The first trimester screen [nuchal translucency, pregnancy-associated plasma protein A (PAPP-A), and the beta subunit human chorionic gonadotropin ([beta]-hCG)] used for Down syndrome risk assessment may be useful for stillbirth risk assessment. PAPP-A is a protease for insulin-like growth factor (IGF) binding proteins 4 and 5. Low PAPP-A will lead to decreased free IGF. IGFs are crucial for regulation of fetal growth and trophoblast function. In a cohort of 7934 pregnancies, PAPP-A, defined as <5th class="fulltext-RA" href="http://ovidsp.tx.ovid.com.ezproxy.galter.northwestern.edu/sp-3.2.4b/ovidweb.cgi?&S=FFAEFPFFLFDDDDNFNCDLFBJCLMOKAA00&Link+Set=S.sh.15.17.19%7c24%7csl_10#59" style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; padding-top: 0px; padding-right: 0px; padding-bottom: 0px; padding-left: 0px; font-weight: normal; text-decoration: none; color: rgb(7, 104, 169); ">7
The role of second trimester serum screening using [alpha]-fetoprotein, hCG, uE3, and inhibin-A, in stillbirth prediction has been studied. Unexplained elevated maternal serum alpha-fetoprotein (in the absence of neural tube defect or ventral wall defect) has been associated with stillbirth via a defect in placentation.
The role of second trimester serum screening using [alpha]-fetoprotein, hCG, uE3, and inhibin-A, in stillbirth prediction has been studied. Unexplained elevated maternal serum alpha-fetoprotein (in the absence of neural tube defect or ventral wall defect) has been associated with stillbirth via a defect in placentation. In a large study of first and second trimester biomarkers, low PAPP-A was not associated with high AFP, suggesting they reflect different aspects of placental dysfunction. *****The OR for antepartum stillbirth for women with a high AFP was 2.5, for women with a low PAPP-A was 2.2, and for women with both low PAPP-A and high AFP was 36.7. Thus, women with low PAPP-A and high AFP had a synergistic increase in stillbirth risk.10 Predictive Markers: Uterine Artery Doppler During pregnancy the spiral arteries undergo a series of vascular transformations to ensure a more than 10-fold increase in the blood supply to the intervillous space. In conditions associated with failure of trophoblastic invasion of the spiral arteries, Doppler studies demonstrate that impedance to flow in the uterine arteries is increased. A review of Doppler studies performed in unselected populations found that abnormal uterine artery studies at 22 to 24 weeks was associated with increased rates of development of preeclampsia, fetal growth restriction, and perinatal death.11In pooled analyses of 4 studies, the likelihood of fetal or perinatal death in those with an abnormal Doppler result was about 2.4 times higher than the background risk. | Predictive Markers: Ultrasound and fetal growth | | Fetal growth restriction is the single largest category of conditions associated with stillbirth and is found in the majority of the cases previously considered unexplained. mproved antenatal detection of fetal growth restriction is crucial to having a positive impact on stillbirth prevention. In up to one-third of pregnancies, fetal growth restriction may be missed and is incorrectly diagnosed about 50% of the time.14Without the correct diagnosis of fetal growth restriction, antenatal surveillance may not be performed and timely delivery of the fetus at risk for stillbirth from an unfavorable intrauterine environment will not occur. The authors proposed initiating antepartum surveillance at 32 weeks or later, acknowledging that a rare patient with earlier fetal compromise may be missed.16 American Congress of Obstetricians and Gynecologists (ACOG) supports this conclusion and states that starting antepartum testing at 32 to 34 weeks is appropriate in healthy pregnant women with a history of stillbirth. In pregnancies with multiple or particularly worrisome high-risk conditions (eg, chronic hypertension with suspected fetal growth restriction), testing may begin as early as 26 to 28 weeks of gestation.17 Fetal kick count t is customary to recommend that women with prior stillbirth be instructed on fetal movement assessment and women who report decreased fetal movement undergo follow-up fetal surveillance. Because stillbirths may be preceded by a reduction or cessation of fetal movements, recognition of decreased fetal movement, followed by testing to confirm fetal compromise and expedite delivery, may prevent such deaths. This observation is the basis for fetal movement assessment by the mother (“kick counts”) as a means of antepartum fetal surveillance. Reviews of stillbirth indicate that almost half of it occurs in low-risk pregnant women with structurally normal fetuses, women who are not candidates for traditional antepartum surveillance. The recommendation is that all women with a prior stillbirth should be instructed to begin fetal movement assessment from 26 to 28 weeks of gestation and those who report decreased fetal movement