Physiological changes of normal pregnancy - technical article
Topics covered:
- Essentials
- Introduction
- Preparing for pregnancy
- Cardiovascular changes in pregnancy
- Immunological changes during pregnancy
- Ventilatory changes during pregnancy
- Renal changes during pregnancy
- Liver metabolism during pregnancy
- Gastrointestinal system in pregnancy
- Endocrine changes in pregnancy
- Carbohydrate metabolism
- Coagulation
- Skin and hair during pregnancy
- Further reading
Essentials
Almost every maternal organ system makes a physiological adaptation to pregnancy that is required for optimal pregnancy outcome. An understanding of these adaptations brings insight into the aetiology and management of gestational syndromes, and also helps the clinician to advise women with pre-existing chronic illness about the risks and consequences of a pregnancy.
Physiological adaptations in pregnancy—these include (1) cardiovascular—cardiac output increases 50%; (2) respiratory—oxygen consumption increases 20%; and (3) renal—glomerular filtration rate increases 55%.
Biochemical and endocrine changes in pregnancy—gestational changes alter the normal ranges for many important metabolic and endocrine laboratory tests, including (1) serum creatinine, urea—both decreased; (2) cholesterol and triglycerides—both increased; (3) liver blood tests—alkaline phosphatase increased up to four fold; and (4) thyroid function tests—free thyroxine and tri-iodothyronine levels fall, thyroid-stimulating hormone (TSH) levels rise. Awareness of these changes is essential, both for recognition of disease in pregnancy and to prevent inappropriate pursuit of test results that are normal in pregnancy.
Long-term implications of pregnancy syndromes—conditions such as pre-eclampsia and gestational diabetes mellitus are abnormal responses to pregnancy that resolve after delivery, but herald similar complications, i.e. hypertension and diabetes mellitus, in later life.
Introduction
The physiological changes of pregnancy make extra demands on almost all maternal organs. Women unable to meet these demands put their own health at risk as well as compromise pregnancy outcome. Pregnancy syndromes such as pre-eclampsia and gestational diabetes mellitus are abnormal responses to pregnancy that resolve after delivery, but herald similar complications, i.e. hypertension and diabetes mellitus, in later life. In this respect pregnancy acts as a maternal ‘stress test’ that identifies a woman’s vulnerability to future disease. An understanding of the normal physiological demands of pregnancy not only brings insight into the aetiology and management of gestational syndromes, but also helps the clinician advise women with pre-existing chronic illness about the risks and consequences of a pregnancy.
Preparation
The female body prepares for pregnancy during every menstrual cycle. It is not only the endometrium that anticipates implantation of a fertilized ovum, but the whole cardiovascular system. During the postovulatory or luteal phase of each menstrual cycle there is a decrease in systemic vascular resistance by approximately 20%, leading to a 10% fall in mean arterial pressure compared with the follicular phase. Cardiac output increases by almost 20%, and renal vasodilatation increases both renal blood flow and glomerular filtration by approximately 10%. All of these changes resolve with involution of the corpus luteum and onset of menses.
Cardiovasular changes in pregnancy
If fertilization is successful the haemodynamic changes established in the menstrual cycle progress further, with systemic vascular resistance falling by almost 40% and creating a maximal decrease in mean arterial pressure by the end of the first trimester. Diastolic blood pressure falls between 5 and 15 mmHg, before rising to nonpregnancy levels at term, whilst systolic blood pressure remains unchanged throughout pregnancy. A gestational increase in heart rate from approximately 72 to 85 beats/min and of stroke volume by up to 30% combine with the reduction in systemic vascular resistance to increase cardiac output. By 24 weeks, cardiac output reaches a maximum of 50% above nonpregnant levels, which is sustained until term. During the third trimester, cardiac output falls in the supine position when the gravid uterus compresses the inferior vena cava. Left ventricular wall thickness and left ventricular mass increase progressively throughout pregnancy, by up to 30% and 50% respectively. Cardiac output returns almost completely to prepregnancy levels within 2 weeks of delivery.
