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Female reproductive

Gamete (oocyte) production

  • 6-7 million oogonia at 20 weeks gestation; these are progenitor cells that give rise to the entire population of oocytes through life. Mitosis to expand number
  • 2 million differentiate into primordial follicles at birth (remaining degenerate). These are arrested in meiosis and stay in this condition until just before ovulation (otherwise seen as foreign)
  • 500,000 left by puberty; 300-500 ovulations throughout life. By age 45-55, reduce responsiveness of oocytes to hormones leads to menopause

Hormone regulation –

  • GnRH (gonadotropin releasing hormone) released by the hypothalamus in a pulsatile manner, stimulating production of…
  • LH (Luteinizing) and FSH (Follicle Stimulating) in the AP; act on ovary to produce:
    • Steroid hormones – androgens (testosterone, androstenedione), estrogen (17β-estradiol), progesterone
    • Glycoprotein hormones – Inhibin A and B (regulatory role, esp. FSH)
  • Steroid hormones act on tissues, causing changes in endometrium (uterus), mucous secretions (cervix) and nature of squamous cell epithelium (vagina)
  • Negative feedback loops go back to the H and AP for regulatory control

OVARIAN cycle – process the oocyte goes through in the ovary. In ovulation, the oocyte, zona pellucida and corona radiate are released from the Graafian follicle. What is left behind is the corpus luteum, which functions to accumulate cholesterol and use it to make steroid hormones. It has a limited life time; if fertilization and implantation does not occur, the corpus luteum degenerates into a corpus albicans that is absorbed back into stroma of the ovary. 4 key hormones:

  • FSH: drives differentiation of oocyte
  • LH: stimulates ovulation at day 14 (idealized cycle)
  • Progesterone and estrogen: produced by developing follicle in the theca and granulosa cells

Follicular development is continual. Early stages are independent of gonadotropins (FSH, LH). They then grow and acquire FSH and LH receptors; can now respond to changing levels of gonadotropin.

Process of selection – 5-10 follicles available to be differentiated into a Graafian, but only one actually will as there is competition between them. They start to produce estrogen that has negative feedback onto AP and H (reduces levels of FSH and LH). If the follicle doesn't have enough receptors so that it is sensitive enough to be activated by falling levels of gonadotropin, it won't be selected.


Early follicular phase (selection)

  • FSH stimulates granulosa cells, which proliferate and start to produce estrogen (3 types of estrogen, including estradiol). Estradiol produced from androgen that moves into the granulosa cells after production in the theca cells (stimulated by LH)
  • FSH on the granulosa cells also stimulates the glycoprotein Inhibin B that then reduces FSH
  • Estrogen has autocrine action upon granulosa cells – increases number of FSH and estrogen receptors so the granulosa cells become more sensitive to FSH. So, FSH levels are decreasing but more receptors = increased sensitivity. More estrogen receptors = estrogen action amplified = even more FSH receptors generated (strong positive feedback loop)
  • Paracrine action onto theca cells – increases LH receptors so it can generate more androgen and thus more estrogen

Mid-Late follicular phase

  • In response to LH, there is increase in androgen and progesterone (that rises briefly just before ovulation)
  • Increased build up of estradiol because of positive feedback (increasing number of FSH and estrogen receptors); leads to a surge in estrogen production two days before ovulation
  • If this surge of estrogen gets above a critical level, there is a switch from an inhibitory to a positive feedback loop. Positive feedback – surge in GnRH and thus LH and FSH
  • LH surge acts on the theca cells (to increase androgen production) as well as the granulosa cells (that acquired LH receptors in the late follicular phase). Action of LH on the granulosa cells inhibits the final conversion of androgen to estradiol; estrogen inhibited for a bit before increasing again in the luteal phase

Luteal phase

  • Increased production of progesterone in the granulosa lutein cells (granulosa cells of the corpus luteum). Surge of estrogen and progesterone that both have a negative feedback effect on AP
  • Switchover from Inhibin B to Inhibin A; same action of inhibiting production of FSH at the anterior pituitary


Ovarian cycle hormonal regulation (overview)

  • Pulsatile release of FSH and LH initiates recruitment of follicle
  • Follicle begins producing estrogen
  • Initial negative feedback. If a follicle is selected and grows sufficiently, it will produce large amounts of estrogen
  • Surge of estrogen reaches a critical level; switch to positive feedback, this initiates ovulation
  • After ovulation, corpus luteum generates progesterone and estrogen that work synergistically to have negative feedback on the hypothalamus and anterior pituitary


UTERINE cycle – changes in the endometrial layer of the uterus. The first day of bleeding is the first day of the menstrual cycle as it is the most visible sign.