should have follow-up fetal surveillance.16 THERAPY FOR PREVENTION OF RECURRENT STILLBIRTH Improved treatment of maternal medical disorders such as diabetes and hypertension has clearly decreased the risk of stillbirth in these situations. The risk of stillbirth associated with antiphospholipid antibody syndrome is decreased with treatment with prophylactic heparin or low molecular weight heparin and low-dose aspirin. ASPIRIN THERAPY There has been a growing interest in the use of low-dose aspirin to improve subsequent pregnancy after fetal death. Low-dose aspirin is an antiplatelet agent, which irreversibly inhibits platelet cyclo-oxgenase thereby decreasing the production of thromboxane A2, a potent vasoconstrictor. Aspirin use was promoted by the recognition that thrombosis was central to the pathophysiology of antiphospholipid syndrome and was first used to treat recurrent pregnancy loss in women with antiphospholipid syndrome. There is speculation that low-dose aspirin may improve the uteroplacental circulation by decreasing placental thrombosis, infarction, and insufficiency, which are associated with fetal death. Management of the Subsequent Pregnancy During the preconception or initial visit, the obstetric provider should obtain a detailed medical and obstetrical history; review the evaluation of the prior stillbirth; determine recurrence risk based on available information; and discuss the risk of other obstetrical complications such as placental abruption, preterm delivery, and cesarean delivery. Counseling should be individualized to the woman's particular circumstances. For example, if a couple experienced a previous second trimester stillbirth as a result of a cystic hygroma and nonimmune hydrops due to Turner syndrome, they can be reassured that it is a sporadic condition and is not associated with advanced maternal age. However, in the subsequent pregnancy one can offer nuchal translucency ultrasound to provide reassurance. First trimester sonogram should be performed for accurate dating. Although the predictive value for maternal serum screening in the first trimester is low, performing maternal serum PAPP-A may provide some reassurance regarding the recurrence risk of stillbirth from “placental causes.” In the second trimester, fetal anatomic survey may be performed at 18 to 20 weeks. Similar to the first trimester screen, the predictive value of second trimester analytes for stillbirth (MSAFP, hCG, estriol, and inhibin-A) is poor but may provide additional information. MSAFP testing may be associated with the presence of a placental abnormality if it is elevated in a chromosomally normal fetus. Likewise, an abnormally elevated [beta]-hCG may be associated with an increased risk of stillbirth but has poor predictive value. Women with a prior stillbirth should be already counseled and monitored clinically based on their previous history of stillbirth. Although there is no evidence to support further alteration in the management plan based on abnormal serum screening, the clinician may consider increasing the frequency of antepartum surveillance. Because nearly half of all stillbirths are associated with fetal growth restriction, serial ultrasounds for fetal growth may be performed, starting at 28 weeks. If there is evidence of fetal growth restriction then the frequency of ultrasound to monitor fetal growth may be increased, usually to every 2 to 4 weeks and Doppler studies and antepartum fetal testing performed. The ACOG technical bulletin on intrauterine growth restriction outlines management strategies. In all women with a previous stillbirth, maternal assessment of fetal movement or fetal kick counts may be started at 28 weeks of gestation. Antepartum fetal testing such as twice weekly nonstress tests and amniotic fluid index or biophysical profiles may be initiated at 32 weeks or 1 to 2 weeks before the gestational age of the previous stillbirth. In women with especially high-risk medical or obstetric conditions, testing should be initiated at 26 to 28 weeks.17 Caution should be used when interpreting the antepartum fetal surveillance of a fetus below 32 weeks of gestation. he delivery plan should be discussed with the couple well in advance of the third trimester. The timing of the delivery depends on maternal anxiety, cervical ripeness, and the cause of the previous stillbirth. In most cases, if the pregnancy is uncomplicated, elective induction at 39 weeks of gestation may be appropriate. In summary, there is limited information to support each step of the management schema outlined in Table 2. The key for the clinician is to gather as much information regarding the circumstances of the previous stillbirth, individualize management of the subsequent pregnancy, be compulsive in monitoring the development of obstetric complications, and to provide support and reassurance to a couple likely to be anxious during their next pregnancy.
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