1 PH Physiological Changes in PregnancyDr nada alibrahemi Dr nada alibraheemiحpp

2 Objectives: Understand the significant difference of the norms for the young pregnant female avoid misinterpretation of physiological changes of pregnancy as abnormal Appreciation of these differences lead to appropriate management of clinical problems in obstetrics.

3 Objectives: Describe the main physiological changes which occur in a mother during a normal pregnancy Describe how maternal adaptations to pregnancy and the support of the fetus influence maternal nutritional requirements

4 Maternal physiological adaptations to pregnancyPhysiological Changes in Pregnancy Cardiovascular system Urinary system & genital tract Respiratory system Metabolic changes Carbohydrate Thyroid hormones Gastrointestinal System Immune system Hematological system

5 Volume Homeostasis Fluid retention is one of the most fundamental systemic changes of normal pregnancy. Most marked expansion occurs in ECF volume, especially in circulating plasma volume. Some increase in ICF volume. The precise underlying mechanism uncertain.

6 Factors contributing to fluid retention :Sodium retention . Resetting of osmostat. Decrease thirst threshold. Decrease plasma oncotic pressure

7 Consecquences of fluid retention:Hb concentration falls. Hematocrit falls. Serum albumin concentration falls. Stroke volume increases. Renal blood flow increases

8 Cardiovascular SystemBlood volume ↑ Cardiac output ↑ Stroke volume ↑ Heart rate ↑ (Remember, CO = HR x SV) Blood pressure ↓

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11 Clinical aspects of CVS changes: Breathlessness, edema of extremities, sinus tachycardia (palpitation), filled and dynamically pulsating jugular veins, but JVP unchanged, forcibly beating cardiac apex, Auscultatory changes: 1)increase loudness of S1, S2. 2)exaggerated splitting of S2. 3)loud S3 by 20 weeks. 5)systolic ejection murmur at left sternal edge (96%). 6)transient diastolic murmur (20%). 7)continuous murmur due to increase mammary blood flow(10%).

12 What are the ECG changes in normal pregnancy?

13 Cardivascular system:Outline the physiological changes of the following parameters during pregnancy. Heart rate Stroke volume Cardiac output Mean arterial pressure Peripheral resistance

14 Hypotension in pregnancyT1 and T2 – Progesterone effects on Systemic Vascular Resistance T3 – Aortocaval compression by gravid uterus. return to the heart Why there is an increase in plasma volume during pregnancy? What is the effect of pregnancy on oncotic pressure & osmotic pressure?

15 Haematology The circulating red cell mass increases by 25% during pregnancy. Plasma volume is increased by 50%. So there is a state of hemodilution erroneously called “physiological anemia of pregnancy”. Consequently hematological indices which depend upon the proportion of plasma in a measured blood sample such as haematocrit, haemoglobin concentration and the red cell count tend to decrease.

16 Pregnancy is a Pro-Thrombotic state Haematology Pregnancy is a Pro-Thrombotic state High amount of fibrin deposition at the site of implantation Increased fibrinogen and clotting factors Reduced anticoagulant system & fibrinolysis Stasis, venodilation Results in Thromboembolic disease in pregnancy Cannot give warfarin – Crosses placenta & is teratogenic  Describe the effect of pregnancy on platelets & ESR? The total white cell count rises(mainly increased polymorphonuclear leucocytes)

17 maternal platelet count usually remains stablethroughout pregnancy, although may be lower than in the non-pregnant state due to increased aggregation. Increases in the platelet count have been reported in the first week postpartum and this may contribute to the increased risk of thromboembolic complications in this period

18 MCV increases secondary to erythropoiesis. MCHCH remains stable. Serum iron & ferritin conc decrease due to increased utilization. TIBC increased. Iron requirements increased & there is a moderate increase in iron absorption. Serum folate decrease. Serum vit B12 decrease due to preferential active transport to the fetus. maternal platelet count usually remains stable throughout pregnancy, although may be lower than in the non-pregnant state due to increased aggregation. Increases in the platelet count have been reported in the fi rst week postpartum and this may contribute to the increased risk of thromboembolic complications in this period

19 The total white cell count rises, mainly because of increased polymorphonuclear leucocytes. Average value in third trimester 9,OOO/µL, while in the early days of the peurperium normal values may reach up to 20,000/µL.

