Physiology, Pregnancy

Issues of Concern

The female body goes through immense changes during a pregnancy that involve all organ systems in the body. These changes result in physiology that differs from that of a non-pregnant female. Additionally, abnormalities in the development of pregnancy can lead to further complications for both mother and fetus. With the maternal mortality rate in the United States reaching almost 18 deaths per 100,000 live births in 2009, a drastic increase from the 7.2 deaths per 100,000 in 1987, it has become more critical for all healthcare providers to understand the typical changes that accompany pregnancy, as well as recognize changes that go beyond typical pregnancy symptoms.[1]

Cellular Level

The fertilization of an egg with a sperm starts the process of embryogenesis. The fertilized egg goes through several divisions to form a blastocyst. This blastocyst then initiates implantation with the maternal endometrium. Implantation triggers the uterine stroma to undergo decidualization to accommodate the embryo. This decidua supports embryo survival and appears to act as a barrier against immunologic responses. Additionally, upon implantation, human chorionic gonadotropin (hCG) begins to be secreted, allowing the sustenance of pregnancy. The blastocyst then begins the process of forming three distinct germ layers, including the ectoderm, mesoderm, and endoderm. At this stage, the blastocyst then becomes an embryo. The embryo goes through a process known as organogenesis, in which the majority of the major organ systems develop. After 8 weeks from implantation, or 10 weeks gestational age, the embryo is then termed a fetus until birth.[2]

Development

The duration of pregnancy, from implantation of a fertilized ovum to birth, is taken as 266 days. However, as pregnancy dating is typically from the first day of the last menstrual period, the duration of pregnancy is considered to be 280 days on average. This duration is the amount of time by which approximately half of all women will deliver their babies. Babies born from 37 0/7 weeks gestation to 38 6/7 weeks are considered early term. Those born between 39 0/7 weeks and 40 6/7 weeks are labeled full term. Babies born 41 0/7 weeks through 41 6/7 weeks are titled late-term. Any baby born at 42 0/7 weeks gestation and beyond is deemed post-term.[3]

Organ Systems Involved

Pregnancy induces a coordinated response of multiple organ systems to support both mother and fetus.

Female Reproductive System [4]

To accommodate a growing fetus, the uterus must undergo extreme structural changes and cellular hypertrophy. During this time, the uterus must maintain a passive noncontractile state; this occurs through elevated levels of progesterone, which act to relax smooth muscle—growth of the placenta results in uterine tissue and vascular remodeling. Hormonal signals, primarily estrogen, are responsible for initiating the uterine growth process during early pregnancy. The uterus increases from 70 g to 1100 g, with its volume capacity increasing from 10 mL to 5 L. Between weeks 12 and 16, the lower uterine corpus unfolds, allowing the uterus to become more spherical and giving room for amniotic sac expansion with minimal stretching of the uterus. When fetal growth rate begins to accelerate at 20 weeks, the uterus rapidly elongates, and the walls thin. The longitudinal diameter grows more rapidly than the left-right and anterior-posterior diameters, with the maximum rate of elongation happening between weeks 20 and 32. By 28 weeks, the maximum fetal growth rate has occurred, and the uterine tissue growth slows while continuing to stretch rapidly and become thin. Within several weeks of delivery, the uterus then returns to its pre-pregnancy structure.

Cardiovascular [5]

During pregnancy, the cardiac output increases by 30 to 60%, with the majority of the increase occurring during the first trimester. The maximum output is reached between 20 and 24 weeks and is maintained until delivery. Initially, the increase in cardiac output is due to an increase in stroke volume. As the stroke volume decreases towards the end of the third trimester, an increase in heart rate acts to maintain the increased cardiac output.

Systemic vascular resistance decreases, resulting in decreased arterial blood pressure. Systolic blood pressure decreases by approximately 5 to 10 mm Hg, and diastolic blood pressure decreases by 10 to 15 mm Hg. This decrease reaches its lowest point at 24 weeks, at which point it slowly returns to pre-pregnancy levels. This decrease in arterial blood pressure is due to the elevated progesterone levels present during pregnancy. Progesterone leads to smooth muscle relaxation, thus decreasing vascular resistance.

