I decided to do Perinatology ABCs for Prematurity Awareness Month this year.
A is for abruptio placentae, aka placental abruption. Partial separation of the placenta from the uterus before delivery often precipitates contractions (and preterm labor). Complete separation of the placenta from the uterus obviously necessitates immediate delivery. There are a variety of risk factors associated with abruptio placentae, including maternal hypertension, advanced maternal age, chorioamnionitis, blunt external maternal trauma, premature rupture of membranes, and non-vertex presentation. Peter’s placenta apparently separated from my uterus when my water broke, immediately prior to delivery. It made for a dramatic entry into the world.
B is for bacteriuria (everything from asymptomatic UTIs to pyelonephritis) and bacterial vaginosis. Infection is an important and common risk factor for preterm labor and delivery. Even pneumonia, periodontal disease, and malaria are associated with preterm birth. Intrauterine infections, however, are the leading cause of infection-associated preterm birth, and the most common route of intrauterine infection is by ascension from the vagina and cervix. Bacteria can be isolated from the amniotic fluid of 12.8% of women experiencing preterm labor with intact membranes and 22% of those who go on to deliver a premature neonate (as a result of preterm labor with intact membranes). For comparison, less than 1% of pregnant women who are full term (and NOT in labor) have bacteria in the amniotic fluid.
C is for cervical incompetence (aka cervical insufficiency). Cervical incompetence can result in second trimester pregnancy loss when it leads to painless cervical dilation and delivery of a previable fetus (i.e., <23 weeks gestational age). Cervical incompetence is believed to result from structural defects in the cervix that result in reduced tensile strength, e.g., a congenital abnormality, collagen disorder, or trauma due to obstetric or gynecologic procedures. Cervical incompetence can be managed through placement of a cervical cerclage (i.e., tying the cervix shut), introduction of a cervical passary (i.e., placing a door in front of or ring around the cervix), or administration of progesterone therapy (vaginal or systemic)
D is for diaphragmatic hernia, a life-threatening birth defect characterized by pulmonary hypoplasia, decreased cross-sectional area of pulmonary vasculature, and alterations of the surfactant system. It occurs at a frequency of 1 in every 2000-3000 births and accounts for 8% of all major congenital anomalies. It is associated with preterm birth because women carrying a child with a diaphragmatic hernia are at risk for polyhydramnios (increased amniotic fluid levels can cause preterm labor). After delivery, diaphragmatic hernias are managed with respiratory respiratory support, blood pressure management, and surgical closure of the diaphragmatic defect.
E is for eclampsia. Hypertension complicates ten percent of all pregnancies, and half of those cases occur in conjunction with preeclampsia or eclampsia. Eclampsia is technically a complication of severe preeclampsia: grand mal seizures and/or unexplained coma. HELLP is another presentation of severe preeclampsia marked by hemolytic anemia, elevated liver functions tests, and low platelet counts. For the baby, preeclampsia results in fetal growth restriction, reduced amniotic fluid, and abnormal fetal oxygenation. Due to the life-threatening nature of severe preeclampsia, preterm delivery is often indicated. Delivery of the baby is the only definitive treatment for preeclampsia, but IV magnesium sulfate is often given to mothers with preeclampsia to prevent progression to eclampsia or to stop eclamptic seizures. Seizures not responsive to magnesium sulfate may be treated with benzodiazepines or phenytoin. Preeclampsia-associated hypertension can be managed with labetalol, hydralazine, or nifedipine after magnesium sulfate infusion.
F is for fetal distress. Fetal distress is most commonly an issue during labor, but it is sometimes an indication for preterm delivery prior to the onset of labor. Fetal distress is usually a sign that the baby is not getting enough oxygen. This may be due to placental insufficiency (as in preeclampsia), placental abruption, cord compression, premature closure of the ductus arteriosus, etc. Blood chemical imbalances may also cause fetal distress, as in cholestasis, uncontrolled diabetes, or kidney disease. Signs of fetal distress include decreased fetal movement, non-reassuring fetal heart rate, meconium in the amniotic fluid, and fetal metabolic acidosis.
G is for gestational diabetes. Most women with gestational diabetes deliver healthy babies, but gestational diabetes does carry an increased risk of preterm labor. Women who are diagnosed with gestational diabetes prior to 24 weeks are 10 times more likely to deliver early than those diagnosed later in pregnancy. Unfortunately, gestational diabetes also carries an increased risk of respiratory distress for the newborn on top of the risk that preterm delivery carries. Even if the mother does not go into early labor, early delivery may be indicated if the gestational diabetes has been poorly-controlled.
