Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
HIV and pregnancy wikipedia , lookup
Menstrual cycle wikipedia , lookup
Maternal health wikipedia , lookup
Prenatal nutrition wikipedia , lookup
Prenatal development wikipedia , lookup
Fetal origins hypothesis wikipedia , lookup
Prenatal testing wikipedia , lookup
Maternal physiological changes in pregnancy wikipedia , lookup
PREGNANCY AND LACTATION • This chapter discusses the biochemical changes that occur in pregnancy and how clinical biochemistry tests can be used in the investigation of infertility. • If the ovum is fertilized, it may implant in the endometrium, which has been prepared by progesterone during the luteal phase. The function of luteinizing hormone (LH) is taken over by human chorionic gonadotrophin (hCG), produced by the chorion and developing placenta. 1 Human chorionic gonadotrophin is similar in structure and action to LH and prevents the involution of the corpus luteum as circulating pituitary gonadotrophin concentrations fall. Consequently, plasma oestrogen and progesterone concentrations continue to rise and endometrial sloughing is prevented. Progesterone is initially produced by the corpus luteum of the ovary for the first 8 weeks of pregnancy, then from implantation of the embryo the placenta takes over progesterone synthesis. • During pregnancy the predominant oestrogen is oestriol produced by the placenta. 2 • Prolactin concentration gradually increases during the first two trimesters and then rises steeply, to about 8000 mU/L, in the third trimester. • Prolactin, oestrogens, progesterone and (human) placental lactogen stimulate breast development in preparation for lactation. High plasma oestrogen concentrations inhibit milk secretion; lactation can start only when plasma concentrations fall after delivery of the placenta. Initially lactation depends on prolactin. 3 • Suckling stimulates secretion of the hormone, but, even during lactation, plasma prolactin concentrations fall progressively post partum and reach non-pregnant levels after 2 or 3 months. • Apart from the effects on the breast, the high plasma concentration of prolactin interferes with gonadotrophin and ovarian function and produces a period of relative infertility. 4 Monitoring pregnancy (placental function) • Substances produced by the fetus or placenta (fetoplacental unit) may be measured in maternal plasma or urine to detect fetal abnormalities or to monitor the progress of the pregnancy, for example • low urine unconjugated oestriol (E3) is associated with poor pregnancy outcome. 5 Such sampling is relatively safe and simple, but occasionally more invasive testing, such as of amniotic fluid obtained by amniocentesis, may be needed. However, the ability to visualize the fetus using ultrasound and the use of cardiotocography for detecting fetal heart rate have reduced the need for such tests. 6 Human chorionic gonadotrophin • The secretion of hCG by the placenta reaches a peak (rising to about 500 000 U/L) at about 13 weeks of pregnancy and then falls. • The fetoplacental unit then takes over hormone production, and the secretion of both oestrogen and progesterone rises rapidly. • Plasma or urinary hCG concentrations, which give positive results at 1 or 2 weeks after the first missed menstrual period, are most commonly used to confirm pregnancy . 7 • However, by using more sensitive immunoassay techniques, plasma hCG may be detected soon after implantation of the ovum and before the first missed period. • Measurement of plasma hCG is also useful if an ectopic pregnancy is suspected, in conjunction with ultrasonography, or if the patient is being treated for infertility. 8 Serial hCG measurements may be used to assess the progress of early pregnancy; single values are diffi cult to interpret because of the wide reference range. • As a rough guide, plasma concentrations should double every 2 days in a normal pregnancy. • Raised plasma hCG not due to pregnancy can be due to gestational or nongestational trophoblastic neoplasia or the menopause. 9 Human placental lactogen • This is a peptide hormone synthesized by the placenta. It is detectable in maternal plasma after about the eighth week of gestation. it has been used to assess the likelihood of threatened miscarriage . to monitor late pregnancy, but now is rarely used. 10 Detection of fetal abnormalities • Some fetal abnormalities may be diagnosed by tests carried out on maternal plasma or amniotic fluid. • Amniocentesis is a procedure by which amniotic fluid is obtained through a needle inserted through the maternal abdominal wall into the uterus and is usually carried out after about 14 weeks’ gestation. • The procedure carries a small risk to the fetus. 