The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Dr. Mary Elaine Patrinos. This current third edition chapter is a revision and update of the original author's work.
A 26 year old G1P0, O+, VDRL non-reactive, rubella immune, HBsAg negative, HIV negative female at 30 weeks gestation presents to labor and delivery with a 2-day history of headache and facial swelling. Maternal history is remarkable for a single prenatal visit in the first trimester.
Exam: VS T 37, P 75, RR 14, BP 170/100. Her exam is remarkable for facial and pretibial edema and hyperreflexia.
Labs: Urine dipstick positive for 3+ protein. Ultrasound demonstrates decreased amniotic fluid. The fetus is in the breech position and no fetal abnormalities are noted. Estimated fetal weight is 650 grams and Doppler ultrasound of the umbilical artery shows reversed diastolic flow.
A decision is made to deliver the infant by cesarean section following maternal treatment with betamethasone.
The risk factors identified in this scenario include poor prenatal care, severe preeclampsia, prematurity, oligohydramnios, and intrauterine growth restriction. For the pediatrician, detailed knowledge of the maternal and pregnancy history is critical to providing timely and comprehensive care to the infant. Therapeutic interventions are planned based on the neonate's anticipated problems. Appropriate steps in preparing for the delivery of the above infant include: 1) mobilization of the high risk delivery team comprised of a physician (typically a neonatologist), neonatal nurse, and respiratory therapist, 2) notification of neonatal intensive care nursery staff, 3) preparation of exogenous surfactant for treatment of anticipated surfactant deficiency or respiratory distress syndrome (RDS), 4) planning for immediate vascular access to meet the infant's fluid and metabolic needs, 5) ensuring adequate temperature regulation. The risk of hypothermia (temperatures below 36.0°C) is dangerous, especially for the preterm neonate. Mechanisms to prevent heat loss include increasing the ambient temperature in the delivery room, use of an incubator, stockinet cap, warming mattresses, and/or plastic wrap, and ultimately skin-to-skin contact with mothers (1).
A high risk pregnancy can be defined as any pregnancy where maternal and/or fetal conditions can lead to an adverse perinatal outcome. Preterm labor (PTL) and delivery, preterm premature rupture of membranes (PPROM), multiple gestation, preeclampsia, diabetes mellitus, maternal substance abuse, and vaginal bleeding, are common high risk conditions. Screening tests for certain high risk problems such as maternal diabetes mellitus, fetal genetic conditions, and congenital anomalies are either routinely or selectively performed during the antepartum period and are important for early recognition and intervention. Lack of, limited, or late prenatal care can delay diagnosis of such conditions and thus also characterizes a high risk pregnancy. A pregnancy may be identified as high risk during the antepartum or intrapartum period. This chapter will focus on a few of the more common pregnancy complications with an emphasis on neonatal outcomes.
Preterm labor
Preterm labor is defined as the onset of labor prior to 37 weeks gestation. The World Health Organization defines preterm delivery as one that occurs between 20 and 37 weeks gestational age. Aside from congenital anomalies and chromosomal abnormalities, prematurity-related complications are the leading cause of infant death.
Preterm birth is either spontaneous (70%) or medically indicated. Spontaneous preterm births are due to spontaneous preterm labor or preterm premature rupture of membranes (PPROM), which is defined as rupture of membranes before 37 weeks gestation and before onset of labor. Decisions regarding preterm delivery are prompted by maternal and/or fetal complications, including but not limited to preeclampsia/eclampsia, non-reassuring fetal heart tracings, bleeding from placenta previa, and intrauterine growth restriction (2).
Major risk factors for preterm delivery are: low socioeconomic status, smoking, substance abuse, poor nutrition and/or gestational weight gain, absent or inadequate prenatal care, previous history of preterm labor/delivery, cervical insufficiency, uterine abnormalities (bicornuate uterus, myomata, etc.), hypertension/preeclampsia, diabetes, multiple gestation, oligo- or polyhydramnios, vaginal bleeding, and infection (especially sexually transmitted infections) (2). Timely recognition of threatened preterm delivery can allow for prompt referral of the mother to a facility with availability of maternal fetal medicine specialists and/or neonatal intensive care unit.