20 Coagulation Normal pregnancy is a hypercoagulable state .(increase in procaoagulant factors & a reduction in fibrinolytic activity). Pregnancy is associated with a dramatic increase in the plasma concentration of coagulation factors I, V, VII, IX, X, XII & VON Willebrand factor ESR rises early in pregnancy due to the increase in fibrinogen and other physiological changes.

21 There are also significant changes in the anticoagulant system, there is a reduction in the concentration of protein S and antithrombin III concentrations while protein C, which inactivates Factors V and VIII, is probably unchanged in pregnancy. Plasma fibrinolytic activity is decreased during pregnancy and labour, but returns to non-pregnant values within an hour of delivery of the placenta, suggesting strongly that the control of fibrinolysis during pregnancy is significantly affected by placentally derived mediators ( plasminogen activator inhibitor II (PAI-II)).

22 Historically, pregnancy was considered an immunosuppressive stateImmune System Fetus is an allograft Genetically different to the mother Non-specific suppression of the local immune response at the materno-fetal interface Transfer of antibodies IgG crosses the placenta Haemolytic disease Antibodies for ABO do not cross Antibodies of Rhesus do cross Graves disease and Hashimoto’s Thyroiditis Antibodies will cross the placenta and either stimulate TSH receptors on or destroy developing fetal thyroid respectively. During pregnancy supresion of immun system. Historically, pregnancy was considered an immunosuppressive state   

23 Urinary System Renal plasma flow increases Glomerular Filtration Rate (GFR) increases Filtration capacity intact Functional renal reserve decreases as GFR increases Urinary Stasis Progesteronerelaxes the smooth muscle in the walls of the renal pelvis & ureters, which can result in stasis, hydronephrosis, hydroureter, UTIs & pyelonephritis. Pyelonephritis can induce pre-term labour. What are the effects of pregnancy on renin angiotensin aldosterone system, prostacyclins & erythropoietein?

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25 Urinary System Renal plasma flow increases Glomerular Filtration Rate (GFR) increases Filtration capacity intact Functional renal reserve decreases as GFR increases Urinary Stasis Progesteronerelaxes the smooth muscle in the walls of the renal pelvis & ureters, which can result in stasis, hydronephrosis, hydroureter, UTIs & pyelonephritis. Pyelonephritis can induce pre-term labour. What are the effects of pregnancy on renin angiotensin aldosterone system, prostacyclins & erythropoietein?

26 The effective renal plasma flow (ERPF) is increased by at least 6 wks gestation by 60-75% This increase is proportionally greater than the increase in cardiac output, presumably reflecting specific vasodilatation, probably via the increased renal prostacyclin synthesis. GFR also increases, by ∼50% by the 9th week This differential changes in ERPF and GFR in late pregnancy suggest a mechanism acting preferentially at the efferent arterioles, possibly angiotensin II. The renal system

27 Renal hormones Renin-angiotensin system: is activated from very early pregnancy Erythropoietin synthesis appears to be stimulated by hCG& its concentration rises from the first trimester, peaking in mid- gestation and falling somewhat thereafter. Prostacyclin is a potent vasodilator, synthesized mainly in the kidney. Concentrations begin to rise rapidly by 8–10 weeks gestation.

28 Respiratory System Diaphragm is displacedA-P and transverse diameters of thorax increase O2 consumption increases 20% Decreases functional residual capacity Vital capacity unchanged Tidal volume increases Respiratory minute volume increased Alveolar ventilation rate increased Respiratory rate unchanged ?