Due to these physiological changes, bounding or collapsing pulses, as well as ejection systolic murmurs, are present in the majority of pregnant women. A third heart sound may be present, and ectopic beats and peripheral edema are also common. The changes in the position of the heart that occur as pregnancy progress lead to ECG changes that are considered normal findings in pregnancy. These include: atrial and ventricular ectopic beats, small Q waves and inverted T waves in lead III, ST-segment depression and T wave inversion in inferior and lateral leads, and left axis shift.

Pulmonary [6]

During pregnancy, the diaphragm elevates, resulting in a 5% decrease in total lung capacity (TLC). However, the tidal volume (TV) increases by 30 to 40%, thereby decreasing the expiratory reserve volume by 20%. Minute ventilation is similarly increased by 30 to 40%, owing to the fact that TV becomes increased while a constant respiratory rate is maintained.

The increase in minute ventilation that occurs during pregnancy allows for an increase in alveolar (PAO2) and arterial (PaO2) PO2 levels and a decrease in PACO2 and PaCO2. PaCO2 decreases from a pre-pregnancy level of 40 mm Hg to 30 mm Hg by 20 weeks. This decrease in PaCO2 creates an increased CO2 gradient between the fetus and mother, thus enhancing oxygen delivery and carbon dioxide removal in the fetus. This gradient is created by elevated progesterone levels, which appear to act to either increase the responsiveness of the respiratory system to CO2 or to be a primary stimulant. These changes are needed to accommodate the 15% increase in metabolic rate and the 20% increase in oxygen consumption that occurs during pregnancy.

Decreased PaCO2 levels, increased tidal volume, and decreased total lung capacity combine to result in dyspnea of pregnancy in approximately 60% to 70% of pregnant patients. This feeling is a subjective sensation of breathlessness with no hypoxia present. It is most common during the third trimester but can start at any time.

Gastrointestinal [6]

Elevated levels of estrogen, progesterone, and human chorionic gonadotropin (hCG) combine to bring about nausea and vomiting, commonly termed morning sickness. Hypoglycemia can be an additional cause of nausea. Morning sickness develops in over 70% of pregnancies and can occur at any time of day. It typically resolves by weeks 14 to 16 but persists beyond week 20 in about 10-20% of pregnant patients. If nausea and vomiting are severe enough to lead to ketosis and weight loss greater than or equal to 5% of pre-pregnancy weight, the term for this is hyperemesis gravidarum. In these patients, intravenous fluid and vitamin substitution may be necessary.

Elevated progesterone levels induce smooth muscle relaxation, leading to prolonged gastric emptying time. When combined with decreased gastroesophageal sphincter tone and upwards displacement of the stomach, reflux often occurs. Progesterone-mediated smooth muscle relaxation also leads to decreased motility in the large bowel, resulting in increased water absorption and constipation.

Renal [6]

The renin-angiotensin-aldosterone system is activated in early pregnancy, consequently increasing sodium reabsorption. However, an increased glomerular filtration rate (GFR) acts to maintain sodium plasma levels. Additionally, elevated progesterone and prostacyclin, along with angiotensin I receptor modification in pregnancy, leads to a relative resistance to angiotensin II. This state acts to balance the vasoconstrictive effect of angiotensin and allows for vasodilation of the renal arteries mediated by relaxin stimulation of endothelium to synthesize nitric oxide.

Due to renal vasodilation, both the GFR and renal plasma flow increase. The GFR increases 50% starting in early pregnancy, and this increase remains until delivery. The decrease in systemic vascular resistance results in both afferent and efferent arterioles experiencing decreased vascular resistance, thus maintaining glomerular hydrostatic pressure—the resulting increased renal blood flow results in an increase in kidney size. Progesterone acts to reduce ureteral tone, peristalsis, and contraction pressure, thereby dilating the ureters.

The elevation in GFR acts to decrease blood urea nitrogen and creatinine by 25%. The elevated GFR, combined with increased glomerular capillary permeability to albumin, results in an increase of fractional excretion of protein to as much as 300 mg/day. Less effective tubular reabsorption of both glucose and urea results in increased excretion rates.