Menses occurs over the first 4-5 days; the endometrium is lost and sloughed off. There is a dramatic drop in progesterone and estrogen levels from the previous part of the luteal phase, causing contractions of spiral arteries that pull away from the endometrium. There is tissue death as blood flow decreases; dead tissue is shed into vagina causing the menstrual flow.

Proliferative phase – (follicular phase, 5-14) a slow rise in estrogen has a positive regenerative effect on endometrium (promoter of cell growth and differentiation); the layer grows 3-5-fold to a max of 8-10mm. Endometrial glands enlarge and spiral arteries elongate (to support growth of the endometrium). There is also myometrial hypertrophy (thickening of smooth muscle)

Secretory phase (luteal phase 14-26) endometrium ready to accept fertilized egg and prepared for implantation. Progesterone required to maintain endometrium in secretory growth, with further growth inhibited (high progesterone levels during luteal phase=secretory phase). Blood supply increased; spiral arteries elongate and coil to support growth of placenta should implantation occur. Glands also enlarge and secrete glycogen-rich fluids (uterine 'milk').

There is a short premenstrual or ischemic stage where the arteries begin to constrict periodically, triggered by reduction in progesterone. Uterine glands cease to secrete and endometrium is reduced in thickness.

Ovulation – occurs in response to LH surge

  1. With exponential growth, the follicle reaches 20mm diameter in the last 48 hours before ovulation
  2. Graafian follicle gently ruptures due to proteolysis of the basal lamina;
  3. Oocyte and surrounding corona radiata released into peritoneal cavity
  4. The meiotic division is completed and the first polar body is discarded
  5. Fimbriae draw oocyte into the fallopian tube; oocyte lasts just 12-24 hours

Indicators of ovulation

  • Vaginal epithelial cells are usually squamous. At ovulation, there are cornified cells – estrogen causes cells to die and lose their nucleus; they produce glycogen which is broken down to lactic acid (acidic environment). After ovulation there is a return of squamous epithelial cells, maintained by progesterone. Leukocytes (neutrophils) also appear due to tissue damage and to mop up any bacteria.
  • Body temperature is increased during progesterone secretion
  • Cervical mucus is produced in the glands (crypts) of the cervical canal. Low viscosity mucus is stimulated by estrogen, high viscosity stimulated by progesterone.
    • Pre-ovulatory – high viscosity, forms impenetrable plug to sperm. Also high viscosity post-ovulatory
    • Peak of ovulation – low viscosity , elastic, allows sperm to move though it; forms 'fern' pattern when dried

Effects of estrogen in non-pregnant female (produced in the granulosa cells of the developing follicle)

  • Promote development of secondary sex characteristics during puberty and maintenance of these in adult life
    • Onset of menstruation (menarche); together with LH cause ovulation
    • Stimulate growth of external genitalia
    • Stimulate growth of mammary glands and adipose tissue in the breasts; pigmentation of nipples
    • Broader pelvis; shorter period of long bone grown due to early closure of epiphyseal plates
  • Cause characteristic subcutaneous fat deposits (hip and thighs); growth and development of mammary glands
  • Responsible for soft skin (sebaceous glands more fluid)
  • Cause some sodium and water retention
  • Have a plasma cholesterol lowering action
  • Endometrial proliferation, mucus ferning (show estrogen spike presence = fertile), vaginal epithelial cell cornification

In the first half of the cycle estrogen dominates, in the second half, actions of progesterone become apparent. In the luteal phase, high levels of both exert negative feedback on the HPA, suppressing FSH and LH secretion and causing degeneration of the corpus luteum. Levels then fall, and the endometrium that has developed under the influence of these hormones breaks down, leading to menses. If fertilisation has occurred, it is essential that the estrogen and progesterone secretion continue so the endometrium is maintained.


Male reproductive

Testes function to produce and store sperm:

  • Seminiferous tubules are the site of differentiation of stem cells into sperm (spermatogenesis). They empty into the rete testis -> efferent ductules -> epididymis -> ductus deferens
  • Leydig cells outside the ST produce testosterone
  • Sertoli cells in the ST provide the hormonal stimulus and environment required to nurture development of sperm. Tight junctions between these cells prevent easy diffusion between them; to get from basal to apical surface, they generally have to cross the cell membrane (only exception is the sperm cells themselves). This forms the blood-testis-barrier; prevents immune system from attacking sperm (they only have a single copy of each chromosome).
  • Mature sperm are in the lumen of the apical compartment
  • Surrounding smooth muscle cells important in forming pulsatile contractions to move mature cells out of the seminiferous tubules and into the epididymis


Spermatogenesis Mitosis to increase population continues throughout life of the male so there is continued differentiation through adult life (unlike female population of oogonia that is fixed after birth). In the male, meiosis is initiated at puberty and must occur inside the BTB to avoid immune attack. Mitosis occurs outside the tight junction, must migrate past this to undergo meiosis. A tight junction forms behind the spermatagonia and the one in front of it dissolves.