29 Lung Volumes TV TLC IRV ERV FRC RV VC IC

30 During pregnancy there is a physiological hyperventilation driven by progesterone, so the mother can blow off the extra CO2 the fetus produces.   This leads to respiratory Alkalosis   2,3-DPG (2,3-Diphosphoglycerate) is an organophosphate, which is created in erythrocytes during glycolysis. The production of 2,3-DPG is likely an important adaptive mechanism, because the production increases for several conditions in the presence of diminished peripheral tissue O2 availability,An increased concentration of DPG in red blood cells favours formation of the T, low-affinity state of hemoglobin and so the oxygen-binding curve will shift to the right (2,3-DPG bound to deoxyHb).

31 RESPIRATORY TRACT Pregnancy is associated with substantial increase in blood flow and tidal volume, this will facilitate gas transfer which leads to a reduction in PCO2 by % with slight increase in PO2 (respiratory alkalosis), but this is compensated for by the buffering systems (increase conc of carbonic anhydrase in RBC & increase renal excretion of bicarbonate) During pregnancy increase conc of 2,3-DPG in RBC so shifting of O2-Hb dissociation curve to the right (facilitate release of O2 from RBC so increase availability of O2 to tissues.

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33 What is the effect of pregnancy on chronic respiratory disease eWhat is the effect of pregnancy on chronic respiratory disease e.g asthma? How it could be tested by ventilation tests during pregnancy

34 The gastrointestinal systemConstipation Delayed gastric emptying Heartburn Cholestasis

35 Anatomical Changes (pressure by gravid uterus)Anatomical Changes (pressure by gravid uterus) Alterations in the positions of viscera E.g. appendix moves from RLQ to LUQ as the uterus enlarges Physiological Changes Smooth muscle relaxation by Progesterone GI – Delayed gastric emptying, constipation Biliary tract – Stasis Pancrease – Increased risk of pancreatitis  Why is heartburn is so common during pregnancy especially at late gestation? Cholestasis is almost physiological during pregnancy, how it clinically presents?

36 Endocrinological changes in pregnancyFrom the beginning of conception there are dramatic increases in hormones produced by the fetus, placenta & maternal intrauterine tissues. These may have paracrine as well as endocrine functions. PROTEINS: Pregnancy-specific: hCG & hPL. Hypothalamus-related: Gn-RH & CRF. Pituitary-related: prolactin, hGH & ACTH Other peptides: Insulin-like GF I&II, Parathyroid hormone- related peptide, 1,25 Dihydrocholecalciferol , Renin & Angiotensin II STEROIDS: oestradiol & progesterone

37 Human chorionic ghonadotrophin:Chemical structure: hCG is a glycoprotein composed of 2 subunits α & β-subunits. α-subunit is not unique to this hormone & it is similar to the α-subunit of LH , FSH & TSH. SOURCE: almost exclusively the product of trophoblastic tissue especially syncytitrophoblast. Secretion pattern: Normally hCG rises rapidly as early as 6- 8 days post-conception doubles every 2-3 days & reaching a peak at 9-10 wk gestation. It declines after 12 wk gestation to a plateau for the reminder of pregnancy

38 Biological functions of hCG:Signals the ovary to maintain corpus luteum & continues progesterone production. Regulates fetal testicular testosterone production, which is critical in the development of male external genitalia Possesses some TSH-like properties the rapidly rising hCG suppresses secretion of both FSH & LH, thus inhibiting ovarian follicle development by a blunting of response to GnRH. It may be involved in the production of sex steroids by the intrauterine tissues

39 Detection of hCG in the serum or the urine is the basis of pregnancy tests. Serum assays detect pregnacy at 8-12 days of ovulation whereas urine assays at days of ovulation. After delivery at term hCG can normally be detected in maternal serum or urine for up to 4 wk. After first trimester abortion it can be detected for up to 10 days.

