Overview
This lecture covers the maternal physiological adaptations of pregnancy: growth and contractile behaviour of the uterus (including the Ferguson reflex and postpartum involution), mammary gland development, the cardiovascular changes that redistribute and expand maternal blood flow (including fetal circulatory shunts and the vascular basis of preeclampsia), increased blood coagulation to limit blood loss at delivery, respiratory changes that support fetal gas exchange, metabolic adaptations (weight gain, insulin resistance and gestational diabetes, leptin resistance), and cervical remodelling in preparation for labour. The systems are linked by a common driver, rising estrogen (and other steroid/peptide hormones), which primes the uterus, cervix and maternal metabolism for pregnancy, delivery and lactation.
1. Reproductive organ changes
Uterine growth
- Mass: 50 g (non-pregnant) -> 900 g at term
- Growth mechanism: hyperplasia (increased cell number) and hypertrophy (increased cell size), driven by estrogens
- Myometrial cells elongate from 50 to 500 µm
- Internal capacity: ~50 ml -> ~5 L
- Dextro-rotation: the uterus rotates to the right because the rectosigmoid colon lies on the left
- Lower uterine segment forms after 12 weeks; dilates and thins in labour, unlike the upper segment
- Braxton Hicks contractions: normally painless, may be mistaken for false labour
Myometrial contractions
- Smooth muscle cells are connected electrically by gap junctions, so the myometrium behaves as a coordinated syncytium
- Braxton Hicks contractions (2nd/3rd trimester): infrequent, irregular, mild
- Birth contractions: frequent, regular, rhythmic
- [slide does not elaborate: the mechanism that triggers Braxton Hicks contractions is posed as an open question, not answered]
Ferguson reflex (positive-feedback loop that drives labour contractions)
- Cervical stretching during labour stimulates the cervix/reproductive tract
- Afferent signal travels via the spinal cord dorsal horn
- Ascends the anterolateral columns (ipsilateral and contralateral)
- Passes through the brainstem and medial forebrain bundle
- Reaches the hypothalamus (paraventricular and supraoptic nuclei), increasing firing along the hypothalamo-hypophyseal tract
- Posterior pituitary releases oxytocin into the blood
- Oxytocin acts back on the uterus/cervix, increasing myometrial contraction, which further stretches the cervix (positive feedback)
- Myometrial oxytocin receptors increase ~100-fold by late pregnancy, in response to high estrogen levels
Uterine involution (postpartum recovery)
- Occurs over 6 weeks postpartum
- Loses 50% of its weight within the first week; nearly normal size by 4 weeks
- Promoted by breastfeeding
Mammary gland development
- Stages: Prepubertal -> Puberty -> Early Pregnancy -> Late Pregnancy (lactogenesis) -> Lactation
- Prepubertal: duct growth, limited branching
- Puberty: duct branching, layered epithelium (secretory and myoepithelial cells), fat deposition, cyclical growth/regression
- Early/late pregnancy (lactogenesis): duct sprouting and branching, loss of adipose tissue, alveolar formation, little milk production
- Lactation: full alveolar development, copious milk secretion
- Driving hormones: oestradiol and progesterone rise cyclically at puberty, then rise steadily through pregnancy, peaking at term and dropping sharply at lactation onset; prolactin has a small cyclical puberty bump, rises steadily through pregnancy to a peak at term, drops sharply after birth, then partially recovers during lactation
2. Maternal blood flow and fetal circulation
- Placenta at term requires ~625 ml blood/minute
- Maternal blood volume increases up to 40%, due to greatly increased water balance/body fluid
- Blood flow is redistributed: uterus 2% -> ~20% of flow, plus increased flow to the mammary gland and skin (for fetal heat loss from active fetal metabolism)
- Cardiac output increases from 4 to 7 L/min, due to increased heart rate and stroke volume
Fetal circulatory shunts (bypass the non-functional fetal lungs and partly the liver):
- Ductus venosus: diverts some blood past the liver, most passing to the right atrium via the inferior vena cava
- Foramen ovale: shunts most blood from the right atrium to the left atrium (and ventricle), bypassing the lungs; oxygen-rich blood is then sent to the brain, heart and body via the aorta
- Ductus arteriosus: shunts spent (deoxygenated) blood past the lungs into the descending aorta and umbilical arteries
Uterine vessels and preeclampsia
- Uterine artery and vein diameter triples in pregnancy
- Normal pregnancy: trophoblast invasion remodels and widens the spiral arteries, funnelling blood into the placental villi
- Preeclampsia: this remodelling fails to occur adequately, leaving narrower, less-remodelled spiral arteries
- Early symptoms of preeclampsia: high blood pressure, protein in the urine
3. Blood coagulation
- Prepares for blood loss at birth (~500 ml lost during normal vaginal delivery)
- Ovarian/placental steroids induce:
- increased platelet aggregation
- increased coagulation factors