Distribution of increased cardiac output
Although it is technically difficult to measure blood flow to particular maternal viscera during pregnancy, it is clear that the timing and extent of changes to blood flow varies between organs. Mammary artery blood flow increases early in pregnancy, breast tenderness and swelling being amongst the first symptoms.
Mechanism of gestational cardiovascular change
The onset of physiological change during the menstrual cycle suggests that maternal rather than fetoplacental factors initiate gestational adaptation. Oestrogen, mainly in the form of 17β-oestradiol, is a potent vasodilator. It is produced by the corpus luteum during the luteal phase of each menstrual cycle and for the first 10 weeks of pregnancy. After 10 weeks, the placenta elaborates its own 17β-oestradiol, so that by term maternal oestradiol levels are approximately 250-fold higher than those found during the menstrual cycle. 17β-Oestradiol relaxes vascular smooth muscle through both endothelium-dependent and independent mechanisms, and all of the endothelium-derived vasodilators—nitric oxide, prostacyclin, and endothelial-derived hyperpolarizing factor—have been implicated in the gestational fall of systemic vascular resistance.
Much less is known about the vascular effects of progesterone, whose circulating levels increase by a similar amount to 17β-oestradiol and may play a role in reducing pressor responsiveness to angiotensin II.
Although the precise mechanism of maternal vasodilatation is likely to be different in different vascular beds, a healthy endothelium is essential for normal cardiovascular adaptation to pregnancy.
Fluid balance during pregnancy
Arterial dilatation creates a relatively ‘underfilled’ state, which stimulates the renin–angiotensin–aldosterone system. As a result, sodium and water retention throughout pregnancy leads to a 6 to 8 litre rise in total extracellular fluid volume. Plasma volume increases steadily until week 32, when it is 40% (or c.1.2 litres) above nonpregnant levels. This is partly mediated by a fall in the osmotic threshold for thirst, with a concomitant fall in the threshold for secretion of antidiuretic hormone (AVP) preventing a water diuresis and sustaining a low plasma osmolality (lower by 10 mosmol/kg) until term. During the second half of pregnancy, placental production of vasopressinase increases maternal AVP degradation, but plasma AVP levels remain stable as pituitary secretion of AVP normally increases fourfold. A failure of increased AVP secretion leads to transient diabetes insipidus of pregnancy. Plasma atrial natriuretic peptide levels are normal until the second trimester, when they rise by approximately 40%.
Immunological changes during pregnancy
It is often presumed that pregnant women are immunosuppressed in order that the fetal ‘semiallograft’ can survive. This is not true: certain aspects of maternal immunity are modulated, but it is the placenta that deserves most credit for eluding maternal immunity. Much harm is prevented by the physical separation of maternal and fetal blood, fetal haemolytic disease being an example of the harm that can follow a breach in this barrier, a rhesus-negative mother becoming isoimmunized against rhesus-positive fetal blood.
In normal pregnancy the placenta has to invade uterine tissue and become bathed in maternal blood. To avoid a hostile immune response the surface layers of placenta express a unique nonpolymorphic HLA G, rather than classical histocompatibility antigens. It is thought that HLA G confers resistance to lysis by maternal T cells and natural killer (NK) cells. The placenta also expresses a plethora of complement control systems to protect itself from the gestational rise in serum levels of maternal complement factors C3 and C4.
Innate immunity is modulated in pregnancy so that maternal NK cell activity at the uteroplacental interface promotes placental invasion, but intercurrent infection can activate latent NK cytolytic activity to harm fetal and maternal tissues. Fetal survival is also enhanced by a shift away from maternal T-helper 1 cytokine responses that promote cell-mediated immunity towards a stronger T-helper 2 cytokine response that promotes antibody production. In consequence, pregnant women are more prone to severe infections with intracellular pathogens such as malaria, tuberculosis, listeria, and Salmonella typhimurium, and they are also more likely to suffer reactivation of viruses such as Epstein–Barr.