The pathogenesis of spontaneous, isolated PTL is multifactorial; however, most theories have a common pathway of various inciting events that lead to activation of pro-inflammatory pathways and increased production PGE2 and PGF2a. These mediators increase dramatically during labor and facilitate the major processes that trigger the onset of spontaneous labor: cervical ripening, expression of myometrial oxytocin receptors, and formation of myometrial gap junctions. Early onset preterm labor is typically triggered by an infectious or inflammatory (bleeding, over distention, etc.) etiology, whereas late onset preterm labor is more related to premature changes in estrogen and progesterone ratio secondary to early activation of the fetal hypothalamic pituitary adrenal axis. (2,3)
Studies assessing prevention methods, such as education and surveillance programs and home uterine activity monitoring, have demonstrated no benefit in reducing the frequency of preterm birth. Interventions with some promise involved in the prevention of preterm birth include cervical length surveillance and progestin supplementation (2). Furthermore, various interventions are aimed at reducing the morbidity and mortality associated with preterm birth, including tocolytics, antenatal corticosteroids, magnesium sulfate, and antibiotics (see Table 1). Tocolytics are agents used in the setting of preterm labor to inhibit uterine contractions and delay preterm delivery. Although it has been difficult to demonstrate the efficacy of tocolytics and antibiotics in clinical trials for preterm labor, these agents may provide a 48-hour latency period during which a complete course of antenatal corticosteroids can be administered to provide maximal fetal protection before delivery. Maternal and fetal side effects must also be considered with the use of any intervention for PTL.
Table 1: Preterm Birth Interventions (2,3)
| Intervention | Indications | Side Effects |
| Primary Prevention of Preterm Birth | ||
|---|---|---|
| Cerclage (transvaginal or transabdominal suture placement around the internal cervical os ideally between 12 to 14 weeks gestation) | -Recurrent 2nd trimester losses from painless cervical dilation (cervical insufficiency). -Prior preterm birth and cervical length ≤25 mm before 24 weeks in current pregnancy. -Painless cervical dilation in current pregnancy. | Maternal: risk of anesthesia, bleeding, infection, rupture of membranes, soft tissue injury, spontaneous suture displacement, cervical lacerations. Fetal: infection, preterm birth. |
| Progesterone* | -Intramuscular progesterone if history of prior spontaneous preterm birth before 24 weeks gestation. -Vaginal progesterone if cervical length ≤20 to 25 mm before 25 weeks gestation. | Maternal: local irritation. Fetal: unknown - no neurodevelopmental benefits or harms have been established (4). |
| Management of Preterm Labor | ||
| Antenatal corticosteroids (betamethasone or dexamethasone) | Delivery of fetus <34 weeks, though some studies show benefit up to 36 6/7 weeks, to accelerate lung maturity | Maternal: glucose abnormalities. Fetal: glucose abnormalities, transient suppression of hypothalamic pituitary adrenal (HPA) axis, repeated doses associated with decreased birth weight and neurogenesis (5). |
| Indomethacin (non-selective COX prostaglandin synthetase inhibitor) | -Short-term tocolysis (<48 hours) for <32 weeks gestation. -1st line tocolytic. | Maternal: minimal, GI upset. Fetal: oligohydramnios secondary to decreased fetal urine output, ductal constriction with the potential for subsequent persistent pulmonary hypertension in the neonate. |
| Nifedipine (dihydropyridine calcium channel blocker) | -Tocolysis for <34 weeks gestation. -1st line tocolytic. | Maternal: dizziness, flushing, headache, peripheral edema. Fetal: not well studied but appears to be well-tolerated. |
| Terbutaline (stimulates beta-2 receptors in uterus) | -Inpatient short-term tocolysis for <34 weeks gestation. -Acute management of uterine tachysystole (excessively frequent uterine contractions). -2nd line tocolytic. | Maternal: tachycardia, hypotension, tremor, headache, fever, shortness of breath, hypokalemia, hyperglycemia, pulmonary edema. Fetal: elevation in baseline heart rate, rhythm disturbances, septal hypertrophy, and hypoglycemia. |