  1. Primordial germ cell
  2. [Spermatogonia-http://php.med.unsw.edu.au/embryology/index.php?title=S] - first cells of spermatogenesis (from mitosis not meiosis)
  3. [Primary spermatocytes-http://php.med.unsw.edu.au/embryology/index.php?title=P] - large, enter the prophase of the first meiotic division
  4. [Secondary spermatocytes-http://php.med.unsw.edu.au/embryology/index.php?title=S] - small, complete the second meiotic division
  5. [Spermatid-http://php.med.unsw.edu.au/embryology/index.php?title=S] - immature spermatozoa
  6. [Spermatozoa-http://php.med.unsw.edu.au/embryology/index.php?title=S] - differentiated gamete

Spermatogenesis is continual and constant (not phasic like in females). It occurs over about 74 days, with 1-10 days in the epididymis maturing and developing maturity. Spermatozoa are stored in the vas deferens and the tail of the epididymis. Each day, 2 million spermatogonia, each one giving rise to 64 sperm cells, begin this process in each testis. Sperm have an acrosome at front of their head, containing enzymes that enable sperm to penetrate and fuse with the egg during fertilization by dissolving the zona pellucida. Mitochondria in the mid-piece generate the ATP required to drive the whip-like movements of the tail. They can survive for weeks in the male tract, and up to 72 hours once ejaculated into the female.

Composition of semen – 2.6 ml per ejaculation (via urethra), pH neutral (7.2-.6)

  • Bulbourethral gland secretions (\~10%) – mucoproteins to neutralise any urine and lubricate the urethra (released prior to ejaculation)
  • Spermatozoa (<10%) – need 50-150 million/mL to be fertile; <20 million/mL is infertile.
  • Prostate gland secretions (20%) – thin and milky, alkaline for neutralisation. Contains PSA (prostate specific antigen), a protease that breaks down clotted semen to allow release, and acid phosphatase to initiate capacitation
  • Seminal vesicle fluid (60%) – fructose and other nutrients to support sperm, fibrinogen to clot the semen (so it doesn't leak out of the vagina), prostaglandins for stimulating rhythmic contractions of the uterus. This is the last volume to be ejaculated, as we don't want the semen to clot during ejaculation

Capacitation is a process of morphological, physiological and biochemical changes during the journey through the female reproductive tract. It must occur before the sperm are capable of penetrating the corona radiata and zona pellucida and fertilizing an ovum. Many sperm are required to dissolve the zona pellucida of the ovum, but only one gets the chance to fertilize

  • Head changes shape
  • Nature of lipid at the head in front of the acrosome changes chemical nature; becomes more sensitive to receptors on surface of zona pellucida, to initiate release of enzymes in the acrosome
  • Motility of sperm greatly enhanced

Hormonal regulation GnRH stimulates production of LH and FSH that then act on the testes:

  • LH stimulates testosterone production in the Leydig cells
  • FSH acts on Sertoli cells to stimulate spermatogenesis and promotes LH receptor synthesis on Leydig cells (increases their testosterone production)

Testosterone has paracrine action on Sertoli cells, stimulating spermatogenesis. It then goes into the circulation and is converted into 5α-dihydrotestosterone in the peripheral tissues; this also acts on the Sertoli cells to stimulate spermatogenesis. It limits its own secretion by negative feedback loop to both the H and AP

  • Inhibin produced by Sertoli cells, and relates to levels of spermatogenesis (low Inhibin=low spermatogenesis). If there is too much FSH there will be too much spermatogenesis and increased Inhibin. This then selectively suppresses the release of FSH by negative feedback to the anterior pituitary
  • Excess testosterone causes negative feedback on the H and AP, resulting in decreased LH and decreased testosterone production
  • Loss of spermatogenesis (castration) leads to decreased Inhibin, reduction in negative feedback, and increased FSH in an attempt to stimulate spermatogenesis

Testosterone actions include:

  • Intrauterine differentiation into male
  • Imprint male pattern of gonadotropins, sex drive behavior
  • Sperm production and seminal fluid secretion
  • Beard growth, larynx changes, muscle mass, skeleton, abdominal visceral fat, sebum formation, prostate
  • Liver – increased VLDL and LDL, decreased LDL

Natural family planning

NFP can be used in helping to conceive or to avoid pregnancy. If taught properly it can be up to 98% effective.