40 Human placental lactogenChemical structure: hPL is a non-glycosylated protein. It has partial homology with prolactin & hGH. SOURCE: hPL is secreted by syncytitrophoblast. Secretion pattern: Normally hPL is produced by the placenta as early as 3wk post-conception. Levels increases in maternal circulation up to 34wk gestation & then plateau for the reminder of pregnancy. Biological function: 1)preparing the mammary glands for lactation 2) It plays a part in the diabetogenic effect of pregnancy.

41 Prolactin Chemical structure: it is a non-glycosylated protein.SOURCE: 1. ant. Lobe of maternal pituitary gland 2. ant. Lobe of fetal pituitary gland 3. decidual tissue of the uterus & secreted in amniotic fluid. Secretion pattern: Prolactin levels increase under the influence of estrogen .plasma prolactin begins to rise within a few days of conception and by term maybe 10–20 times as high as in the non- pregnant woman. Biological function: 1) preparing the mammary glands for lactation. 2) decidual prolactin is thought to be important for fluid & electrolytes regulation of AF.

42 Progesterone: Chemical structure: 21-c steroid. SOURCE: It is produced by C.L until 8th-10th wk gestation then the placenta assumes its production until parturition. Maternal LDL cholesterol is the main precursor. Secretion pattern: level is increasing progressively until parturition Biological function: Its primary function is to support pregnancy. It prepares the endometrium for implantation of embryo. It relaxes the myometrium. It prevents rejection of the fetus by maternal immune system. Acts on breast tissue in preparation for lactation Acts on smooth muscles of vascular tree, UT & GIT

43 Cholesterol Pregnenolone progesterone mineralo- corticoid 17-OH-pregnenolone OH-progesterone gluco- DHEA androstendione androgen estrogen

44 Esterogen: Chemical structure: 18-C steroid. SOURCE: Corpus luteum is the main source at beginning of pregnancy which is mainly Estradiol (E2), then placenta takes over. Estriol (E3) accounts for 80% of the esterogen produced during pregnancy. Its synthesis involves integration of metabolic steps in maternal liver, placenta ,fetal liver & fetal adrenal cortex. The later provides immediate androgen precursors for esterogen synthesis. Secretion pattern: significant amounts of E3 produced during second trimester & levels continue to rise until parturition.

45 Estrogen regulates progesterone Biological function: Estrogen regulates progesterone It is involved in the maturation of placenta and most of fetal organs.E3 is an index of normal function of fetus & placenta. Causes myometrial hypertrophy and promotes blood flow within the uterus Regulates fetal bone density Esterogen regulates onset of labour (placental clock theory) Assists in the lactation process

46 The hypothalamus & pituitary glandThe pituitary gland increases in weight by 30% -50%. The number of lactotrophs is increased and plasma prolactin secretion is inceased progressively throughout gestation The secretion of other anterior pituitary hormones is unchanged or reduced e.g GH. ACTH concentrations rise during pregnancy, partly because of placental synthesis of ACTH and of a corticotrophin-releasing hormone (CRH) and do not respond to normal control mechanisms.

47 Thryoid-binding globulin(TBG) production increased T3 increased Thyroid Thryoid-binding globulin(TBG) production increased T3 increased T4 increased Free T4 in normal range due to increased TBG hCG has a direct effect on the Thryoid, stimulating T3 and T4 production TSH can be decreased in early normal pregnancies as a result of negative feedback from T3 and T4 produced due to hCG secretion

48 The thyroid gland hCG may suppress TSH in early pregnancy because they share a common α-subunit. HCG & thyroid hns may have a role in nausea & vomiting during pregnancy, hyperemesis gravidarum may be associated with biochemical hyperthyroidism. TBG concentrations double during pregnancy & iodine requirements increased. Overall for the remainder of pregnancy, free plasma T3 and T4 concentrations remain at the same levels as outside pregnancy (although total levels are raised) and most pregnant women are euthyroid & there is no longer considered to be a physiological, the increase in the size of the gland in iodine-replete pregnant women. So it is a feature of iodine depletion. .

