Maternal changes in pregnancy Flashcards
What happens in the first few days following fertilisation?
- Fertilisation occurs in the ampulla of the uterine tube
- The uterine tube itself is not just a passive tube from the ovary to the uterus; it is actually the place where the embryo spends the first week or so of its life. It is a very protected, special (in that there are many signalling molecules going backwards and forwards between the embryo and the walls of the tube themselves) environment.
- These are the stages of embryo development = ovulation, fertilisation, cleavage (zona pellucida and 8 cell stage), morula, early blastocyst (inner cell mass), late blastocyst (trophoblasts and blastocoel cavity)
- For the first few days, the embryo divides. Around day 4 to 5, the embryo differentiates for the first time. There are now two cell types. There is the trophoblastic layer around the edge which forms the embryonic part of the placenta. This is the part that implants into the uterus. There is another type of cell, which is the inner cell mass. The inner cell mass will form the foetus. This is where embryonic stem cells (totipotent stem cells; can differentiate into any cell type) are obtained from.
- The remainder of the space makes up the fluid-filled cavity.
Describe the components of a human blastocyst.
1) Inner cell mass = Forms the foetus
2) Trophoblast = Forms part of the placenta
3) Blastocoel = Fluid filled cavity
How does the uterus become receptive?
- Endometrial changes reach their maximum about 7 days after ovulation. The implantation window 6 – 10 days after the LH spike.
- Pre-decidualizaton 9 to 10 days after ovulation -decidual cells cover surface of uterus.
- Decidualization if pregnancy occurs, decidual cells (modified become filled with lipids and glycogen. Decidua becomes maternal part of the placenta.
- Decidual cells on surface of endometrium become filled with lipids and glycogen- becomes maternal part of the placenta.
- Glandular secretions of endometrium contains growth factors, adhesion molecules, nutrients, vitamins, matrix proteins and hormones
- The uterus is quite receptive at this point.
- The CL (that the egg was released from) has been producing progesterone in the second half of the cycle, resulting in pre-decidualisation. The secretory glands are more active, the spiral arteries become more tortuous to increase the surface area, there are some adhesion molecules and various other things expressed on the surface that these trophoblastic cells will attach to.
- Trophoblastic cells will attach here.
- The syncytiotrophoblast results from cell fusion (forms a multi-nucleated cytoplasmic mass) and invades the endometrium.
- Chorionic gonadotropin is an autocrine growth factor for the blastocyst.
- As the embryo approaches the surface of the uterus (the endometrium), these cells attach and invade.
- The cytotrophoblastic cells from the surface fuse together to form one big cell with many nuclei (a syncytium). They release all kinds of adhesion molecules and proteases etc. This is called the syncytiotrophoblast.
How does implantation occur?
1) Implanting day 7-8 = Syncytiotrophoblast erodes the endometrium. Cells of the embryonic disc form epiblast and hypoblast. Epiblast develops fluid filled amniotic cavity.
2) 12 day blastocyst = Implantation complete as extraembryonic mesoderm forms discrete layer beneath cytotrophoblast.
3) 16 day embryo = cytotrophoblast and associated mesoderm have become the chorion and chorionic villi are extending. Lacunae filled with maternal blood mingle with villi
- There is invasion.
- The embryonic part of the placenta is formed with the chorionic villi (increasing surface area). The maternal portion of the placenta forms lacunae (blood-filled spaces) at the same time.
- The villi will project into the blood filled spaces to allow the exchange of gases etc.
- Looking at the embryo itself, the first differentiation into two cell types has already occurred. The inner cell mass differentiates into another two cell types, forming a bilayered embryonic disc which continues to grow (two layers to the disc).
- The embryo itself is really small; the rest is the yolk sac, the placenta, the amniotic sac etc.
- The yolk sac can be seen along with the beginning of the amniotic cavity on top. From the disc, there are now three layers of the embryo. These three layers are so important = ectoderm, mesoderm and the endoderm. All of the different tissue types arise from these three layers.