Advantages Disadvantages
* No interference with normal physiology
  • No drugs or devices or required; cost-effective
  • Both partners share responsibility for family planning
  • May improve communication about sexuality
  • Can help sub-fertile couples to conceive
  • Morally and culturally acceptable
* Takes time to learn, recognise and chart symptoms
  • Requires initial teaching
  • Fear of unplanned pregnancy during learning phase
  • Both partners require motivation and commitment
  • Abstinence during fertile phase
  • No protection against STDs
  Estrogen

\[pre-ovulatory (follicular) phase\]

Progesterone

\[post-ovulatory (luteal)\] safest for protected sex

Endometrium Thicker Secretes nutrients in preparation for implantation
Cervix Higher, softer and open Lower, firmer and closed
Cervical mucus 'Sperm-friendly' – increased salts, sugar and amino acids for nourishment, 98% water. Transparent, slippery and stretchy 'Hostile' – dense network of filaments form a thick sticky plug impeding penetration
Temperature Remains at lower level Raised by 0.2-0.5·C

Indicators of fertility:

  • Waking temperature – rise in basal body temperature indicates ovulation. A sustained rise for 3 days indicates 48 hours past ovulation (determines onset of post-ovulatory infertile phase). Temperature gives no indication of the onset of the fertile phase
  • Cervical mucus changes – observed at the vulva, recorded at end of each day. Dryness indicates infertility, dampness is potential fertility, and a sensation of wetness indicates maximum fertility. Cervical mucus changes gives the most accurate means of timing intercourse to optimise chance of conception
  • Changes in the cervix – low, long, tilted, firm, close and dry indicate infertility
  • Calculation of cycle length – measured from the first day of a period (fresh red bleed) up to but not including the first day of the next period. Can be used to double check in identifying last day of the pre-ovulatory infertile phase. Ovulation occurs 12-16 days before the following menstruation;
    • Shortest cycle – 20 = last infertile day
    • Longest cycle – 10 = last fertile day
  • Minor indicators (least reliable)
    • Ovulation (Mittelschmerz) – sharp pain or dull ache on one side of the lower abdomen for <few hours
    • Breast symptoms – characteristic tenderness or tingling around ovulation
    • Spinnbarkeit – property of mucus allows it to stretched and drawn into a thread (>10cm at ovulation)

Rat prac – effects of sex hormones on the reproductive tract:

  Uterus (% of total body weight) Vaginal epithelial cells
Progesterone 0.2%, less growth, less blood flow and fluid accumulation Predominantly nucleated epithelial cells (blue-green with pink nuclei). Different to leucocytes (also green, but smaller)
Estrogen 0.7%, uterus larger, as growth is encouraged, increased blood supply and fluid content Predominantly large squamous cornified epithelial cells (orange-red)

Pregnancy tests use the presence of human chorionic gonadotrophin (hCG) in the urine. Monoclonal antibodies specific to the β-subunit on hCG form an antigen-antibody complex, appearing as the 'test band'. Antibody specificity enables the test to distinguish between other similar glycoprotein molecules – LH, FSH and TSH

Maternal physiology

The peptide hormones – hCG is secreted by the conceptus and acts on the maternal ovaries to prevent the disintegration of the corpus luteum, thereby maintaining progesterone production (necessary in pregnancy). It appears early and decreases after 10 weeks; the basis of pregnancy tests. HPL affects maternal metabolism; decreases insulin sensitivity and decreases glucose utilization to ensure adequate fetal nutrition. It increases gradually in proportion to placental mass.

'Weight gain:' approximately 12.5kg, mostly in the second half of pregnancy:

* Fetus (3.5)
  • Placenta (0.65)
  • Amniotic fluid (1)
  • Uterus (1)
* Breasts (0.5)
  • Plasma, red cells and fluid retention (2)
  • Maternal fat (4) – variable


Renal function:

  • Renal blood flow (30%) and renal plasma flow (45%)
  • Glomerular filtration rate (50%) – due to increased RPF and fall in colloid osmotic pressure
  • Plasma creatinine and urea – fetus producing it; easily crosses the placenta to be excreted if low in mother
  • Tubular function changes
    • ↓ Reabsorption of filtered glucose leads to glycosuria. Massive GFR ↑ leads to imbalance between increased filtration and inability to reabsorb
    • Amino acid excretion as tubular reabsorption is limited
  • Sodium retention (900mmol) – retention outweighs loss
Loss promoted by Retention promoted by
Rise in GFR

Expanded plasma volume Progesterone rise (anti-aldosterone effect) Prostaglandin rise

Activation of renin-angiotensin system

Rise in aldosterone Estrogen Cortisol

  • Water retention– retain more water relative to sodium; left shift of threshold for AD release, diuresis after delivery
  • Dilation of renal pelvis and ureters due to progesterone. More volume so more prone to UTIs
  • Bladder symptoms start early in pregnancy (week 6) and then subside. Recurs later due to bladder compression. Frequency (day and night), sensitive due to increased blood flow and irritation by enlarging uterus.