11 • Both the safety and the reliability of the procedure can be improved if combined with ultrasound examination in order to locate the position of the fetus, placenta and maternal bladder. • Analytical results may be misleading if, for example, the specimen is contaminated with maternal or fetal blood or maternal urine, is not fresh or is not properly preserved. 12 Close relation between the clinician and the laboratory staff helps to ensure the suitability of the specimen and the speed of the assay. Amniotic fluid is probably derived from both maternal and fetal sources, but its value in reflecting abnormalities arises from its intimate contact with the fetus and from the increasing contribution of fetal urine in later pregnancy. 13 Detection of neural tube defects • α-Fetoprotein (AFP) is a low-molecular-weight glycoprotein synthesized mainly in the fetal yolk sac and liver. Its production is almost completely repressed in the normal adult. It can diffuse slowly through capillary membranes and appears in the fetal urine, and hence in the amniotic fluid, and in maternal plasma. 14 • Severe fetal neural tube defects, such as open spina bifida and anencephaly, are associated with abnormally high concentrations in these fluids. • The reason for this is not clear, but the protein may leak from the exposed neural tube vessels. 15 • As well as neural tube defects, the causes of raised AFP concentration in amniotic fl uid and maternal plasma include: • multiple pregnancy, • serious fetal abnormalities, • exomphalos. • In some countries, pregnant women attending for antenatal care are offered plasma AFP assay at between 16 and 18 weeks’ gestation to screen for the presence of a fetus with a neural tube defect (although highresolution ultrasound is beginning to replace this test). 16 The gestational age should be confirmed by ultrasound, which should also exclude a multiple pregnancy as a cause of high concentrations. • Positive results should be confirmed on a fresh sample, which, if still high and if the diagnosis has not been confirmed by ultrasound, may be followed by AFP estimation on amniotic fluid. • 17 • This is a more precise diagnostic test and yields fewer false-positive results than plasma assays if sampling is properly performed. • It should be reserved for subjects known to be at risk, either because of a family history of neural tube defects or because of the finding of a high concentration in maternal plasma with a normal or equivocal ultrasound scan. 18 • Amniotic fluid acetylcholinesterase assay is now rarely used to detect certain fetal malformations, • including neural tube defects and exomphalos. • It gives reliable results up to about 23 weeks’ gestation. • The interpretation of the result is less dependent on fetal age than AFP, but is equally invalidated by contamination with fetal or maternal blood. • The assay is less widely available than that for AFP. 19 Detection of Down’s syndrome • Low maternal plasma AFP and unconjugated oestriol, and raised hCG and inhibin A concentrations, measured between 15 and 20 weeks’ gestation, are associated with an increased risk of the fetus having Down’s syndrome (trisomy 21) and used as a second trimester screening test. This combination of tests (quadruple or Quad test) to screen for the congenital disorder is available in specialized laboratories. 20 Fetal nuchal translucency determined by highresolution ultrasound, along with raised pre-β-hCG and reduced pregnancy-associated plasma protein A (PAPP-A), are used as a first trimester (10–14 weeks’ gestation) screening test; increased nuchal thickness is associated with chromosomal abnormalities. A definitive test is amniocentesis, which allows the collection of fetal cells for karyotyping. The • risk of Down’s syndrome increases with maternal age. 21 Detection of other fetal abnormalities • Chromosomal abnormalities and some inborn errors of metabolism may be detected by cytogenetic, biochemical or enzymatic assays on cells cultured from amniotic fluid or after biopsy of chorionic villi. • These tests are performed only in special centres and usually on individuals with a family history of a genetic condition. • Circulating fetal (DNA) in maternal blood may also prove to be useful. 