49 The adrenal gland Both the plasma total and the unbound cortisol and other corticosteroid concentrations rise in pregnancy from about the end of the first trimester. Concentrations of CBG double. Excess glucocorticoid exposure in-utero appears to inhibit fetal growth in both animals and humans. However, the normal placenta synthesizes a pregnancy-specific 11b- hydroxysteroid dehydrogenase which inhibits transfer of maternal cortisol. There is marked rise in secretion of the mineralocorticoid aldosterone in pregnancy. Plasma catecholamine concentrations fall from the first to the third trimesters.

50 The parathyroid glands and calcium metabolismCalcium homeostasis changes markedly . Maternal total plasma calcium concentration falls, because albumin concentration falls, but unbound ionized calcium concentration is unchanged. The fetus has higher calcium concentration than the mother . Synthesis of 1,25 dihydroxycholecalciferol increases, substantially promoting enhanced gastrointestinal calcium absorption. Parathyroid hormone (PTH) ,which increases by about one- third, regulates the synthesis of 1,25 dihydroxyvitamin D in the proximal convoluted tubule. placentally-synthesized 1,25DHCC & PTH-related protein is also present in the maternal circulation

51 What is the effect of pregnancy on BMR?Metabolism, nutrition and weight gain in pregnancy The peak energy cost is estimated at 2000 cal/day in late pregnancy which is fairly easily met and do not require a major adjustment of calorie intake. The only dietary requirements which may need supplementation are calcium and iron. Average total weight gain is 12.5 kg (7-17kg). Weight gain at around 0.5 kg/wk for the last 20 wk fetus and placenta (5kg) increased body fat (3-4kg) uterus and breasts (1.5kg) blood (1 kg), ECF (1kg). What is the effect of pregnancy on BMR?

52 Carbohydrate Metabolism Glucose and amino acid metabolism are altered in pregnancy to favour nutritional supply to the fetus. The fat which is laid down in the first half of pregnancy in the mother helps meet the demands of the fetus later in the pregnancy when the fetus is most demanding, metabolically. Progesterone stimulates appetite in the first half of pregnancy and diverts glucose into fat synthesis. Oestrogen stimulates an increase in prolactin release, which, along with other hormones, generates a maternal resistance to insulin. Maternal glucose usage thus declines and gluconeogenesis increases, maximising availability of glucose to the fetus.   In later pregnancy, the mother’s energy needs are met by metabolising peripheral fatty acids.

53 After mid-pregnancy Resistance to the action of insulin develops progressively and plasma glucose concentrations rise. Glucose crosses the placenta readily and the fetus uses glucose as its primary energy substrate, so this rise is presumably beneficial to the fetus. Fetal and maternal glucose concentrations are significantly correlated. The insulin resistance is presumably largely endocrine-driven, possibly via increased cortisol or hPL.

54 Carbohydrates/insulin resistancePregnancy is hyperlipidaemic & glucosuric. By 6–12 weeks gestation FBS concentrations fall, and by the end of the first trimester the increase in blood glucose following a carbohydrate load is less than that outside pregnancy. This increased sensitivity stimulates glycogen synthesis and storage, deposition of fat and transport of amino acids into cells.

55 Maternal insulin is a major factor in controlling the metabolic response to pregnancy. The rate of secretion of insulin (both basal and stimulated) normally increases as pregnancy proceeds. The ability of pancreatic-cells to meet this increased demand for insulin secretion is achieved by -cell hyperplasia and hypertrophy as well as the increased rate of insulin synthesis in the -cell. In some women, the endocrine pancreas is unable to respond to the metabolic demand of pregnancy and the pancreas fails to release the increased amounts of insulin required. As a consequence there is a loss of control of metabolism, blood glucose increases and diabetes results (Gestational Diabetes). After birth, when the increased metabolic demands of pregnancy are removed and hormone levels change, the endocrine pancreas can respond adequately and the diabetes disappears. Women who experience gestational diabetes are more likely to develop overt diabetes later in life.