What does the maternal-foetal interface look like?
- Looking at the mature maternal-foetal interface, the foetal is shown at the bottom and the maternal is shown at the top. There are these chorionic villi projecting into the lacunae and the mother’s supply is going through these lacunae. There is no mixing of blood supplies, but they are so close together that transfer can take place.
What is the difference between a morula, blastocyst and gastrula?
- Embryo, becomes a morula, and then forms a blastula.
- The primitive endoderm develops into the amniotic sac
- The epiblast gives rise to the three germ layers of the developing embryo during gastrulation (endoderm, mesoderm, and ectoderm).
- On day 4, there is a ball of cells. By day 6, there are two cell types. One will become the embryonic part of the placenta, the inner cell mass will become the foetus. The inner cell mass then differentiates into two (each has their own fluid-filled space); they will become the yolk sac and amniotic sac. In between those two, there is a third layer. Can see the embryo part and the embryonic disc can also be seen. All tissue comes from one of these three layers.
1) Ectoderm = skin (epidermis), brain spinal cord (CNS) sensory organs
2) Mesoderm = heart, skeletal muscle, kidneys, urogenital, connective tissue
3) Endoderm = lining of gastro-intestinal, respiratory and urogenital tract
How do pregnancy tests work?
- Human chorionic gonadotrophin (hCG) secreted by the syncytiotrophoblast increases rapidly and is basis of pregnancy test.
- hCG prevents the death of the corpus luteum so the endometrium is not shed.
- The corupus luteum continues to produce steroids estrogen and progesterone. Rapid change in maternal systems in response to luteal and later placental steroids
- hCG has a similar structure to LH (almost identical)
- FSH, LH, hCG, TSH are all alpha and beta subunits; have the same alpha subunit but different beta subunit (all dimers of two protein chains = an alpha and beta chain).
- Binds to LH receptor
- At the end of the menstrual cycle, when the CL dies and stops making progesterone, the lack of progesterone induces the endometrium to disintegrate and be shed. It drops so low, that the brakes are taken off from the hypothalamus and pituitary, so there is no negative feedback on them. They start making FSH and LH, so a group of follicles are recruited into a new menstrual cycle to begin again. This is disastrous if the woman is pregnant.
- The cycle needs to be stopped to maintain progesterone production so the embryo can progress.
- hCG binds to LH receptors on the CL to keep it alive and maintain progesterone production. It suppresses the pituitary and hypothalamus; there is no more FSH or LH. There are high, maintained levels of progesterone; the cycle has stopped, progesterone keeps the endometrium in tact, the placenta starts to develop.
When does the placenta take over progesterone production?
- Serum hCG maximal by 9 – 11 weeks. Useful for monitoring early pregnancy complications e.g. ectopic pregnancy or miscarriage.
- The placenta takes over progesterone production at 9-11 weeks (CL becomes less important).
- There is a lot of hCG present. A lot of hCG is produced very early on in pregnancy; it is produced by the trophoblastic cells of the embryo.
- Once the placenta takes over fairly early on, placentally-derived oestrogen and progesterone continue.
What two steroid hormones cause lot of the maternal changes in pregnancy (Placental steroidogenesis = 7 – 8 weeks)?
1) Progesterone
- Decidualization (CL)
- Smooth muscle relaxation – uterine quiescence
- Mineralocorticoid effect – cardiovascular changes
- Breast development (glands and stroma)
2) Estrogens - Estradiol (E2), Estriol (E3)
- Rely on steroids from foetus and maternal adrenals
- Development of uterine hypertrophy
- Metabolic changes (insulin resistance)
- Cardiovascular changes
- Increased clotting factor production (haemostasis)
- Breast development (glands and stroma)
- Being steroids, their receptors are transcription factors so they have very direct effects. They get right to the nucleus and turn on a lot of genes, having widespread effects across the body. Not all, but a lot of the maternal changes in pregnancy are due to these two steroids. Oestrodiol and oestriol have different OH groups (steroid pathway shows the similarities between steroids). There is quite a bit of oestriol in pregnancy, while oestrodiol is more common in the menstrual cycle.