22 Assessment of fetomaternal blood group incompatibility • Rhesus or other blood group incompatibility has effects on the fetus, which may be assessed by measuring amniotic fluid concentrations of bilirubin in conjunction with maternal antibody titres. Normally bilirubin concentrations in amniotic fluid decrease during the last half of pregnancy. The concentrations at any stage correlate with the severity of haemolysis. 23 The result is read off a Liley chart relating optical density of amniotic fluid at 450 nm (an indirect measure of bilirubin) against gestational time. Such tests may allow the optimum time for induction of labour or the need for intrauterine transfusion to be assessed 24 Assessment of fetal lung maturity • The examination of amniotic fluid has also been used to assess pulmonary maturity. • Immature lungs do not expand normally at birth and may cause neonatal respiratory distress syndrome (hyaline membrane disease), with the need for respiratory support. • It is therefore important to have evidence of pulmonary maturity before labour is induced. • At about 32 weeks’ gestation, the cells lining the • fetal alveolar walls start to synthesize a surfacetensionlowering complex 25 • (surfactant), 90 per cent of which is the phospholipid lecithin, which contains palmitic acid. • Surfactant is probably washed from, or secreted by, the alveolar walls into the surrounding amniotic fluid, inwhich both lecithin and palmitic acid concentrations steadily increase. • The concentration of lecithin, relative to another lipid, sphingomyelin, which remains constant in amniotic fluid, can be measured. 26 A rise in the lecithin to sphingomyelin ratio may help determine pulmonary maturity, and a ratio less than 2 implies immaturity. This invasive test is rarely indicated now as steroids, which induce surfactant synthesis, are sometimes given to patients who have premature rupture of the membranes. 27 Maternal biochemical changes in pregnancy • Weight gain of about 12 kg occurs due to increased maternal fluid retention, increased maternal fat stores and also the products of conception, including the • fetus, placenta and amniotic fluid. • Many plasma constituents are influenced by sex hormones. For example, the reference ranges of plasma urate and iron differ in males and females after puberty. 28 • Therefore it is not surprising to find that during pregnancy the very high circulating concentrations of oestrogens and progesterone alter the concentrations of many substances in plasma (Table 10.1). • The plasma concentrations of many specifi c carrier • proteins increase during pregnancy, accompanied by a proportional increase of the substance bound to them, without any change in the unbound free fraction. 29 • Because the protein-bound fraction is a transport form and because, in all cases, it is the free substance that is physiologically active, this rise in concentration is of importance in the interpretation of the results of such assays as those of plasma thyroxine. • Other changes in maternal plasma are due to progressive haemodilution by fluid retained during pregnancy. This is maximal at about the thirtieth week and the effects are most evident in reduced concentrations of albumin, and of calcium, which is bound to albumin. 30 These changes are more marked in pre-eclamptic toxaemia, in which fluid retention may be greater than normal. The glomerular filtration rate (GFR) increases and creatinine clearance can be over 140 mL/min by about 28 weeks. There is a reduced renal threshold for glucose and increased excretion of urate and some amino acids. • There is a mild increase in ventilation rate. Oxygen consumption is increased, but PO2 remains fairly constant despite a small decrease in PCO2. There is increased fasting glucose utilization, and therefore fasting glucose concentration is lower. 31 • Renal glycosuria is common in pregnancy and sometimes in individuals taking oral contraceptives. • The GFR increases by about 50 per cent during pregnancy, resulting in a reduced plasma creatinine. • Glycosuria may partly be due to an increased glucose load in normal tubules. positive protein and purine balance during the growth of the fetus and the increase in GFR that occurs during pregnancy result in lowered maternal plasma urea and urate concentrations. 