| Magnesium sulfate (calcium competitor; decreases the release of acetylcholine; reduces risk of cerebral palsy by up to 45%) | -Neuroprotection for delivery at <32 weeks gestation. -Eclampsia or seizure prevention in preeclampsia. -Short-term tocolysis. -2nd line tocolytic. | Maternal: flushing, nausea, headache; toxic levels lead to diminished deep tendon reflexes, respiratory or cardiac depression. Fetal: respiratory, cardiac, motor depression at high maternal levels. |
| Antibiotic therapy (prolongs latency with PPROM) | -Erythromycin or azithromycin and ampicillin for PPROM <34 weeks gestation. -Penicillin for preterm labor if maternal group B streptococcus vaginal culture is positive or unknown. | Maternal: allergic reaction, gut/vaginal dysbiosis. Fetal: gut microbiome dysbiosis (6) associated with increased risk of respiratory, GI, metabolic, and immune-related disease; emergence of antimicrobial resistance genes has also been implicated (7). |
The incidence of neonatal mortality and morbidity increases with decreasing gestational age. Although it is outside the scope of this chapter to address the multiple medical, psychosocial, neurodevelopmental and financial problems associated with prematurity, it should be emphasized that the periviable population of infants (generally 22 to <26 weeks gestation) remain the greatest challenge. Periviability refers to the earliest stage of fetal maturity where there is a reasonable chance of extrauterine survival. Due to statistically poor outcomes, the question of whether or not to provide life supportive measures in the delivery room is, ideally, discussed with the prospective parents prior to delivery. Despite recent improvements, delivery before 23 weeks still has a 5% to 6% survival rate and among survivors, studies show only about 1% survive without neurodevelopmental impairment (8,9). As expected, survival rates increase and neurodevelopmental impairments decrease with gestational age. Many centers may also utilize the NICHD Extremely Preterm Birth Outcomes Tool to objectively assess prognosis (based on gestational age, birth weight, sex, plurality, and use of antenatal corticosteroids) and guide decision making. Nonetheless, the management of these most fragile newborns remains an ongoing area of controversy and debate in neonatal medicine.
Preterm birth, even outside the periviability period, is associated with a spectrum of neurodevelopmental morbidities, including psychiatric abnormalities such as attention deficit/hyperactivity disorder (ADHD), depression, anxiety, autism spectrum disorder (ASD), motor and sensory deficits, and developmental delay, which manifest as poor academic performance and behavioral problems (10). Interestingly, sensory processing deficits may be due to repeated painful stimulation and separation from caregivers. Poor neurodevelopment is multifactorial, secondary to perinatal risk factors, brain immaturity, and environmental exposures (10). Neurosensory impairments such as cerebral palsy (CP), blindness associated with retinopathy of prematurity (ROP), and deafness hypothesized to be due to use of ototoxic agents are also associated with prematurity. Though advances in neonatal medicine have improved outcomes, it is important for the pediatrician to monitor developmental milestones closely and identify the need for intervention early.
Preeclampsia
Preeclampsia is defined as new-onset hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg), and proteinuria after 20 weeks gestation, defined as ≥300 mg per 24-hour urine collection, protein:creatinine ratio ≥0.3, or urine dipstick protein reading ≥2+. In the absence of proteinuria, signs of end-organ dysfunction such as renal insufficiency or persistent cerebral or visual symptoms, can meet criteria for preeclampsia. Preeclampsia complicates approximately 5% of pregnancies in the United States and is a major cause of maternal and perinatal morbidity and mortality. Risk factors include nulliparity, multifetal gestation, hydatidiform mole, older maternal age, family or personal history, pre-existing hypertension, obesity, diabetes, and vascular disorders (11).