Hematology [6]

In pregnancy, the RBC volume increases by 20% to 30%, while the plasma volume increases by 45 to 55%. This disproportionate volume increase leads to dilutional anemia with decreased hematocrit. WBC count increases to 6 to 16 million/mL and can be as high as 20 million/mL during and shortly after labor. Platelet concentration decreases slightly due to the increased plasma volume but typically stays within normal limits. A small proportion of women (5 to 10%) will have platelet levels between 100 and 150 billion/L without any pathology present. Fibrinogen and factors VII – X levels increase, but the clotting and bleeding times remain unchanged. However, increased venous stasis and damaged vessel endothelium result in higher rates of thromboembolic events during pregnancy. The increase in the risk of thromboembolic events starts in the first trimester and continues at least 12 weeks postpartum.

Endocrine [6]

The increased levels of estrogen in pregnancy result in a stimulation of thyroid-binding globulin, which then increases levels of thyroxine (T4) and tri-iodothyronine (T3). Free T3 and T4 levels are slightly altered, but remain relatively constant, with a slight decrease in the second and third trimesters. TSH levels decrease somewhat in the first trimester due to the weakly stimulating effect of hCG on the thyroid but increase again by the end of the first trimester. Despite the changes, pregnancy is considered to be a euthyroid state.

During pregnancy, there is an increase in hormone production by the adrenal glands. The reduced vascular resistance and blood pressure stimulate the RAA system, resulting in a three-fold increase in aldosterone by the end of the first trimester and a ten-fold increase by the end of the third trimester. There is also an increase in the production of cortisol, adrenocorticotropic hormone (ACTH), corticosteroid-binding globulin (CGB), and deoxycorticosterone, resulting in a hyper cortisol state. By the end of the third trimester, total cortisol levels are three times higher than in non-pregnant women. By the end of pregnancy, the placenta contributes to the increased cortisol state due to its production of corticotropin-releasing hormone, thus helping to trigger labor.

The increased levels of estradiol in pregnancy result in an increase in prolactin, with serum prolactin levels increasing ten-fold by the end of pregnancy. This increased production induces growth in the pituitary gland caused by the proliferation of cells in the anterior lobe. Oxytocin levels, produced by the posterior pituitary, increase throughout pregnancy and peak at term. Elevated estrogen, progesterone, and inhibin act to inhibit the production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), making these levels undetectable.

Musculoskeletal and Dermatologic [6]

The shift in the center of gravity that occurs with pregnancy results in increased lordosis of the lower back and flexion in the neck. This shift in posture can cause lower back strain that worsens as the pregnancy progresses. Increased mobility and widening of the sacroiliac joints and pubic symphysis occur, as well as joint laxity in the lumbar spine. Carpal tunnel syndrome is a common occurrence in pregnancy due to compression of the median nerve.

Increased estrogen levels result in spider angiomata and palmar erythema. Elevated melanocyte-stimulating hormones and steroid hormones lead to hyperpigmentation of the face, nipples, perineum, abdominal line, and umbilicus.

Metabolism [6]

The placenta produces human placental lactogen (hPL), which acts to supply nutrition to the fetus. It induces lipolysis to increase free fatty acids, which are preferentially used by the pregnant mother for fuel. It also acts as an insulin antagonist to induce a diabetogenic state. This activity prompts hyperplasia of pancreatic beta-cells to create increased insulin levels and protein synthesis. In early pregnancy, maternal insulin sensitivity increases, followed by resistance in the second and third trimesters.

Total serum cholesterol and triglyceride levels increase during pregnancy due to increased synthesis in the liver and decreased activity of lipoprotein lipase. LDL cholesterol increases throughout pregnancy, with a 50% increase by term. HDL cholesterol increases during the first half of pregnancy and then falls in the third trimester while still staying above non-pregnant levels. The increase in triglycerides is essential for supplying the mother’s energy while sparing glucose for the fetus. The increased LDL levels are crucial for placental steroidogenesis.

There are increased caloric and nutritional requirements during pregnancy, including increased requirements for protein, iron, calcium, folate, and other vitamins and minerals. The protein requirement in pregnancy increases from 60 g/day to 70 to 75 g/day, as the amino acids are transported to the developing fetus. The calcium requirement increases to 1.5 g/day, due to the fetus's requirement of 30 g of calcium. Maternal serum levels of calcium are maintained in pregnancy, with fetal needs being met by increased intestinal absorption starting at week 12.