32 • Plasma alkaline phosphatase activity rises in some women during the last 3 months of pregnancy due to the presence of the placental isoenzyme and should not be misinterpreted . • Placental alkaline phosphatase does not cross the placenta and therefore it is not present in the plasma of the newborn infant. 33 34 35 Delivery • During delivery, blood gases and lactate can be measured in fetal blood to monitor for hypoxia. • Capillary blood samples may be collected from the fetal scalp during delivery. • Transcutaneous oxygen electrodes can determine fetal PO2. 36 Hypertension in pregnancy and pre-eclampsia • Pregnancy-induced hypertension or pre-eclampsia is associated with convulsions (as occurs in eclampsia), oedema, impaired renal function, proteinuria and maternal death as well as with placental insufficiency and intrauterine fetal growth retardation. • Pre-eclampsia is defined as a blood pressure taken • on two occasions, at least 6 h apart, of 140/90 mmHg or greater (after 20 weeks’ gestation) in a woman with previously normal blood pressure and who has proteinuria (defined as 300 mg protein in 24-h urine collection). 37 • Plasma urate may rise in pre-eclampsia and is predictive of maternal complications. • Detection and follow-up of trophoblastic • tumours • Trophoblastic tumours (hydatidiform mole, choriocarcinoma), which may follow abnormal pregnancy or a miscarriage, and some teratomas secrete hCG, which can be estimated in plasma or urine by sensitive tests allowing early detection and treatment of recurrence. 38 However, these tests will not necessarily differentiate pregnancy or retained products of conception from recurrence of a tumour, because plasma hCG concentrations rise in both situations. In monitoring trophoblastic tumours it is important to monitor plasma hCG down to undetectable levels. 39 INFERTILITY • Infertility can be defined as primary when conception has never occurred despite at least 1 year of unprotected coitus, and secondary when there has been a previous pregnancy, either successful or not. • Investigation earlier than at 1 year may be appropriate if the woman is more than 35 years old or where pregnancy is associated with other risks. • In cases of infertility, both partners should be investigated. 40 The history should include coital frequency and success, serious illnesses, use of alcohol and drugs, and sexually transmitted diseases. • Female Examination should include looking for anorexia nervosa, hirsutism, virilism, galactorrhoea and ambiguous genitalia. A history should also be taken for medications and drugs . 41 Investigations • A woman may be infertile despite having a clinically normal menstrual cycle (about 95 per cent of such cycles are ovulatory). Thus, even if the cycle seems to be regular, it is important to determine whether ovulation is occurring and if luteal development is normal. • Anovulatory infertility is probably the most common form of female infertility and is associated with • oligomenorrhoea or amenorrhoea. 42 • • • • If the patient is menstruating regularly, measure plasma progesterone concentration during the luteal phase on day 21 of the cycle. A normal plasma concentration is strong evidence that the patient has ovulated. • A low plasma concentration of < 30 nmol/L suggests either ovulatory failure orimpaired luteal function. • This investigation should be repeated on more than one occasion. • 43 • The most common cause of a low progesterone concentration (< 30 nmol/L) is inaccurate sample timing, although, if authentic, it suggests lack of ovulation. • However, a plasma progesterone concentration of more than 100 nmol/L suggests pregnancy. • Follicular development and ovulation may be • monitored by ovarian ultrasound examination. • Polycystic ovary syndrome should be excluded • Plasma follicle-stimulating hormone (FSH), LH, oestrogen and testosterone concentrations are useful, as is the exclusion of thyroid disease. 44 • If there is primary amenorrhoea, consider karyotyping the patient, for example Turner’s syndrome (45,XO). • Sometimes histological examination of an endometrial biopsy specimen or the appearance of cervical mucus can indicate whether luteal function is normal. 45 An oral progestogen challenge can be used: a withdrawal bleed 5–7 days later implies adequate endometrial oestrogen, whereas failure to bleed despite oestrogen treatment implies uterine disease. • Hyperprolactinaemia should be excluded by checking the plasma prolactin concentration. • Do the plasma FSH, LH and oestrogen results suggest hypergonadotrophic hypogonadism or • hypogonadotrophic hypogonadism? 