H is for hemolytic disease of the (fetus and) newborn. Hemolytic disease of the newborn occurs when the antibodies of a mother who has been sensitized to a foreign erythrocyte antigen pass through the placenta and attack the red blood cells of a fetus that expresses that antigen. (This includes ABO hemolytic disease of the newborn, Rh disease, and anti-Kell hemolytic disease of the newborn.) It can range from mild to severe, but in moderate-to-severe cases, babies used tobe routinely delivered at 32 weeks to avoid stillbirth or fetal hydrops. When the fetus becomes anemic, intrauterine transfusion becomes necessary. This used to be done by intraperitoneal transfusion (IPT, transfusion of PRBCs into the fetal peritoneal cavity), but IPT had limited efficacy and a high rate of complications. Nowadays, intravascular transfusion (IVT, transfusion of PRBCs into an umbilical vein) is a safer and more effective option. As a result, preterm delivery can usually be avoided.
I is for intrauterine growth restriction (IUGR), which occurs when a fetus is pathologically unable to attain its genetically-determined size. Causes may be maternal (e.g., pregnancy-associated hypertension, autoimmune disease, thrombophilias, hemoglobinopathy, cyanotic heart disease, or diabetes with vascular disease) or placental/umbilical (e.g., placental abruption, cord anomalies, and other conditions I’ll cover later this month). IUGR carries a 10-fold increase in the risk of stillbirth; therefore the goal in managing pregnancies affected by IUGR is to maximize gestational age at delivery while minimizing the risks of neonatal morbidity and mortality caused by a “hostile uterine environment.” The decision of when to deliver is made based on umbilical artery dopplers, biophysical profile scores, amniotic fluid levels, and gestational age. IUGR has repercussions that last into adulthood, with IUGR-born adults being at increased risk for metabolic syndrome, ischemic heart disease, reduced kidney function, and mental health problems.
J is for Just Bad Luck. In the majority of cases, the cause of preterm labor is unknown and occurs in women with otherwise normal pregnancies. Research indicates that some women may be genetically predisposed to preterm labor. Personal or family history of spontaneous preterm labor is a leading risk factor for recurrent preterm birth. (Lucky me, I have both a personal and family history.) There are also racial disparities in the rate of preterm birth even after controlling for socioeconomic factors, with African Americans being more likely to deliver prematurely than Caucasians. Most current evidence suggests that genetic links may occur through an abnormal inflammatory response (e.g., certain TNF-alpha, IL-1beta, and IL-6 polymorphisms). Inflammation is an important component of both preterm labor and labor at term.
Just Bad Luck can be extended to many pregnancy complications. For example, the majority of cases of IUGR occur in women with no apparent risk factors.
K is for kidney disease. Mothers with chronic kidney disease are at increased risk of pregnancy-associated hypertension and preeclampsia. That, in turn, leads to an increased risk of preterm birth, IUGR, and stillbirth. ACE inhibitors and ARBs, a mainstay for management of CKD and hypertension, should be discontinued prior to conception as these medications are pregnancy risk category D.
L is for labor. (Decided to go for the obvious choice today.) Preterm labor is the most common obstetric precursor to preterm birth. 45% of preterm deliveries are preceded by preterm labor with intact membranes, 25% are preceded by preterm premature rupture of membranes (i.e., water breaks prior to onset of contractions), and 30% are indicated for medical reasons prior to the onset of labor or rupture of membranes. Distinguishing between preterm labor and non-progressive Braxton Hicks contractions can be tricky, especially at earlier gestations, but preterm labor is defined as regular contractions of the uterus resulting in changes in the cervix that start before 37 weeks of pregnancy. Women with an “irritable uterus” often have regular preterm contractions that do not cause cervical changes, hence the confusion between preterm labor and “false labor.” Preterm labor can usually be stopped or stalled with tocolytic medications such as nifedipine, terbutaline, indomethacin, or magnesium sulfate. The purpose of tocolytic medications is to buy time for administration of antenatal corticosteroids (to reduce neonatal morbidity) and transfer to a unit that is able to handle preterm deliveries. Maintenance use of tocolytic medications (e.g., >5-7 days) does not delay delivery and may be associated with adverse maternal or fetal side effects. The only medication indicated for prevention of preterm labor/delivery is 17-hydroxyprogesterone acetate (Makena). Makena is taken as a weekly IM injection from week 16 to 36 of pregnancy and reduces the rate of preterm birth in women with a history of spontaneous preterm delivery of a singleton by about a third. (Recall that history of preterm birth is one of the strongest predictors of subsequent preterm birth.)