Blood volume and composition:

  • Total blood volume –by about 1.5L (30-40%), mostly by 34 weeks
  • Plasma volume –by 1.25L (45%)
  • Red cell mass –by 240ml if no iron supplements, 400mL if iron given (18-30%)
  • Anaemia – physiological anaemia of pregnancy, or dilutional (plasma increasing more than red cell mass). The haematocrit falls from 40 to 31%; Hb concentrations fall from 13.5 to 11-12%
  • Total oxygen carrying capacity, also increase in oxygen consumption (but not as much, the mother overcompensates). Arterio-Venous oxygen difference increases
  • White cell count from 7000 to 10-11,000/µl, mainly due to neutrophils
  • Total plasma proteins, but concentration actually falls (from 7 to 5.5-6g/100ml) because plasma volume is increased. The albumin/globulin ratio falls as globulins (angiotensinogen, transferrin, thyroid binding globulin, coriticosteroid binding globulin) are increased, stimulated by estrogen. This affects colloid osmotic pressure (determined by number of particles), glomerular filtration rate (increased) and oedema (more prone to)
  • Blood coagulates and clots more readily, due to estrogen stimulating the liver:
    • Fibrinogen, clotting factors II, VII, VIII, IX, X and platelet turnover increases
    • Anti-thrombin III falls (inhibits action of clotting factors 9-12)
    • Fibrinolysis falls – once clots form, they don't degenerate as quickly

Cardiovascular changes: mostly primary events, not secondary to demand (happens before it's needed)

  • Blood pressure (BP= CO x TPR) should fall in mid pregnancy, rising to normal at term as CO↑ but TPR ↓
    • Cardiac output (CO= SV x HR) by about 1.5 L/min, with a plateau in late pregnancy
      • Stroke volume from 64 to 71mL
      • Heart rate from 70 to 85bpm
    • Total peripheral resistance, mainly because of vasodilation (due to E, P and prostaglandins)
  • Venous pressure in lower limbs leading to hemorrhoids, ankle oedema, varicose veins
    • Mechanical compression of IVC by uterus
    • Haemodynamic effect due to increased uterine blood flow –venous return from the uterus AND maternal blood from limbs both trying to enter the IVC
    • Veins more distensible– effect of progesterone causing dilation
  • Supine hypotension (a pregnant woman is lying on her back – uterus pressure on venous return )
  • Blood flow distribution changes, with increases to –
    • Breast
    • Uterus – increases progressively throughout pregnancy; early pregnancy 50 ml/min, late 700 ml/min
    • Skin – dissipate heat that the fetus and increased metabolism produces
    • Kidney – blood flow increases around 30%; more waste to excrete

Respiratory changes:

  • Minute ventilation (up to 50%) (volume of gas exhaled from lungs per minute)
    • ↑Tidal volume (volume of gas inhaled and exhaled during one respiratory cycle, depth of breathing)
    • – Respiratory rate unaltered
  • PaCO2 (level of CO2 in maternal blood) to about 30mmHG at term, due to progesterone and increase in ventilation. A lower level in the mother is better for the fetus as diffusion if facilitated
  • Thoracic ligaments soften and allow more expansion of the thoracic cage – costo-vertebral angle widens
  • Diaphragm elevated around 4cm – relaxant effect of progesterone and increasing abdominal contents
  • Residual volume(gas remaining in lung after maximum exhale) by 20%, and ↓Functional residual capacity
  • FEV1

GIT changes:

  • Maternal appetite
    • Progesterone – orexigenic (stimulates appetite)
    • Leptin resistance (normally decreases appetite)
  • 'Morning sickness' – feelings of nausea and vomiting, possibly due to estrogen; usually subsides
  • Motility and constipation; progesterone slows muscle contraction > ↑ transit time and ↑ water reabsorption
  • ↓Reduced lower esophageal sphincter tone – reflux and heart burn
  • ↑Gallbladder stone formation due to impaired gallbladder contraction and increased volume
  • ↑ saliva secretion
  • ↑ iron and calcium absorption
  • – Liver size unaltered and plasma alkaline phosphatase elevated (usually a marker of liver disease).

Metabolic change: ↑ metabolic rate Carbohydrate metabolism

  • ↓Blood glucose levels in 1st trimester, as more is going to the fetus
  • ↑Insulin levels in 3rd trimester – maternal insulin resistance to preserve it for the fetus
  • Insulin resistance develops in late pregnancy. Changes mainly due to human placental lactogen:
    • ↓peripheral insulin sensitivity (increased insulin resistance)
    • Mobilizes free fatty acid from fat stores – mother can utilize fatty acids so fetus can have glucose
    • Free fatty acids converted to glucose which is transported to the fetus

Protein, high protein diet necessary; ↓ plasma amino acid Fat, main maternal energy store

  • ↑Plasma free fatty acids and cholesterol
  • ↓Glycogen stores; ketosis may occur – an 'accelerated starvation' response

Fetal physiology

GROWTH happens in the fetal period (week 9-40); 95% of weight is gained through this period. Mean birth weight for non-indigenous Australians was 3.48kg for males and 3.34kg for females. Indigenous figures were lower (3.24, 3.13). LBW (<2.5kg) and VLBW (<1.5kg) can be due to prematurity or growth retardation (born at term but small for gestational age). LBW babies have increased mortality and morbidity. There is an inverse relationship between birth weight and adult disease like hypertension and diabetes.