Uteroplacental ischemia is the fundamental abnormality of this disorder; however, the etiology appears to be multifactorial, including genetic, immune, and placental developmental processes. Final pathophysiologic mechanisms include an increased ratio of anti-angiogenic to pro-angiogenic factors and increased circulating inflammatory markers which contribute to endothelial dysfunction (11). The most effective treatment is delivery. However, the decision is often weighed against the risks of prematurity, which contributes significantly to the perinatal morbidity and mortality associated with preeclampsia (12). Early-onset preeclampsia (<34 weeks) is managed with close maternal and fetal observation in the inpatient setting until deterioration of maternal or fetal status mandates delivery. Otherwise, delivery is recommended at ≥37 0/7 weeks for preeclampsia, at ≥34 0/7 weeks for severe preeclampsia.
Aside from prematurity, the uteroplacental insufficiency and abruptio placenta associated with preeclampsia contribute to poor fetal outcomes. The overall incidence of stillbirth or intrauterine fetal demise (IUFD) after 28 weeks gestation is about 3 per 1000 births; this rate increases to 9 per 1000 with mild preeclampsia and 21 per 1000 with severe preeclampsia. Preeclampsia is also the most common cause of intrauterine growth restriction (IUGR) in the otherwise normally developing infant (11). Weight below the 10th percentile at any gestational age increases risk of mortality. Preeclampsia has also been associated with neonatal thrombocytopenia and neutropenia. Most cases are self-resolving and there is mixed evidence on whether or not the neutropenia increases neonatal risk of nosocomial infection (12). Severe preeclampsia is also an independent risk factor for neonatal bronchopulmonary dysplasia (BPD) outside of the risk attributed to prematurity (12). Neurodevelopmental outcomes of infants and children exposed to preeclampsia are highly variable. Interestingly enough, some studies show decreased rates of cerebral palsy, while other studies suggest adverse effects on neurodevelopmental outcomes. Lastly, large population-based studies have shown that infants exposed to preeclampsia have an increased risk of diabetes and cardiovascular disease in adulthood, even after adjusting for differences in lifestyle habits and socioeconomic factors (12). The pathophysiology behind these findings is still being studied but is suggested to be related to the extreme sensitivity of the immature fetus to disruptions in utero blood flow. Ultimately, there is a lot to consider when weighing the risks of prematurity present even in late-preterm infants versus prolonged exposure to preeclampsia. Decisions to optimize fetal outcomes vary with each case and require a multidisciplinary approach between maternal-fetal medicine and neonatology.
Diabetes mellitus
Diabetes mellitus is classified as type 1 (lack of insulin production) vs. type 2 (insulin resistance) and/or as pre-gestational vs. gestational. Gestational diabetes (GDM) is defined as carbohydrate intolerance first recognized during pregnancy. Women with longer standing gestational diabetes can have vascular disease that increases risk of preeclampsia and intrauterine fetal growth restriction. GDM accounts for the majority of pregnancies complicated by diabetes and has dramatically increased within the last few decades. The underlying pathophysiologic mechanism is a decrease in peripheral insulin sensitivity that occurs as a part of normal pregnancy physiology along with a concomitant inability of the pancreas to produce adequate insulin to compensate for a glucose load (13). Because this condition is often asymptomatic, screening is indicated for all pregnant women between 24 and 28 weeks gestation, earlier if risk factors are present. Glucose management is strict with treatment targets of <95 mg/L fasting and <140 mg/L one hour postprandial. It is well established that tight metabolic control is associated with a marked reduction in the fetal and neonatal complications associated with diabetes in pregnancy listed in Table 2 below.