Function

The primary function of pregnancy is to allow for the growth and development of the fetus. All changes that occur within the mother’s body are intended to allow for this growth, as well as for the development of the placenta to nourish the fetus and sustain the pregnancy.

Mechanism

The menstrual cycle ranges from 26 to 35 days, with 28 days being the average duration. Menstrual bleeding begins on the first day of the menstrual cycle, and the heaviest flow occurs, on average, on day 2. The beginning of the menstrual cycle comprises the follicular phase, during which FSH from the pituitary gland stimulates the development of a primary ovarian follicle. This follicle induces estrogen production, allowing the uterine lining to proliferate. A spike in LH, triggered by the estrogen surge, stimulates ovulation and begins the luteal phase. The greatest probability of conception occurs in the follicular phase, one day before ovulation. However, the fertile phase spans the time between 5 days before and the day of ovulation. After ovulation, the corpus luteum secretes progesterone, maintaining the endometrial lining for a fertilized ovum. If fertilization does not occur or the fertilized ovum does not implant into the endometrial lining, then the corpus luteum degenerates, progesterone levels fall, and the endometrial lining sloughs off to begin the menstrual cycle again. [7]

If a fertilized ovum successfully implants into the endometrium, the trophoblast cells proliferate into syncytiotrophoblast cells and begin to produce hCG.[7] This sustains the corpus luteum to maintain the secretion of progesterone and estrogen, allowing the pregnancy to develop. The syncytiotrophoblast, along with the cytotrophoblast and extraembryonic mesoderm, goes on to form the placenta. The primary purpose of the placenta is to sustain the pregnancy and meet the demands of the fetus. The placental membrane allows for the exchange of nutrients and gases between the fetus and the mother’s body, acting as the fetal respiratory, gastrointestinal, endocrine, renal, hepatic, and immune systems.[8]

Pregnancy ends with the delivery of the fetus. There are several theories as to how labor initiates. Some studies show that labor becomes triggered by the withdrawal of progesterone and mechanical stretch experienced by the uterine wall.[4] Other studies suggest that inflammatory mediators, such as prostaglandins, are vital in initiating uterine contractions.[9]  Oxytocin then goes on to sustain contractions during labor and delivery.[10]

Related Testing

Indications for testing to confirm pregnancy, either through urine or serum sample, include a female of child-bearing age with amenorrhea, dysmenorrhea, pelvic pain, abdominal pain, syncope, lightheadedness, dizziness, hypotension, tachycardia, nausea or vomiting, vaginal discharge, or urinary symptoms. Levels of hCG in a viable intrauterine pregnancy double approximately every 48 hours in early pregnancy. Levels peak around 10 to 12 weeks gestation, then decline to a steady state after 15 weeks.[11] Ultrasound confirmation of early pregnancy is utilized when an individual has a positive pregnancy test along with pelvic pain, abdominal pain, or vaginal bleeding.[12]

Confirmation of a viable pregnancy occurs with an ultrasound, which shows a gestational sac on transvaginal ultrasound at five weeks or with an hCG level of 1,500 to 2,000 mIU/mL. Fetal heart motion is visible on transvaginal ultrasound at six weeks or with hCG levels starting at 5,000 to 6,000 mIU/mL.[12]

Pathophysiology

As the purpose of the placenta is to support and maintain the pregnancy, any abnormality in placenta formation can result in adverse outcomes for both mother and fetus. Abnormalities can be in the form of the structure of the placenta, the location of the placenta, and the implantation of the placenta.