Fundal height gives an index of growth rate. Week 12: just palpable above the symphysis pubis; week 20-22: level of umbilicus; week 36: level of xiphisternum. At week 40, fundal height actually drops as that baby's head points downwards into the pelvis in preparation for birth.

At 28 weeks, the fetus is about half of the weight of the conceptus. It forms a larger proportion as gestation proceeds. Placental weight increases slowly then hardly changes during the last month. Amniotic fluid volume increases until about 34 weeks then declines, possibly contributing to the drop in fundal height.

Body composition: total body water falls from 95% in young fetus, to 85% at 32 weeks, to 70% at term. Protein accumulation reaches a maximum (about 300g) at 35 weeks. Fat accumulation begins at about 32 weeks. Fat exceeds the weight of protein by 38 weeks.

Growth potential is determined by the genome, but influenced by:

  • Nutrient supply and space (limits growth)
  • Hormones and tissue growth factors (stimulates growth)
Fetal factors Maternal factors Placental
Genetic:
  • Chromosome abnormalities frequently associated with reduced birth weight (Trisomy 21, Turner's syndrome)
  • Single gene loci may influence birth weight eg. cystic fibrosis
  • Sex - males tend to be larger
  • Different races have different mean birth weights
  • Rough correlation between birth weight and the height and weight of parents.

Hormones: most importantly insulin-like growth factors (IGF1, IGF2) Fetal infection – rubella and CMV are associated with growth retardation

* Maternal constraint
  • Same mother produces offspring of a similar size regardless of paternal genotype
  • Multiple pregnancy (smaller)
  • Maternal age (teenagers tend to have small babies)
  • Parity (primiparous have smaller babies than multiparous)
  • Maternal nutrition
  • Smoking, drugs and alcohol (growth retardation)
  • Maternal diseases - especially associated with impaired circulation, chronic illness
  • Uterine abnormalities and site of implantation (less vascular if lower uterine segment)
True placental insufficiency is unlikely to affect fetal growth before the 7th month. There is a correlation between weight of fetus and placenta towards term

PLACENTA: discoid, 3cm thick, 15-20cm diameter, containing approximately 200 lobules. Fetal villi are suspended into the maternal intervillous spaces and bathed in maternal blood; Maternal arterial supply is from spiral arteries which terminate at the basal plate. Blood is ejected into the intervillous space in funnel shaped spurts and exits by endometrial veins. Functions of the placenta

  • Secretion of hormones to maintain pregnancy; estrogen, progesterone, hCG and hPL
  • Exchange of heat, gases, water electrolytes, nutrients, urea, bilirubin
  • Metabolism; converts glucose to lactate, oxidizes catecholamines
  • Immunological barrier

PLACENTAL EXCHANGE of gases and nutrients –

  • Oxygen transfer by passive diffusion. Maternal PO2 = 90-100 mmHg; fetal PO2 umbilical artery 15mmHg, umbilical vein 30mmHg. The placenta uses 45% of the O2 that is transferred (PO2 = partial pressure of O2 in blood)
  • Carbon dioxide transfer by passive diffusion. Fetal PCO2 (53mmHg in umbilical artery) is higher than maternal (30)
  • Water freely crosses the placenta and membranes down osmotic gradients
  • Glucose transfer by facilitated diffusion. It supplies at least 50% fetal calories; 70% of glucose taken up is used by the placenta. Some is converted to lactate (25% fetal calories) in the placenta
  • Amino acids provide 25% of fetal calories and are important for new protein synthesis. Most (except histidine) are transported actively from maternal plasma into the placental cytosol
  • Fatty acids are important for cell membranes, brain development, and use as a surfactant (reduces surface tension). At least 50% are maternally derived (though some are synthesised) and transferred passively as fetal plasma levels of free fatty acids, cholesterol, triglycerides and phospholipids are lower than maternal
  • Urea is passively transferred from the fetus to mother

FETAL CIRCULATION – in the adult the RV and LV each pump the same amount of blood and act in series; in the fetus they pump different amounts of blood and work in parallel. This is done by 2 shunts - the foramen ovale and the ductus arteriosus. Combined cardiac output (CCO) in the fetus is considered to be the sum of the outputs of both ventricles (the RV pumps 2/3; LV pumps 1/3 so wall of the RV is thicker in the fetus).