What is the average total weight gain in pregnancy?
- Average total weight gain 9-13kg
- Can see a breakdown of where this weight comes from.
1) Foetus and placenta = 5 kg
2) Fat and protein = 4.5 kg
3) Body Water (excluding that in other listed structures) = 1.5 kg (intravascular, interstitial, intracellular)
4) Breasts = 1 kg
5) Uterus = 0.5 - 1kg - About 2.0 kg in total in the first 20 weeks
- Then approximately 0.5 kg per week until full term at 40 weeks
- A total of 9 -13 kg during the pregnancy.
- They used to be an obsession with weighing pregnant women; this can be anxiety- inducing. Weight fluctuates quite a bit daily. Therefore, failure to gain weight or a sudden change in weight requires investigation, but constant weighing is not appropriate as it causes too much anxiety.
How does basal metabolic rate change?
- Rises by:
1) 350 kcal/day mid gestation
2) 250 kcal/day late gestation
(75% foetus and uterus; 25% respiration) - 9 calories = 1g fat, therefore 40g fat for 350kcal
- Glucose increases in the maternal circulation in order to cross the placenta.
- “eating for two”
- Basal metabolic rate (basic metabolic rate without carrying a baby around and without activity) increases quite a lot.
How are glucose levels affected in pregnancy?
1) First trimester (Maternal reserves) = Pancreatic cells increase in number raising circulating insulin so more glucose is taken up into tissues. Pancreas releases more insulin in the first trimester (hyperinsulinaemia). Induces glucose receptors in different tissues, so glucose is quickly cleared from the mother’s circulation. It is either stored as fat, metabolised or stored as glycogen in the liver. Fasting serum glucose decreases. If a pregnant woman’s fasting glucose levels or blood glucose levels were measured, they may appear low. If it was not known that she was pregnant, it could appear as diabetes or a metabolic problem. As she is pregnant, it is acceptable. One problem with pregnancy (a recurring theme) is that it is difficult to differentiate between normal adapted physiology in pregnancy and pathology.
2) Second trimester (Foetal reserves) = Placental Lactogen causes insulin resistance, ie less glucose into stores and increase in serum glucose. In the second trimester, placental lactogen is produced. The placenta has developed by then and it produces lactogen. Lactogen causes insulin resistance. When there is sugar in the blood stream, it is not taken up and blood sugar levels rise (higher than normal). Again, this only looks normal when it is known that the woman is pregnant (otherwise, she would look diabetic etc).
3) Transfer of glucose to foetus = Increased glucose level in blood during 2nd trimester. Glucose is transported across placenta as foetal energy source. Foetus stores some in liver.
- During early pregnancy, the embryo’s metabolic demands are very low. The mother’s body wants to store as much glycogen, fat and energy as possible because her metabolic demands are still quite low, so there is this increase in insulin. In the second trimester, the baby is much bigger, and its metabolic demands are much higher. The mother no longer stores. There is a high level of glucose in the blood so that there is a bigger concentration gradient across the placenta. This insulin resistance in the second trimester causes high blood sugar levels in the mother which increases the concentration across the placenta and drives sugar to the now growing foetus.
How much water is gained during pregnancy and why?
- Up to 8.5 litres total water gain
- During pregnancy, a woman gains a lot of water due to the foetus, the placenta, the plasma volume (volume of blood) increases a lot, amniotic fluid, there is a lot of fluid in uterine muscles. All of the tendons and muscles become softer, get a bit of oedema (lungs, connective tissue, leakage, swollen ankles), and she becomes very supple (this is useful later).
- Due to the increase in the blood volume, she is a little bit less osmotic. There is a little bit more oedema, e.g. swollen ankles. Oestrogen and progesterone tend to do this. There are a couple of things that happen. Firstly, as they are so high, they act a little bit like a mineralocorticoid. They retain more sodium from kidneys, which partly increases the blood volume.