- decreased fibrinolytic activity
4. Respiratory system
- Hyperventilation: minute volume increases 50%, to supply oxygen for the fetus and for increased maternal metabolic rate
- Progesterone increases sensitivity to CO2, lowering pCO2 from ~40 to ~30 mmHg, which encourages CO2 diffusion from the fetal circulation across the placenta into the mother
- This causes respiratory alkalosis (raised blood pH from low CO2), which is minimised because the kidneys excrete extra bicarbonate to compensate
5. Metabolism
Substrate demand and weight gain
- Metabolic substrates are needed for: placental growth, fetal growth, maternal energy reserves for lactation, and increased body temperature
- It is appropriate to gain weight during pregnancy: ~3.4 kg fat is typically added
- Energy cost of pregnancy: ~320 MJ (77,000 kcal) total, an average of ~1.2 MJ (300 kcal) extra per day
Modulation by insulin
- Insulin levels rise during pregnancy
- Placental lactogen decreases maternal insulin sensitivity (a type-2-diabetic-like state)
- This raises maternal blood glucose to supply fetal demand: ~6 mg/kg/min at term, versus ~2.5 mg/kg/min in the non-pregnant state
Gestational diabetes (GDM)
- Insulin trajectory: normal pregnancy shows a steady rise in insulin then a sharp drop after delivery; in GDM, insulin dips around 10-12 weeks, then rises earlier and higher before delivery
- OGTT glucose curves: GDM (filled circles) rises higher and stays elevated longer than non-GDM (open circles); the gap between GDM and non-GDM is larger at 30-32 weeks than at 14-16 weeks, i.e. the glucose-intolerance effect of GDM becomes more pronounced later in pregnancy
- Mechanism of fetal effect: maternal hyperglycaemia delivers extra glucose to the fetus, causing the fetus to gain extra weight (macrosomia)
Case study (Ms J): 38-year-old Samoan woman, second pregnancy, family history of diabetes (father and uncle), BMI 32. A GTT at 28 weeks confirmed gestational diabetes; despite specialist monitoring, glucose remained high and a scan showed fetal abdominal circumference >95th percentile for gestational age (consistent with macrosomia). Insulin therapy controlled her glucose. Labour was induced at 38 weeks; she delivered a boy whose glucose levels were monitored, and Ms J had a repeat GTT 6 weeks later.
Modulation by leptin
- Leptin is produced by fat cells and acts in the hypothalamus to inhibit appetite (a satiety signal): food intake -> GI tract -> neural/hormonal signals -> hunger (positive loop back to food intake); separately, energy absorbed -> adipose tissue -> leptin release -> inhibits hunger; adipose tissue also drives energy expenditure, which reduces adipose tissue
- In pregnancy, plasma leptin rises (secreted by fat cells and the placenta), yet appetite and food intake also increase, a state termed leptin resistance
- [slide does not elaborate: the mechanism of pregnancy leptin resistance is posed as open questions rather than resolved] Proposed explanations:
- down-regulation of hypothalamic leptin receptors
- impaired leptin transport across the blood-brain barrier
- increased presence of negative regulators of leptin signalling
6. Cervical remodelling
- The cervix becomes hypertrophied in pregnancy
- A thick cervical mucous plug obstructs the cervical canal
- Cervical ectropion occurs in response to elevated estrogens: glandular columnar epithelial cells normally adjacent to the cervical canal protrude into the exo-cervix
- Cervical softening throughout late pregnancy involves changes in collagen bundling; the hormone relaxin (produced by the corpus luteum and placenta in late pregnancy) may regulate this
- Prematurely elevated relaxin (e.g. if multiple corpora lutea are present) is associated with preterm birth
Self-test
- Describe the changes in uterine mass, cell growth mechanism, and internal volume between the non-pregnant state and term.
- What causes dextro-rotation of the pregnant uterus, and when does the lower uterine segment form?
- Distinguish Braxton Hicks contractions from birth contractions.
- Describe the steps of the Ferguson reflex, from cervical stretch to increased myometrial contraction.
- By how much do myometrial oxytocin receptors increase by late pregnancy, and why?
- Describe uterine involution after birth: over what time course does it occur, and what promotes it?
- List the hormones driving mammary gland development, and describe how each changes from puberty through lactation.
- What increases occur in maternal blood volume and cardiac output in pregnancy, and what produces the increased cardiac output?
- Describe how blood flow is redistributed in pregnancy, including the change in proportion of flow to the uterus.
- Describe the three fetal circulatory shunts and the route each provides.
- Distinguish spiral artery remodelling in normal pregnancy from that in preeclampsia, and state preeclampsia’s early symptoms.
- List the three haemostatic changes that occur in pregnancy to prepare for blood loss at delivery, and state their hormonal driver.
- Describe the respiratory changes of pregnancy and how respiratory alkalosis is minimised.