46 • In the presence of amenorrhoea, a plasma FSH of more than 40 U/L is suggestive of ovarian failure. • Low concentrations of plasma gonadotrophins may necessitate a gonadotrophin-releasing hormone (GnRH) test to look for pituitary or hypothalamic disease . • Anti-Müllerian hormone (AMH) is released by granulosa cells of the ovarian follicle and low serum concentrations suggest poor ovarian ‘reserve’ (the size of the ovarian ovum supply). 47 Serum AMH may, thus, have a place in the investigation of infertility. • Male • Systemic illness, for example cystic fibrosis, thyroid disease, gynaecomastia, eunuchoid appearance and ambiguous genitalia, should be excluded and any history of mumps, drugs and medications should be obtained. • Investigations • Semen analysis: the volume should be at least 2 mL. 48 • There should be more than 20× 10 9/L spermatozoa, more than 50 per cent being motile at 4 h post ejaculation and more than 30 per cent normal morphology. A post-coital test is useful so that cervical mucus can be examined for the presence of spermatozoa and their activity. Sperm antibodies may exist. • Plasma testosterone, LH and FSH concentrations should be measured. • – 49 • Raised plasma FSH and LH concentrations with a low testosterone concentration (hypergonadotrophic hypogonadism) indicate a testicular problem such as Leydig cell failure. • Low plasma FSH and LH and testosterone concentrations suggest pituitary or hypothalamic disease (hypogonadotrophic hypogonadism). • In the case of the latter, a GnRH test may be required . 50 • A raised plasma FSH concentration in comparison with LH may indicate seminiferous tubular failure, irrespective of the plasma testosterone concentration. • There is usually azoospermia or oligospermia. Oligospermia with a low plasma FSH concentration suggests pituitary or hypothalamic disease. • If there is evidence of feminization, karyotype should be considered. 51 • This should also be considered if azoospermia is present, for example Klinefelter’s syndrome (47,XXY). • Plasma prolactin should be measured and • hyperprolactinaemia and thyroid disease excluded Defects of the male reproductive tract may also be found and necessitate a urology opinion. An hCG stimulation test may be indicated if absence of testes is suspected or to assess Leydig cell reserve • 52 • Some tumours can release b-hCG or oestrogens and may induce features of feminization. • These can be assayed in plasma if the cause of infertility is unclear. • Sometimes, despite both partners being investigated, no cause for the infertility can be found. Some couples decide to try in vitro fertilization 53 SOME DRUG EFFECTS ON THE HYPOTHALAMIC–PITUITARY– GONADAL AXIS • The combined oral contraceptive pills contain synthetic estrogens and progestogens and suppress pituitary gonadotrophin secretion and thus inhibit ovulation. • Withdrawal mimics involution of the corpus luteum and results in menstrual bleeding. • Progesterone or progestin only (mini) pills may inhibit ovulation and also thicken cervical mucus, thereby inhibiting sperm penetration. 54 • Clomiphene blocks oestrogen receptors in the hypothalamus and so prevents negative feedback. It may stimulate gonadotrophin release, even when circulating oestrogen concentrations are high. Clomiphene may be used to induce ovulation in patients with amenorrhoea or infertility. Gonadotrophin treatment may be used if clomiphene fails to induce ovulation. 55 This therapy may cause dangerous follicular enlargement due to hyperstimulation, or may stimulate many follicles and so cause multiple pregnancy. Treatment must therefore be monitored either by frequent plasma oestradiol estimations (which would be expected to be very high) or by ovarian ultrasound examination. • Ovulation may be assessed by demonstrating rising plasma progesterone concentrations or by ultrasound. 56 • Gonadotrophins may also be used to stimulate the production of enough oocytes to enable them to be ‘harvested’ for in vitro fertilization or gamete intrafallopian transfer. • Gonadotrophin-releasing hormone treatment can be used for patients with infertility secondary to hypogonadotrophic hypogonadism. It is given subcutaneously in pulses, such as every 90 min, using a portable syringe pump. 57 Bromocriptine may reduce high plasma prolactin concentrations, after which menstruation may resume and fertility may be restored. 58