Table 2: Fetal and Neonatal Complications of Diabetes in Pregnancy (13)
| Congenital anomalies | -CNS anomalies: neural tube defects, holoprosencephaly, caudal regression syndrome, sirenomelia (a birth defect with a single lower extremity or with two legs that are fused together). -Cardiac anomalies: transposition of great arteries, VSD, truncus arteriosus, hypertrophic cardiomyopathy*. -GI anomalies: intestinal atresia, imperforate anus, TEF (tracheoesophageal fistula). -Renal anomalies: renal agenesis, horseshoe kidney. -Skeletal anomalies: poly/syndactyly, rib/spine/sacral defects, limb deficiency. -Often times, multiple systems are involved. |
| Macrosomia** and visceromegaly | -Birth trauma: shoulder dystocia, clavicle fractures, brachial plexus injuries, diaphragmatic paralysis. -Perinatal asphyxia |
| Metabolic consequences | -Hypoglycemia: tremor, seizures, poor feeding. -Hypocalcemia |
| Hematologic consequences | -Polycythemia (secondary to hypoxemia). -Hyperbilirubinemia |
| Respiratory consequences | -Neonatal respiratory distress syndrome (insulin inhibits production and secretion of surfactant). -Transient tachypnea of newborn. |
Most congenital anomalies are less likely to occur in infants if mothers develop gestational diabetes after embryogenesis is complete (the first 8 weeks of pregnancy). Malformations in infants of mothers with pregestational diabetes can occur in up to 25% of pregnancies (compared to 2% to 5% for non-diabetic pregnancies) depending upon the status of glucose control during embryogenesis. Macrosomia occurs in 25% to 45% of pregnancies complicated by diabetes and is a direct result of fetal hyperglycemia and hyperinsulinemia, as are the other metabolic, hematologic, and respiratory complications listed above (13). Neonatal management of all infants of diabetic mothers includes a thorough evaluation for birth trauma and congenital defects, screening for and management of hypoglycemia, and close scrutiny of the infant for signs of respiratory distress.
For further information on management of infants of diabetic mothers, see Chapter III.10. Infants of Diabetic Mothers.
Substance abuse
Maternal substance abuse occurs in 5% to 6% of all pregnancies and is a condition that presents the greatest clinical challenge to the pediatrician because prevention and treatment strategies are often nonexistent or inadequate. Comorbidities include sexually transmitted diseases (syphilis, HIV), tuberculosis, hepatitis, and preterm labor, many of which have potential to result in acute and long term consequences to the newborn as isolated conditions. Identification of agent specific neonatal outcomes is frequently confounded by polysubstance abuse, poor nutrition, poor health care and unsatisfactory home environments, often making it difficult to single out a culprit (14). In Hawaii, the most commonly abused drugs are alcohol, marijuana, amphetamines, and methamphetamines. Beyond illicit drug use, several other prescribed maternal drugs can also lead to withdrawal syndrome behaviors in the neonate: prescription opioids, benzodiazepines, barbiturates and SSRIs (selective serotonin re-uptake inhibitors). Generally, the severity and frequency of fetal/neonatal side effects associated with maternal substance abuse is related to timing, dose, and duration of use (14). Antenatal drug exposure affects the developing fetus in a variety of ways, including disruption of fetal growth, major morphologic abnormalities, alteration of brain chemistry, and reduced cognitive function. Several drugs can lead to symptoms of neonatal withdrawal such as fussiness, irritability, poor feeding, temperature abnormalities, and neurological abnormalities (14).
For more information on neonatal management of infants with intrauterine drug exposure related to narcotics, stimulants, barbiturates, benzodiazepines and SSRIs, please see Chapter III.15. Neonatal Drug Withdrawal.