- Explain how placental lactogen alters maternal glucose homeostasis, and why this benefits the fetus.
- Vignette: Ms J is 38 years old, in her second pregnancy, with a family history of diabetes and a BMI of 32. What condition is she at high risk of, what test should be requested, and what fetal complication can result if it is uncontrolled?
- What is leptin resistance in pregnancy, and what three mechanisms have been proposed to explain it?
- Describe the changes in the cervix during pregnancy, including the mechanism of cervical ectropion and cervical softening.
- Explain how rising estrogen links the uterine, oxytocin-receptor and cervical changes described in this lecture to prepare the body for labour.
Answers
Reveal answers
- Mass rises from 50 g to 900 g at term via hyperplasia (more cells) and hypertrophy (larger cells) driven by estrogen; muscle cells elongate from 50 to 500 µm; internal volume rises from ~50 ml to ~5 L.
- Dextro-rotation occurs because the rectosigmoid colon lies on the left, pushing the uterus to rotate right; the lower uterine segment forms after 12 weeks and dilates/thins in labour, unlike the upper segment.
- Both arise from gap-junction-coupled smooth muscle acting as a syncytium, but Braxton Hicks contractions are infrequent, irregular and mild, while birth contractions are frequent, regular and rhythmic.
- Cervical stretch stimulates the cervix -> afferent signal via the spinal dorsal horn -> anterolateral columns -> brainstem -> medial forebrain bundle -> hypothalamus (paraventricular/supraoptic nuclei) -> hypothalamo-hypophyseal tract -> posterior pituitary releases oxytocin -> oxytocin acts on the uterus/cervix to increase contraction, further stretching the cervix (positive feedback).
- They increase ~100-fold, in response to the high estrogen levels of late pregnancy.
- Involution occurs over 6 weeks postpartum; the uterus loses 50% of its weight in the first week and is nearly normal size by 4 weeks; breastfeeding promotes the process.
- Oestradiol and progesterone: cyclical bump at puberty, then steady rise through pregnancy peaking at term, dropping sharply at lactation onset. Prolactin: small cyclical puberty bump, steady rise through pregnancy to a peak at term, sharp drop after birth, then partial recovery during lactation.
- Blood volume increases up to 40%; cardiac output rises from 4 to 7 L/min, due to increased heart rate and increased stroke volume.
- Flow to the uterus rises from ~2% to ~20% of output; flow to the mammary gland and skin also increases (skin for fetal heat loss).
- Ductus venosus diverts some blood past the liver to the inferior vena cava/right atrium; foramen ovale shunts most right atrial blood to the left atrium, bypassing the lungs; ductus arteriosus shunts spent blood from the pulmonary circulation into the descending aorta, also bypassing the lungs.
- In normal pregnancy, trophoblast invasion remodels and widens the spiral arteries; in preeclampsia this remodelling fails, leaving narrower arteries. Early preeclampsia symptoms are high blood pressure and proteinuria.
- Increased platelet aggregation, increased coagulation factors, decreased fibrinolytic activity, all induced by ovarian/placental steroids, prepare for the ~500 ml blood loss of normal vaginal delivery.
- Minute ventilation rises ~50% for fetal and maternal metabolic oxygen needs; progesterone raises CO2 sensitivity, dropping pCO2 from ~40 to ~30 mmHg to favour fetal-to-maternal CO2 diffusion; the resulting respiratory alkalosis is minimised by renal excretion of extra bicarbonate.
- Placental lactogen reduces maternal insulin sensitivity (a T2-diabetic-like state), raising maternal blood glucose so more is available to cross to the fetus, which needs ~6 mg/kg/min at term versus ~2.5 mg/kg/min in the non-pregnant state.
- She is at high risk of gestational diabetes (age, family history, BMI 32); a glucose tolerance test (GTT) should be requested. Uncontrolled hyperglycaemia delivers excess glucose to the fetus, causing fetal macrosomia.
- Leptin resistance is a state where plasma leptin rises (from fat cells and the placenta) yet appetite and food intake also increase rather than being suppressed. Proposed mechanisms: down-regulation of hypothalamic leptin receptors, impaired leptin transport across the blood-brain barrier, and increased negative regulators of leptin signalling.
- The cervix hypertrophies and a mucous plug obstructs the canal; elevated estrogen causes cervical ectropion, where glandular columnar epithelium normally in the canal protrudes into the exo-cervix; late-pregnancy softening involves collagen bundling changes, possibly regulated by relaxin from the corpus luteum and placenta, with prematurely elevated relaxin linked to preterm birth.
- Estrogen drives uterine hyperplasia/hypertrophy, upregulates myometrial oxytocin receptors ~100-fold, and produces cervical ectropion, together priming the uterus and cervix so that oxytocin released via the Ferguson reflex can generate coordinated, effective labour contractions.