M is for Mullerian anomalies. These are birth defects of the female reproductive tract that occur when the Mullerian ducts (which normally fuse to form the vagina, cervix, uterus, and Fallopian tubes) incompletely fuse or fail to form altogether. Different Mullerian anomalies are associated with different rates of obstetric complications, but in general, women with Mullerian anomalies are at increased risk for miscarriage, placental abruption, cervical incompetence, preterm labor, intrauterine growth restriction, and breech presentation. I was born with a septate uterus, the most common Mullerian anomaly. Septate uterus carries about a 65% miscarriage rate (sucks) and about a 20% preterm birth rate. The good thing about a septate uterus, though, is that the uterine septum can be surgically resected, greatly reducing the miscarriage rate.
N is for nutrient deficiencies. An inadequate diet during pregnancy increases the risk of premature delivery. In particular, iron-deficiency or pernicious anemia, vitamin D deficiency, calcium deficiency, zinc deficiency, magnesium deficiency, and folic acid deficiency have been associated with an increased risk of premature delivery. That’s part of the reason why it’s important to take prenatal supplements and have adequate protein intake during pregnancy.
O is for omphalocele. Omphalocele and gastroschisis are relatively common abdominal wall birth defects. In an omphalocele, the baby’s abdominal organs (e.g., bowels, liver, spleen) herniate into the umbilical cord. In gastroschisis, intestines herniate through a hole beside the umbilical cord into the amniotic fluid. Gastroschisis is the birth defect most commonly encountered by pediatric surgeons. Repair of the hernia is sometimes simple and sometimes requires multiple surgeries. Depending on how much inflammatory or ischemic injury the intestines experienced, the newborn may be able to tolerate feedings by mouth right away or may require over a month of total parenteral nutrition while the intestines heal. Up to 50% of omphaloceles are associated with other birth defects, and babies with omphaloceles are more likely to be growth restricted and born prematurely.
P is for placenta previa. Placenta previa occurs when the placenta implants over or near the cervical os during the second or third trimester. It can cause hemorrhage, fetal anemia and Rh isoimmunization, intrauterine growth restriction, and/or preterm birth. Vaginal bleeding often occurs in women with placenta previa during the third trimester as the lower uterine segment develops, placental attachment is disrupted, and the implantation site bleeds. Due to the presence of the placenta, the uterus is unable to adequately contract to stop the bleeding. Meanwhile, thrombin released at the bleeding site promotes uterine contraction that further disrupt placental attachment, leading to a vicious cycle: bleeding –> contractions –> placental separation –> bleeding.
Bonus terminology today! P is also for placenta accreta, increta, and percreta. In all cases, the placenta implants too deeply in the uterine wall. With placenta accreta, the placenta does not penetrate the uterine muscle; with placenta increta, the placenta does penetrate the uterine muscle; with placenta percreta, the placenta penetrates through the uterine muscle and also adheres to other internal organs (e.g., the bladder). Placenta accreta is associated with previous cesarean delivery and placenta previa, occurring in 5-10% of women with placenta previa. Because the placenta is reluctant to detach after delivery of the baby, placenta accreta carries a high risk of postpartum maternal hemorrhage and the need for a hysterectomy. Damage to other organs can occur in cases of placenta percreta. Planned preterm cesarean delivery/hysterectomy may be required, or massive preterm hemorrhage may lead to emergency preterm delivery.
Q is for Questionable Lifestyle Choices that increase the risk of preterm delivery, e.g., smoking, drinking alcohol, illicit drug use, domestic violence, stress, and late or no healthcare during pregnancy. (I should acknowledge, of course, that most people don’t CHOOSE to live a stressful life, and addiction is a very challenging disorder to overcome.)
R is for rupture of membranes. Preterm premature rupture of membranes (PPROM), that is. PPROM complicates 3% of pregnancies. In cases of second trimester PPROM, less than 40% of fetuses deliver within a week of membrane rupture, and more than 30% of women remain pregnant after 5 weeks. Fetal survival rates after PPROM at 16-19 weeks are only about 12%, while fetal survival after PPROM at 25-26 weeks is about 60% (similar to survival rates for babies born at 25-26 weeks). Management of PPROM is a balancing act with the goal being to minimize both prematurity-related and infection-related morbidity. When immediate delivery is not required (e.g., due to infection or fetal distress or risk of umbilical cord prolapse), women who elect for expectant management should receive broad-spectrum antibiotics for 7 days to help prolong the pregnancy and reduce infection-related morbidity. Antenatal corticosteroids (betamethasone or dexamethasone) should also be administered for women experiencing PPROM at 24-34 weeks gestation to reduce the risk of neonatal respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis. In general, the risks of infection-related morbidity outweigh the risk prematurity-related morbidity at 34+ weeks gestation, at which point delivery by c-section or induction of labor is recommended.
S is for subchorionic hematoma and single umbilical artery.