Blood is oxygenated at the placenta instead of the lungs. At least 40% of the CCO goes to the placenta via the umbilical arteries. Well oxygenated blood (saturation 80-85%) returns to the fetus via the umbilical vein. From the umbilical vein, 55% flows through the ductus venosus (bypasses liver) and 45% goes to the left and right lobes of the liver.

Blood shunted through the ductus venosus joins IVC, but doesn't completely mix with blood returning from the lower body. The posterior left stream in the IVC (40% of IVC return) is blood that has come from the ductus venosus; the anterior right stream (60% of IVC return) is blood that has come from the lower body. The well oxygenated (posterior left) stream tends to flow through the foramen ovale and into the left atrium (about 27% of venous return). It is mixed with a small amount of blood returning from the lungs (7% of combined cardiac output). It then enters the left ventricle. Blood entering the ascending aorta from the left ventricle (about 35% of the combined cardiac output) has an O2 saturation of about 60-65%. This blood supplies the head and upper body (20%) and the heart (3%). 10-15% continues in the aorta.

Blood from the poorly oxygenated stream of the IVC, as well as blood from the SVC, enter the right atrium and then the right ventricle. Blood leaving the right ventricle (about 65% of the combined cardiac output) has an O2 saturation of about 50-52%. From the pulmonary artery, about 7% of the combined cardiac ouptut goes to the lungs. The rest of the blood leaves the pulmonary artery via the ductus arteriosus which enters the aorta below the exit of the left subclavian artery. Thus blood in the descending aorta has an O2 saturation of about 55-58%. This blood supplies the rest of the body (including the placenta).

  • In the adult all systemic arteries have the same PO2, but in the fetus, arteries which come off the aorta proximal to the ductus arteriosus have a higher PO2 (Saturation 60-65 %) than those which are distal (Saturation 55-58%)
  • Fetal CCO much higher than adult
  • Fetal arterial pressure is about half adult values
  • Fetal heart rate is faster than in the adult.
  • Fetal kidneys only receive 2-3% of the combined cardiac output.

AMNIOTIC FLUID surrounds the fetus. It is formed from fetal urine and lung liquid (a clear colourless liquid produced by the lungs; isosmotic with plasma; high chloride content; either swallowed directly or enters the amniotic cavity). Fluid leaves the amniotic cavity via

  • Fetal swallowing (200-1000 ml/day associated with fetal breathing movements; needed in gut development)
  • Equilibration across the membranes with maternal and fetal plasma

Functions

  • Protection against trauma
  • Allows symmetrical growth
  • Stops the amnion sticking to the fetus
  • Important for lung development
  • Allows limb movement, swallowing and breathing movements
  • Potential source of fluid and electrolytes to the fetus
  • Maintains constant body temperature


Newborn adaptation to extra-uterine life

Cardiovascular changes at birth result in conversion from fetal to adult circulation: Removal of the placental circulation (closure of the umbilical artery) Contraction of the umbilical cord muscle layers close off the umbilical artery. In order of importance

  Effect of contraction Stimulus to contract
Longitudinal \*\*\* Lumen becomes non-circular, vessel shortens Stretch
Small coiling\* Provides twist to complete closure of a narrow area of artery Temperature drop (27˚C)
Helical Coiling of cord Stretch, high PO2
Circular Narrows lumen, lengthens vessel High PO2, NE,E, ADH

Stretch and drop in temperature are inevitable with delivery; this facilitates closure of the artery.

LSC HC -

Closure of the ductus venosus and umbilical vein Both are thin walled and probably close passively – as blood flow through them ceases, the lumen collapses. There is no problem with retrograde flow, and permanent closure of the DV usually occurs by 3 months.

Increase in pulmonary blood flow as lungs become functional With the first breath, air replaces the fluid in the lungs (fluid expelled or absorbed into circulation and lymphatics). Expansion of the alveoli with oxygen causes "uncoiling" of the pulmonary vascular bed and the high PO2 of air causes dilation of the pulmonary vasculature (fall in PCO2 may also contribute). Thus, pulmonary vascular resistance falls and pulmonary blood flow increases (8-10 fold). Closure of the foramen ovale Although functionally closed quite quickly, anatomical closure may take up to a year or more, and in 10% of adults a probe may be passed through it. Two main factors contribute to its functional closure:

  • As umbilical flow ceases, the venous return via the IVC decreases. The stream of blood that kept the foramen ovale open is removed, and the valve tends to fall back onto the crista dividens
  • Increased pulmonary blood flow after the baby has breathed causes an increase in pulmonary venous return and therefore an increase in blood flowing into the left atrium, helping close the valve

Closure of the ductus arteriosus ↓ pulmonary vascular resistance and ↑systemic vascular resistance (due to loss of placental circulation) causes flow through the DV to reverse i.e. blood flows from the aorta into the pulmonary artery. This left-to-right shunt is the transient/neonatal circulation, lasting for minutes to hours.

