calcium
• Actions during absoprtion, kidney functions will increase
• Extracellular levels will decline and reduce phosphate

The Adrenal Glands & Steroid Functions

• outer and inter glands produce adrenalyn
• the steroid hormones also help increase balance and blood transmission as well as stimulate two receptors (alpha and beta)

Adrenal levels

• Under circumstances ACTH is reduced; In normal periods pregnancy has no changes

Progesterone Levels

• the adrenal and progesterone protects effects High angiotension is produced, angiotension reacts and protects glands which increases with high angiotension production

Ovary Hormones

• Ovaries in pregnancy are identifiable in the 19th century
• In early pregnancies (before 7 weeks) ovaries need to quickly fall for hormone supplementation
• Eventually placental hormones kick into place

CL

• No longer needed for the period of pregnancy in the 17 week mark unless the hormones are supplemented with something to promote CL secretion , with sever pain and abdomen in tact