Marijuana: Due to recent legalizations of use, prevalence of marijuana use disorder continues to grow, with an estimated 4.0 million people in 2016. Although difficulty in studying the effects of marijuana alone is complicated by polysubstance use, multiple studies have suggested potential long-term effects on behavior and problem-solving skills (14,15). Studies also show higher risk of low birth weight associated with maternal marijuana use in pregnancy with moderate to heavy use (at least once per week). There is inconsistent data linking marijuana use to increased risk of preterm birth, intrauterine growth restriction (IUGR), congenital anomalies, and stillbirth. There is no conclusive evidence regarding the effects of exposure to cannabis during breastfeeding, as outcomes are often difficult to distinguish from in utero exposure to marijuana (15). Thus marijuana use is not considered an absolute contraindication for breastfeeding; however the current recommendation from American College of Obstetrics and Gynecology (ACOG) and American Academy of Pediatrics (AAP) is that providers should counsel mothers about possible adverse long-term neurobehavioral effects related to the transmission of marijauna through breast milk and encourage mothers to eliminate or reduce their use of cannabis (16).
Alcohol: According to a 2022 CDC Morbidity and Mortality Weekly Report, nearly 1 in 7 pregnant people reported concurrent alcohol drinking (17). While there is no safe time or amount to consume alcohol during pregnancy, studies show that consequences are associated with moderate to heavy levels of consumption. The National Institute on Alcohol Abuse and Alcoholism defines heavy drinking for women as consuming more than 3 drinks on any day or more than 7 drinks per week (18). Of note, prenatal exposure to alcohol remains the leading cause of intellectual disability. Fetal alcohol spectrum disorder (FASD), as its name suggests, describes a spectrum of symptoms and diagnoses secondary to varying degrees of insults to the central nervous system that can result from in utero exposure to alcohol. The most well-known and well-studied is fetal alcohol syndrome (FAS), which is considered to be among the worst outcomes. Microcephaly, intellectual disability, and subtle cognitive, behavioral, and language deficits have all been well described. Additional features of FAS include growth deficiency and characteristic craniofacial features, including short palpebral fissures, smooth philtrum, and thin upper lip. Recent meta-analyses suggest FASD can cause abnormalities in all organ systems, including but not limited to impaired immunity in the lungs, congenital heart disease, abnormal bone growth, and chronic serous otitis media (19). Unfortunately, there is no curative treatment for FASD outside of alcohol abstinence during pregnancy (and even in women planning to become pregnant) and management is primarily supportive.
While a large part of the prevention aspect falls on obstetricians, pediatricians play a role through 1) consistent screening and early counseling of potential future mothers about high risk sexual and substance use behaviors and 2) thorough interviewing and social history taking of the mother/caregiver postpartum. Furthermore, it is important to remember that maternal drug screening and self-report have limitations and may not adequately reflect neonatal drug exposure. Thus, it is important for the pediatrician to be familiar with community substance use patterns and the clinical manifestations of potential substance exposure. Selective drug screening of mothers and newborns takes place routinely at most perinatal centers. Decisions regarding who to screen is often related to other perinatal risk factors such as inadequate prenatal care, previous history of substance abuse, high risk clinical signs in the mother (inappropriate or unusual behavior), history of prostitution, history of preterm labor, and presence of sexually transmitted disease(s), congenital malformations, unexplained intrauterine growth restriction, and overt signs of neonatal drug withdrawal. Documentation of fetal illicit drug exposure by newborn urine or meconium toxicology screening typically results in referral to child welfare services (CWS), as pediatricians and social workers are mandated to report illicit drug use. It is the role of CWS to determine the best next steps on a case by case basis, depending on the mother's motivation to abstain, commitment to participating in treatment programs, and the existing home situation among other factors. Regardless of the decision made, it is important to utilize trauma informed care approaches when counseling and working with these mothers.
