Spontaneous Pregnancy Loss
Any pregnancy that implants outside of the uterine endometrial cavity is called an ectopic pregnancy. Despite improved diagnostic and therapeutic approaches to this disorder, ectopic pregnancy remains the most common cause of pregnancy-related maternal death in the first 12 weeks of pregnancy. A ruptured ectopic preganacy is a medical emergency. Overall, ectopic pregnancies cause 4–10% of pregnancy-related deaths with maternal hemorrhage the ultimate fatal pathway. The incidence of ectopic pregnancy rose in the USA from the 1950s through the 1990s when national recording was halted. At that time the best estimate for the incidence of ectopic pregnancy was 2 in 100 pregnancies.
The known risk factors for ectopic pregnancy focus on alterations in appropriate function of the fallopian tube. The fallopian tube is not simply a conduit for sperm and embryo passage but rather a delicate microenvironment in which cilia help to move the fluids within the fallopian tubes that transport gametes and blastocysts. Decreased ciliary movement due to exposure to elevated levels of progesterone or direct damage, ciliary and cellular destruction as the result of trauma or infectious disease, and tubal blockage from surgical interruption or scarring all promote abnormal embryo transport. Over 90% of ectopic pregnancies can be directly related to tubal pathologies. From highest to lowest risk, these include: (i) previous ectopic pregnancy; (ii) tubal sterilization or reconstructive surgery; (iii) in utero exposure to diethyl stilbesterol (DES); (iv) prior genital tract infection (often silent, particularly with chlamydia); (v) infertility; (vi) multiple sexual partners; (vii) cigarette smoking; (viii) young age at initiation of sexual activity; (ix) maternal age at conception of >35 years; and (x) the practice of vaginal douching. The remaining 10% of ectopic pregnancies are of unknown etiology. They may result from embryonic factors, although there is no increase in embryonic or fetal karyotypic abnormalities when ectopic gestations are compared with intrauterine gestations. Two commonly cited risk factors for ectopic pregnancy are frequently misinterpreted. The use of assisted reproductive techniques, including in vitro fertilization, has recently been shown to have little effect on the overall incidence of ectopic pregnancies, although the rate of the otherwise rare heterotopic pregnancy (an ectopic gestation coexisting with an intrauterine gestation) is increased. The use of an intrauterine contraceptice device (IUD) protects against all pregnancies and thereby decreases the overall ectopic pregnancy rate. However, when pregnancy does occur with an IUD in place, the gestation is more likely to be ectopic.
Almost all ectopic pregnancies (∼95%) occur in the fallopian tube (Fig. 36.1). The most common site of implantation of an ectopic gestation within the fallopian tube is in its ampullary portion. Ampullary and fimbrial ectopic gestations frequently dislodge and abort prior to rupture. As the interstitial portion of the fallopian tube has thick muscular support, interstitial ectopic gestations may develop to relatively late gestational ages prior to clinical presentation. Cervical, interstitial and heterotopic (intrauterine + ectopic) ectopic pregnancies are rare but appear to be more frequent after in vitro fertilization. Ovarian ectopic gestations are random events without documented risk factors. Abdominal ectopic pregnancies are exceedingly uncommon.
A miscarriage is defined as a spontaneous pregnancy loss before 20 weeks’ gestation; the medical term is spontaneous abortion. Miscarriages occur in 15% of clinically recognized pregnancies. The total number of human conceptions far exceeds the number of births. It is estimated that at least 60% of all human conceptions do not result in a viable pregnancy, with the majority of these being spontaneously lost before or shortly after an expected menses. These pregnancies can be documented by the appearance and disappearance of a pregnancy-specific hormone (human chorionic gonadotropin, hCG; Chapter 18) from the maternal bloodstream. It is clear that there is a sensitive and effective mechanism in the maternal system that can detect abnormal pregnancies and prevent survival of the overwhelming majority.
It is impossible to know the causes of those pregnancy losses that occur around the time of the expected menses, the so-called biochemical pregnancies. They probably result from a myriad of abnormalities and pregnancy loss represents the final common clinical outcome. Abnormalities may occur in the conceptus or in the microenvironment of the maternal reproductive tract at the time of conception. The latter may result from congenital or acquired anatomic defects in the uterus. They may also be caused by endocrine abnormalities that alter the maturation of the ova prior to ovulation, the development of the embryo during transit to the intrauterine cavity or the growth and maturation of the endometrium as it prepares for implantation.