Umbilical cords usually have two arteries and one vein, but about 1% of fetuses have a single umbilical artery. Twenty percent of fetuses with a single umbilical artery have other birth defects, and women with diabetes are more likely to have a baby with a single umbilical artery as well. A single umbilical artery is associated with an increased risk of fetal growth restriction.
Subchorionic hematoma (SCH, bleeding between the gestational sac and the uterine wall) is the most common abnormal sonographic abnormality found in women with a viable embryo. A small, asymptomatic SCH is usually harmless and resolves spontaneously, but SCH accompanied by vaginal bleeding increases the risk of miscarriage, stillbirth, placental abruption, and PPROM, particularly when vaginal bleeding occurs in the late first trimester and early second trimester.
T is for Twin-to-Twin Transfusion Syndrome (TTTS), a complication that can affect pregnancies with monochorionic twins (i.e. identical twins that share their placenta). In TTTS, blood is transfused from one twin (the donor) to another (the recipient) through the placenta. The donor twin ends up with low blood and amniotic fluid volumes, while the recipient becomes hypervolemic with large amniotic fluid volumes. Either twin can develop hydrops fetalis (abnormal build up of body fluids). The donor can develop anemia and high-output heart failure, while the recipient can develop hypertension, cardiomegaly, disseminated intravascular coagulation, and neonatal jaundice after delivery. Due to the risk of fetal demise and ischemic brain injury in moderate-to-severe cases, premature delivery is often indicated.
U is for uterine rupture. An early delivery may be indicated for women at particularly high risk for uterine rupture. The risk of uterine rupture is increased (>1/200) in women with a history of cesarean delivery and one of the following: multiple previous cesarean deliveries, classic midline cesarean delivery, cesarean delivery less than 2 years ago, no history of successful vaginal birth, congenital uterine anomaly, fetus predicted to weigh over 4 kg, or induction or augmentation of labor. The risk of uterine rupture is particularly high in cases of pregnancy in a rudimentary horn (the underdeveloped uterine horn of a unicornuate uterus), with the majority of ruptures occurring in the second trimester. In cases of uterine rupture, delivery within 10-37 minutes is necessary to avoid serious fetal morbidity and mortality.
V is for velamentous cord insertion and vasa previa. In velamentous cord insertion, the umbilical cord inserts into the fetal membranes and travels between the chorion and amnion to the placenta, rather than inserting directly into the placenta. This condition is associated with low birth weight, premature birth, and fetal distress during labor. The umbilical vessels are at risk of tearing when the fetal membranes rupture, which leads to hemorrhage and carries a 50-75% fetal mortality rate. Velamentous cord insertion is also associated with vasa previa, the situation where the umbilical vessels lie across the opening to the birth canal during delivery. Cesarean delivery is indicated to reduce the risk of fetal distress and fetal hemorrhage.
W is for weight. (Sorry to bring this up just before Thanksgiving.) Women who are underweight prior to conception are at increased risk for both spontaneous preterm birth and medically-indicated preterm birth (relative risk generally on the order of 1.5). Women who are obese prior to conception are at increased risk for medically-indicated preterm birth and spontaneous delivery prior to 32 weeks gestation. Overall, though, several studies indicate that obesity actually decreases the risk of spontaneous preterm birth. Central adiposity (as indicated by waist circumference) appears to be an independent risk factor for medically-indicated preterm birth.
X is for eXtra babies. Multifetal births (i.e., twins and higher-order multiples) account for 3% of all live births but make up 24% of low birth weight infants (birth weight <2000 grams) and 26% of very low birth weight infants (<1500 grams). The average birth weight of a twin is 5 lbs 3 oz, the average birth weight of a triplet is 3 lbs 11 oz, and the average birth weight of a quadruplet is 2 lbs 14 oz. The average gestation of a twin pregnancy is 35.3 weeks, the average gestation of a triplet pregnancy is 32.2 weeks, and the average gestation of a quadruplet pregnancy is 29.9 weeks. 25% of twins require a NICU admission, 75% of triplets require a NICU admission, and virtually all quadruplets require a NICU admission. The risk of death during infancy is increased 4-fold for twins and 17-fold for triplets compared to singletons. For these reasons (not to mention the risk of neurodevelopmental disability), fertility treatments generally strive to achieve singleton pregnancies.
Y is for Y chromosome. Boys are more likely to be delivered prematurely than girls (odds ratio ~1.2), and neonatal outcomes are better for premature girls as compared to premature boys born at a given gestation. Girls are developmentally about a week “ahead” of boys in utero, so the outcomes of boys born at, for example, 25 weeks are comparable to the outcomes of girls born at 24 weeks. For these reasons, I’m happy to be carrying a girl this time.
Last letter today! But I couldn’t come up with anything perinatology and prematurity-related for Z. So for lack of other ideas, Z is for zygote. This gummy bear was a zygote on the 4th of July.