Preeclampsia appears to involve both maternal and fetal factors, leading to abnormal development of the vasculature in the placenta; this ultimately leads to under-perfusion, resulting in hypoxia and growth restriction. Maternal endothelial dysfunction, believed to be due to antiangiogenic factors, leads to increased vascular permeability, with activation of the coagulation cascade, vasoconstriction, and microangiopathic hemolysis. These factors lead to the clinical manifestations of preeclampsia, including hypertension, proteinuria, seizure, cerebral hemorrhage, DIC, renal failure, pulmonary edema, uteroplacental insufficiency, placental abruption, premature delivery, and increased rate of cesarean section deliveries. Preeclampsia falls into two categories, preeclampsia without severe features and preeclampsia with severe features. To be diagnosed without severe features, third-trimester blood pressure greater than 140/90 mm Hg on two occasions at least 6 hours apart is needed, as well as proteinuria over 300 mg/24 hours or protein to creatinine ratio greater than 0.3. Women with preeclampsia without severe features are managed with delivery at 37 weeks. If diagnosed before 37 weeks, they are closely monitored as inpatients, although outpatient monitoring can be utilized if there are no other comorbidities. To be diagnosed as preeclampsia with severe features, blood pressure must be greater than 160/110 mm Hg in addition to proteinuria. Alternatively, blood pressure can be greater than 140/90 mm Hg on two occasions with at least one other feature, including renal insufficiency, thrombocytopenia, pulmonary edema, impaired liver function, or cerebral or visual disturbances. These patients should be delivered at 34 weeks and should receive treatment with magnesium sulfate for seizure prophylaxis. If blood pressure is greater than 160/110 mm Hg, antihypertensives should be used to decrease the risk of stroke.[13][14]

Approximately 10% of patients with preeclampsia with severe features will go on to develop HELLP syndrome—these patients present with hemolysis, elevated liver enzymes, and low platelets. Hypertension and proteinuria do not need to be present in these patients. These patients diagnosed after 34 0/7 weeks should be delivered once stabilized. If diagnosed before 34 weeks, these women should be delivered 24 to 48 hours after betamethasone administration. They should also be administered magnesium sulfate until 24 hours postpartum.[15][14]

Eclampsia is diagnosed when grand mal seizures occur in a preeclamptic patient. It can occur in women both with and without severe features. Eclampsia appears to occur when there is a breakdown in autoregulation of cerebral circulation due to endothelial dysfunction, hyperperfusion, and brain edema. Treatment includes seizure management and prophylaxis, blood pressure control, and delivery once the patient has been stabilized and convulsions controlled.[14]

Placenta previa occurs with abnormal implantation of the placenta covering the internal cervical os. It can be considered complete, in which the internal os is completely covered by the placenta, partial previa, with the placenta covering a portion of the internal os, or marginal previa, where the edge of the placenta approaches the margin of the os. The placenta is considered low-lying when it is in the lower uterine segment but does not extend to the internal os. During the third trimester, the lower uterine segment begins thinning, leading to disruption in the placental attachment and painless bleeding. This bleeding irritates the uterus, stimulating uterine contractions that cause further separation and bleeding. As the cervix dilates and effaces during labor, placental separation and unavoidable bleeding occur, which may result in hemorrhage and shock. These patients are managed with pelvic rest after 20 weeks, decreased physical activity, and cesarean delivery between 36 and 37 weeks.[16]

Placenta accreta occurs when the placenta invades into the uterine wall during implantation. If the invasion extends to the myometrium, the term for the condition is placenta increta. If the invasion extends further through the myometrium and into the serosa, this is considered placenta percreta. Placenta percreta may also invade into surrounding organs, such as the bladder or rectum. In these conditions, the placenta is unable to separate from the uterine wall properly, which can lead to hemorrhage and shock. As such, this condition can lead to the need for a hysterectomy at the time of delivery.[17]

Clinical Significance

Understanding changes that occur during pregnancy is critical for the proper management of pregnant patients. They encounter many physical changes that can create physical, mental, and emotional strain for the patient. It is essential to remain sensitive to these changes when providing care.

In addition to remaining sensitive to providing compassionate care, knowing the physiologic changes of pregnancy are essential when determining whether an apparent pathology is indeed pathological versus a normal finding in a pregnant patient. Many lab value limits are adjusted in pregnancy due to the changes in hormones and organ functioning. Hypotension and tachycardia become more prevalent throughout pregnancy, requiring careful considerations in the treatment of a pregnant trauma patient.

Overall, understanding the physiology of pregnancy allows all providers, not only OB/GYNs, to provide the best possible care.