- Ligaments and connective tissue take on water and become a bit softer.
- The steroids affect her osmostat, so there is a decreased thirst threshold (becomes thirsty more easily). The amount of albumin compared to her blood volume is a bit lower (still has plenty of albumin but blood volume has dramatically increased). Slightly decreased oncotic pressure causes swollen ankles etc. Decrease in oncotic pressure (albumin).
- The RAAS system gets involved. Renin is produced by the placenta. There are all of the elements of the RAAS system, e.g. increased angiotensin and aldosterone, increased water retention. This is all except for one thing. Normally, angiotensin II causes peripheral vasoconstriction to increase blood pressure (if there is a drop in renal perfusion, the RAAS system is activated to try and restore blood pressure again). All of the fluid retaining aspects are still activated, but the angiotensin II (which normally binds to the angiotensin II receptor and causes vasoconstriction) is inhibited by progesterone. Progesterone decreases the sensitivity. Therefore, this high blood pressure (vasoconstriction) does not occur but there is fluid retention and aldosterone effects etc.
- Estrogen upregulates angiotensinogen synthesis by liver, leading to increased angiotensin II and aldosterone. Despite higher ANGII, women resistant to AT2 receptor mediated vasoconstriction because progesterone decreases vasosensitivity.
- Overall, there is a lot of water gain.
Why does oxygen consumption change in pregnancy?
- Oxygen consumption increases. There are a couple of reasons for this. Firstly, the respiratory centre in brain becomes more sensitive to CO2. It is the hypercapnic drive mainly (levels of carbon dioxide experienced) that stimulate the respiratory centre to stimulate breathing. Therefore, as carbon dioxide levels rise, breathing increases. This is mainly induced by oestrogen and progesterone levels. Subconsciously, a pregnant woman breathes more deeply (and a little bit quicker).
- The thoracic anatomy changes too. Ribcage is displaced upwards and ribs flare outwards. This is partly to make space for the foetus, but also this increased breathing. Overall, her minute volume (the amount of air breathed in a minute) increases by up to 40%. Like hyperventilating, oxygen concentration increases and CO2 is released. This subconscious deeper breathing increases arterial oxygen levels by up to 10% while carbon dioxide levels fall by about 15-20%. At the maternal-foetal interface, there is a big concentration gradient of oxygen on the maternal side that favours transfer across the placenta to the foetus. There is also a low concentration of CO2 on the maternal side that facilitates effective transfer of CO2 from the foetus to the mother. As with glucose, these concentration gradients are increased across the placenta to favour the needs of the foetus.
- Another aspect here is that the foetus expresses foetal haemoglobin. Foetal haemoglobin has a higher affinity for oxygen than adult haemoglobin. This foetal haemoglobin is kept until six months old. In children with sickle cell, the effects are only seen after about six months of age because it only affects adult Hb. This foetal haemoglobin is another adaptation to increase oxygen affinity in the baby even more.
Why does it appear as if there are fewer red blood cells per ml?
- Due to the steroids, decreased thirst threshold and different RAAS mechanisms etc., there is increased water gain. Can see a rapid increase in plasma volume in pregnancy. As well as a 45% increase in maternal plasma volume, the number of red cells also increase. Therefore, her oxygen capacity goes up by nearly 20%. If there is a 45% increase in the plasma volume and a 20% increase in red blood cell number, even though her oxygen capacity is very high, measuring a blood sample would still appear anaemic due to the dilution effect; it appears as if there are fewer red blood cells per ml. If it was known that she was pregnant, this may be disregarded, but what if she was anaemic or diabetic etc.
- Have to untangle any underlying problem from the changed physiology expected during pregnancy. Non pregnant haemoglobin is 12-16 g/dl, while the pregnant range is 10 - 13 g/dl but a pregnant woman has so many more red blood cells (20% increase). There’s also an increase in white cells and clotting factors. The blood becomes hypercoagulable, which is important in case of tearing during childbirth. This is why pregnant women are warned against flying/sitting still for long periods of time; increased risk of DVT.