Circulating levels of maternal immunoglobulin increase and, once transferred to the fetus, have a role in passive immunity. Neutrophils increase in number and develop a proinflammatory phenotype. Mean total white cell count increases to 9.0 × 109/litre and can rise as high as 40.0 × 109/litre during labour, returning to normal within 6 days. Erythrocyte sedimentation rate (ESR) rises as a consequence of increased fibrinogen and globulin: an ESR over 30 mm/h is usual, and up to 70 mm/h is within normal limits. Circulating levels of C-reactive protein do not change during healthy pregnancy. Anatomical changes to the maternal immune system include involution of the thymus and enlargement of the spleen.
Human chorionic gonadotropin (hCG) and progesterone play important roles in mediating some of these immune changes. Understanding gestational immune modulation and how it sometimes fails in pathological pregnancies will facilitate measures to improve pregnancy outcome.
Ventilatory changes during pregnancy
The increased metabolic demands of pregnancy lead to a progressive increase in oxygen consumption of up to almost 20% by term. Pregnant women breathe more deeply, but not more quickly, to achieve this. Tidal volume increases from approximately 500 to 700 ml, and effective alveolar ventilation actually surpasses the body’s demand for oxygen, creating a respiratory alkalosis with P CO 2 falling from 5.0 to 4.0 kPa. Progesterone stimulates deeper breathing by a direct effect on the respiratory centre, particularly increasing sensitivity to CO2.
Renal changes during pregnancy
By 16 weeks gestation renal blood flow has increased by 80% and glomerular filtration rate by 55%. The rise in renal blood flow causes the kidneys to swell so that they appear approximately 1 cm longer on ultrasonography. The renal pelvis and ureters dilate, sometimes appearing obstructed to those unaware of these changes.
Serum levels of creatinine and urea fall, so that levels considered normal outside pregnancy may reflect renal impairment during pregnancy. Proteinuria increases during pregnancy, but levels above 300 mg/24 h should be considered abnormal. Gestational glycosuria reflects reduced tubular glucose reabsorption and does not necessarily indicate abnormal carbohydrate metabolism. Furthermore, reduced tubular absorption of bicarbonate creates a metabolic acidosis that compensates for the respiratory alkalosis, keeping maternal pH at 7.4.
The production of erythropoietin, active vitamin D, and renin increases during healthy pregnancy, but their effects are masked by other physiological changes. In early pregnancy, peripheral vasodilatation exceeds the renin–aldosterone mediated plasma volume expansion, hence mean arterial pressure falls by 12 weeks. The 40% expansion of plasma volume exceeds the effect of a two- to fourfold increase in maternal serum erythropoietin levels, which stimulates only a 25% rise in red cell mass. This creates a ‘physiological anaemia’, which should not normally cause haemoglobin concentration to fall to less than 9.5 g/dl. Similarly, active vitamin D circulates at twice nongravid levels, but concomitant halving of parathyroid hormone levels, as well as hypercalciuria and increased fetal requirements, keeps plasma ionized calcium levels unchanged.
Liver metabolism during pregnancy
The size of the liver and its blood flow appear not to change during healthy pregnancy, but hepatic synthetic function and metabolism do alter such that there is an increase in serum concentrations of fibrinogen, ceruloplasmin, transferrin, and binding proteins such as thyroid-binding globulin, and a fall in serum albumin levels by approximately 25%. At term, serum cholesterol is raised by 50% and triglycerides by up to 300%. The normal ranges for aspartate transaminase, alanine transaminase, γ-glutamyl transferase, and bilirubin decrease by as much as 20% from the first trimester until term. After the fifth month, placental production of alkaline phosphatase increases maternal plasma levels by up to fourfold. Telangiectasia and palmar erythema are common signs of healthy pregnancy that resolve postpartum.