56 Placental transport of glucose Facilitated diffusion Pregnancy increases maternal peripheral insulin resistance after mid-pregnancy Mother switches to gluconeogenesis and alternate fuels Achieved by Human Placental Lactogen Also prolactin, oestrogen / progesterone, cortisol Decrease in fasting blood glucose Increase in post-meal (post-prandial) blood glucose Does the presence of glycosurea during pregnancy always indicate pathology?

57 Increase in lipolysis from T2 Lipid Metabolism Increase in lipolysis from T2 Increase in plasma concentration of free fatty acids on fasting Free fatty acids provide substrate for maternal metabolism, leaving glucose for the fetus Increased utilisation of free fatty acids increases the risk of Ketoacidosis Combined with pregnancy’s state of compensated respiratory alkalosis this can be extremely bad.

58 Breasts and lactation After the second month of pregnancy the breast progressively increase in size due to proliferation of glands and deposition of fat. The veins beneath the skin become visible as bluish streaks. The nipple becomes larger and more pigmented and erectile. After the first few months a thick yellowish fluid (colostrum) may be expressed. The primary areola becomes larger and more pigmented Hypertrophied sebaceous glands appear as round elevations _Montgomery’s tubercles. Later in pregnancy a secondary less pigmented areola develops around the primary areola. During pregnancy there are increased levels of estrogen which inhibit the effect of prolactin on the breast, after birth there is a rapid fall in estrogen levels which allow lactation to begin.

59 SKIN CHANGES Generalized hyperemia & vasodilatation of the skin with increased activity of the sweat & sebaceous glands. Skin pigmentation increases e.g chloasma & linea nigra Spider naevi & palmar erythema may occur (high estrogen) Striae gravidarum after the 20th week rapid and excessive stretching of the skin is accompanied by breaking of the underlying connective tissue, giving rise to the characteristic purplish depressions, these occur in the skin of the lower abdomen, buttocks , thighs and breasts. Striae of pregnancy are due to the increased secretion of adrenocortical hormones which cause a decrease in the collagen and ground substance of connective tissue and allows the subcutaneous fibrous tissue to rupture wherever he skin is overstretched. Following pregnancy the striae become silvery white in appearance( striae albicans).

60 REPRODUCTIVE ORGANS Uterus: The high levels of maternal estrogen and progesterone stimulate both hyperplasia and hypertrophy of the myometrial cells increasing the weight of the uterus from 50gm prepregnancy to 1000gm by term and increasing its dimensions from approx.(7.5 *5*2.5 cm) prepregnancy to (28*24*21 cm) at term. In early pregnancy uterine growth is the result of both hyperplasia and hypertrophy at this stage it is independent of the growing fetus and occurs even with an ectopic pregnancy, as gestation increases hypertrophy accounts for most of the increase in uterine size. With increasing gestation intercellular gap junctions develop which allow changes in membrane potential to spread rapidly from one cell to another which facilitate myometrial contraction, in the second half of pregnancy these are painless contractions that are increasingly apparent to the woman as pregnancy advances (called Braxton–Hick’s contractions) and these subsequently become the coordinated contractions of labour.

61 The cervix becomes swollen and softer during pregnancyThe cervix becomes swollen and softer during pregnancy. Estradiol stimulates growth of the columnar epithelium of the cervical canal that becomes visible on the ectocervix called ectropion. The cervix looks blue during pregnancy due to increased vascularity. There is a remodeling of cervical collagen towards the end of pregnancy which aids in the softening of the cervix. The mucus glands of the cervix become distended and more complex and the cervical mucus becomes viscous and opaque and fills the endocervix forming a mucus plug, this has an abundance of leucocytes and acts as an antibacterial and mechanical barrier. The vaginal epithelium becomes thicker during pregnancy with increase rate of desquamation this leads to increased vaginal discharge (leukorrhea) which has a more acid pH and may protect against ascending infection. The vagina increases in capacity and length and becomes progressively more distensible in preparation for delivery.

62 Readings: Obstetrics by ten teachers, 19th edition, by Philip N Baker and Louise C Kenny.