Constriction of the DA stops this reversed flow, and the circulation is converted to adult circulation with the two ventricles pumping in series. The stimulus for closure of the DA is a high PO2</u> (after closer, hypoxia may result in re-opening). <u>Prostaglandins keep the DA open; they are important for maintaining patency in utero. Inhibition of prostaglandins (e.g. by indomethacin) is used therapeutically to close the DA in neonates, as persistent DA can cause pulmonary hypertension.

  1. Gradually over the first year the wall of the left ventricle becomes thicker than the wall of the right ventricle; adult ventricular weight relationships are reached.

Respiratory function of the newborn As blood can no longer be oxygenated by the placenta, the lungs must be functioning after birth. This involves:

  • Surfactant – reduces surface tension to ensure the alveoli can be inflated and remain open (necessary for gas exchange). Surfactant consists of phospholipds (90%) and proteins (10%). The enzymes necessary for surfactant synthesis are in fetal lungs from 18-20 weeks onwards, but maturation of surfactant production occurs mainly in the last 4 weeks. Surfactant is produced by the Type II alveolar cells, stimulated by cortisol. Insufficient surfactant production is a problem for premature infants, as greater respiratory effort is necessary for lung expansion (may result in respiratory distress syndrome)
    • Corticosteroids are given to the mother; these will cross to the baby and help mature the surfactant.
    • Surfactant can also be given postnatally; natural surfactants (from animals) are more effective than synthetics, as they contain surfactant proteins (synthetic contain phospholipids only).
  • Regular and continuous breathing – in utero the fetus practises episodic breathing movements. Stimuli for the first breath after birth are an increase in general arousal (tactile (touch), ↓temperature, auditory, visual, gravitational, noxious). Elastic recoil following release of thoracic compression during birth, asphyxiation and increased chemoreceptor sensitivity may contribute.
    • For the first breath, high negative intrathoracic pressures may be generated; subsequent breaths require less pressure. Air becomes progressively trapped in the lungs forming the functional residual capacity
    • Instability of breathing control is particularly a problem in premature infants, sometimes involving apnoea (transient cessation of breathing)
  • Surface area for gaseous exchange needs to be adequate. After 26 weeks, this is not generally a problem except in extreme circumstances like diaphragmatic hernia.

Maintenance of body temperature is difficult in newborns:

  • No behavioural modification – can't shiver, exercise, put on more clothes, move to a warm place etc
  • Large surface area to body weight ratio = high radiant heat loss
  • Lacking thick layer of subcutaneous fat for insulation
  • Wet skin following delivery = high evaporative loss

The main mechanism neonates use to produce heat is chemical thermogenesis (nonishivering thermogenesis), by the oxidation of brown fat. Brown fat is found between the scapulae, behind the sternum, in the nape of the neck and around the kidneys. Brown fat cells have a central nucleus, multiple fat vacuoles, many mitochondria and are supplied by sympathetic nerves. β-receptor stimulation activates the breakdown of triglycerides to free fatty acids and glycerol. Free fatty acids are oxidized in the mitochondria; instead of generating ATP by oxidative phosphorylation, there is uncoupling of metabolism and ATP production so that more heat is produced.

Temperature maintenance is particularly a problem for premature infants:

  • Higher thermoneutral zone (range where you are the most comfortable); decreases with postnatal age
  • Even less fat stores
  • Even higher surface area to body weight ratio
  • Cold stress increases neonatal mortality; it may lead to decompensation (functional deterioration) if the neonate has other problems
Therefore these babies are kept in the controlled environment of incubators which minimize heat losses.

'Neonatal nutrition – 'in utero, the fetus has a continuous infusion of glucose, amino acids and fatty acids from the mother. In the last trimester:

  • Glycogen stores laid down in the liver, muscle, heart, lungs and adipose tissue, stimulated by cortisol. Cardiac glycogen stores are 10x adult levels, 3.5x for skeletal muscle stores
  • Induction of liver gluconeogenic enzymes, also stimulated by cortisol. These enzymes are present in the liver by 4 months gestation, not turned on until birth (e.g. phosphopyruvate carboxylase activity is only 10 % of adult activity in the term neonate, but then increases rapidly).
  • Fat stores are laid down (560g at term).

After birth, glucagon levels are high, insulin levels are low and catecholamine levels are high. Stores of glycogen and lipid are utilized until adequate milk intake is achieved. This is limited though, so if additional energy is required (e.g. in cold or respiratory distress), then neonatal hypoglycaemia may occur, a major preventable cause of brain damage. After birth, plasma glucose declines in all infants, then rises slowly over the next few hours. The lower limit of normal plasma glucose is 1.7mmol/l, but there may be no obvious clinical signs until levels fall below 1.1mmol/l (when convulsions and apnoea occur).