Gastrointestinal system during pregnancy
Nausea and vomiting affect about 60% of women during the first trimester. The rise and fall of hCG levels correlate chronologically with the onset and improvement of these symptoms, but the role of hCG in gestational nausea is unproven and the cause is likely to be multifactorial. Relaxation of intestinal smooth muscle by progesterone and relaxin creates many of the other pregnancy-induced gastrointestinal changes: gastric motility and small-bowel transit are slowed, especially during labour; the gallbladder enlarges and empties slowly in response to meals; a decrease in lower oesophageal pressure leads to gastro-oesophageal reflux in many women.
Endocrine changes in pregnancy
Thyroid function
The thyroid faces three challenges during pregnancy. First, increased renal clearance of iodide and losses to the fetus create a state of relative iodine deficiency, such that pregnancy stimulates growth of thyroid goitres in geographical areas where dietary iodine intake is low. Secondly, high oestrogen levels induce hepatic synthesis of thyroid binding globulin, but free thyroxine (T4) and tri-iodothyronine (T3) levels still fall during pregnancy, occasionally below the normal range for nonpregnant women. Thyroid-stimulating hormone (TSH) levels rise as pregnancy progresses, but generally remain within the normal range for nonpregnancy. Thirdly, placental hCG shares structural similarities with TSH and has weak TSH-like activity. Although hCG rarely stimulates free T4 levels into the thyrotoxic range, trophoblastic disease and hyperemesis gravidarum are often associated with high hCG levels and can lead to hyperthyroxinaemia and suppression of TSH. In these circumstances, the mother remains clinically euthyroid.
Pituitary function
The maternal pituitary makes only a small contribution to a successful pregnancy once ovulation has occurred and the uterus is prepared for implantation. The only pituitary hormone to increase significantly during pregnancy (by c.10-fold) is prolactin, which is responsible for breast development and subsequent milk production.
Pituitary secretion of growth hormone (GH) is mildly suppressed during the second half of pregnancy by placental production of a GH variant, the role of which is unclear, but it may contribute to gestational insulin resistance.
Placental production of ACTH leads to an increase in maternal ACTH levels, but not beyond the normal range for nonpregnant subjects. Free cortisol levels double and in the second half of pregnancy may contribute to insulin resistance and striae gravidarum.
High oestrogen levels during pregnancy stimulate lactotroph hyperplasia and result in pituitary enlargement. These high levels, together with those of progesterone, suppress luteinizing hormone (LH) and follicular stimulating hormone (FSH). Plasma FSH levels recover within 2 weeks of delivery, but pulsatile luteinizing hormone release is only resumed in women who do not breastfeed. In suckling mothers, prolactin inhibits gonadotropin-releasing hormone (GnRH) and hence LH.
Carbohydrate metabolism
Women develop insulin sensitivity during the first half of pregnancy, but insulin resistance develops after 20 weeks gestation such that women in the second half of pregnancy respond to a glucose load by producing more insulin, but with less effect. Obese women who are already insulin resistant are more likely to develop gestational diabetes mellitus. Hormones that might mediate this insulin resistance include cortisol, progesterone, oestrogen, and human placental lactogen. Placental production of human placental lactogen, a GH-like protein, coincides temporally with insulin resistance.
Coagulation
In anticipation of haemorrhage at childbirth, normal pregnancy is characterized by low grade, chronic intravascular coagulation within both the maternal and uteroplacental circulation. There are increased levels of clotting factors (V, VIII, and X), decreased levels of the endogenous anticoagulant protein S, and decreased fibrinolytic activity. These changes lead to an acquired protein C resistance in nearly half of all pregnant women. However, postpartum contraction of the uterus by oxytocin is probably more effective at preventing haemorrhage than any changes to the coagulation system.
Skin and hair during pregnancy
Hyperpigmentation affects up to 90% of pregnant women. Areas that are normally hyperpigmented, such as the areolae and vulva, become darker. This may be mediated by oestrogen and progesterone, which are powerful melanogenic stimulants. Hair growth increases during pregnancy and hair loss is accelerated postpartum. The gestational rise in corticosteroids and ovarian androgens contributes to the number of hairs in the growing phase (anagen). The levels of these hormones fall postpartum and hairs move back into the resting phase (telogen).