It is known that the most frequent cause of overt miscarriage is a chromosomal abnormality in the conceptus. At least 60% of miscarriages have a gross chromosomal abnormality that can be detected in the expelled fetal material. Table 36.1 lists the frequency of specific chromosomal abnormalities in miscarried material. It is usually not possible to identify a specific etiology for the remaining 40% of isolated spontaneous pregnancy losses, although some are the result of an under- lying problem that can lead to recurrent pregnancy losses.
Increasing maternal age is accompanied by an increase in the frequency of chromosomal abnormalities in embryos and fetuses and in the rate of spontaneous pregnancy loss. Age-related egg abnormalities are thought to account for the majority of this effect, consistent with the dramatic rise in spontaneous pregnancy loss that is seen among mothers who are 35 or older. This effect is not noted in association with paternal age until the father of the pregnancy has reached at least 55 or 60 years. Even then, the effect is more subtle. Interestingly, an increase in the frequency of certain psychiatric disorders among off- spring is associated with paternal aging. Ovum deterioration is thought to explain most of the decline in fertility after the maternal age of 40. Most spontaneous pregnancy losses are heralded by vaginal bleeding and a fall in maternal serum hCG during the first trimester of pregnancy. These losses are subcategorized by clinical presentation a soutlined in Table 36.2. During the first 12 weeks of pregnancy, maternal serum hCG normally rises with a doubling time of about 48–72 h. The hCG level will typically plateau or drop before tissue is passed in pregnancies with threatened miscarriages. Thus, it would appear that the common signaling mechanism for abnormal pregnancies may be a disruption in the expression of the hCG gene located on chromosome 19. How trisomies and other chromosomal aneuploidies produce this effect on the hCG gene is not known. Moreover, fetuses with trisomy 13, trisomy 18 and trisomy 21 (Down syndrome) can be carried to viability. It is equally puzzling how these three trisomies escape the hCG signaling surveillance. Trisomy 21 is actually associated with an increase in circulating hCG in the second trimester. This finding is used during the first trimester of pregnancy in serum screening regimens that determine Down syndrome risk.
Recurrent pregnancy loss
Because one in every six pregnancies will result in a miscarriage, it is not uncommon for a woman to experience one or more spontaneous losses during her pregnancy attempts. A woman who has had two consecutive spontaneous losses, but has never carried a pregnancy to full term, has a 35% chance of a loss in her next pregnancy. If a woman has successfully carried a pregnancy in the past, she will not reach a similar level of risk for spontaneous loss in a subsequent pregnancy until she has experienced three losses. For this reason, diagnostic work-up should be initiated in women with two losses if no successful pregnancies have occurred in the past. Clinicians may choose to wait until a third loss in patients who have had successful pregnancies. It is reasonable to consider initiating diagnostic testing at an earlier point in the clinical history among women with infertility or advanced maternal age.
Causes of recurrent pregnancy loss (recurrent miscarriage) include parental chromosome translocations; structural uterine abnormalities such as longitudinal septa and intrauterine adhesions; endocrine disorders, including luteal phase defects, polycystic ovary syndrome (PCOS), hyper prolactinemia, thyroid dysfunction and poorly controlled diabetes mellitus; autoimmune conditions such as the anti phospholipid antibody syndrome and a variety of heritable thrombophilias. Couples experiencing recurrent pregnancy losses are appropriately anxious and should be evaluated for an underlying cause in the hope that a specific intervention may prevent future spontaneous pregnancy losses.
The term stillbirth is synonymous with fetal death or demise. All three terms refer to the delivery of a fetus after 20 menstrual weeks that shows no signs of life. Stillbirth rates vary widely between developed countries where the overall rate is 6–7 in 1000 births and developing countries where the rate may be as high as 30 in 1000 births. Similarly, the etiologies vary by environment and resources; in developed countries fetal growth restriction, congenital or karyotypic anomalies, and maternal medical diseases account for many stillbirths whereas pre-eclampsia, obstructed labor and infection are more common causes in less developed countries. Fetal death before the onset of labor (antepartum fetal death) is much more common than fetal death during labor or delivery (intrapartum fetal death).
There are many causes of stillbirth. An etiology is never identified in at least 25% of stillbirths (unexplained stillbirth) even after complete evaluation. Fetal causes for stillbirth include chromosomal and genetic abnormalities and congenital malformations. Placental causes include premature separation before delivery (abruption), hemorrhage from the fetus into the maternal circulation (fetomaternal hemorrhage) and umbilical cord complications. Other causes such as intrauterine infection and fetal growth restriction are multifactoral, often involving the mother and either placenta or fetus.