Summary
In summary, there are many high risk conditions in pregnancy that can result in adverse neonatal outcomes, especially prematurity. It is important for the pediatrician to be fully aware of maternal risk factors so that he/she can be fully prepared to receive the newborn in the delivery room and provide ongoing care. Timely recognition of certain high risk conditions during pregnancy can result in the appropriate transfer of the mother and fetus to a facility equipped to provide subspecialty care when indicated.
Questions
1. True/False: Preterm labor is defined as the onset of labor prior to 34 weeks gestation.
2. An effective measure for treating preterm labor and delaying preterm delivery is:
a. Oxytocin
b. Cerclage
c. Detection of uterine contractions through the use of home uterine activity monitoring
d. Nifedipine
3. The most widely accepted explanation for the onset of preterm labor is:
a. Adrenal cortical suppression
b. Activation of pro-inflammatory pathways
c. Increased levels of serum oxytocin
d. Premature, idiopathic activation of the normal labor process
4. Which of the following is NOT a risk factor for preeclampsia?
a. Advanced maternal age
b. Pre-existing hypertension
c. Multiparity
d. Multifetal gestation
5. Infants and children with FASD can exhibit which of the following?
a. Intellectual disability
b. Growth deficiency
c. Cardiac defects
d. All of the above
6. True/False: Preeclampsia is often associated with large-for-gestational age infants.
References
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2. Constantine, MM, et al. Chapter 19. Obstetric Management of Prematurity. In: Martin RJ, Fanaroff AA, Walsh MC (eds). Fanaroff and Martin's Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant, 11th edition. 2020. Elsevier, Philadelphia, PA, pp. 312-345.
3. Tosto V, Giardina I, Tsibizova V, Renzo GCD. Preterm Birth, From the Biological Knowledges to the Prevention: An Overview. Maternal-Fetal Medicine. 2020;3:162-171. doi: 10.1097/FM9.0000000000000054
4. Simons, NE, Leeuw, M, van't Hooft, J, Limpens, J, Roseboom, TJ, Oudijk, MA, Pajkrt, E, Finken, MJJ, Painter, RC. The long-term effect of prenatal progesterone treatment on child development, behaviour and health: a systematic review. 2021;128:964-974.
5. Romejko-Wolniewicz E, Teliga-Czajkowska J, Czajkowski K. Antenatal steroids: can we optimize the dose?. Curr Opin Obstet Gynecol. 2014;26(2):77-82. doi:10.1097/GCO.0000000000000047
6. Azad MB, Konya T, Persaud RR, Guttman DS, Chari RS, Field CJ, Sears MR, Mandhane PJ, Turvey SE, Subbarao P, Becker AB, Scott JA, Kozyrskyj AL, CHILD Study Investigators. Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: a prospective cohort study. BJOG. 2016;123(6):983-993. doi: 10.1111/1471-0528.13601.
7. Tapiainen T, Koivusaari P, Brinkac L, et al. Impact of intrapartum and postnatal antibiotics on the gut microbiome and emergence of antimicrobial resistance in infants. Sci Rep 2019;9(1):10635. https://doi.org/10.1038/s41598-019-46964-5
8. Tyson JE, Parikh NA, Langer J, Green C, Higgins RD. National Institute of Child Health and Human Development Neonatal Research Network. Intensive care for extreme prematurity-moving beyond gestational age. N Engl J Med. 2008;358:1672-1681. https://doi.org/10.1056/NEJMoa073059.
9. Younge N, Goldstein RF, Bann CM, Hintz SR, et al. Survival and Neurodevelopmental Outcomes among Periviable Infants. N Engl J Med 2017;376:617-628. DOI: 10.1056/NEJMoa1605566
10. Hee Chung E, Chou J, Brown KA. Neurodevelopmental outcomes of preterm infants: a recent literature review. Transl Pediatr. 2020;9(Suppl 1):S3-S8. doi:10.21037/tp.2019.09.10
11. Jeyabalan, A. Chapter 17. Hypertensive Disorders of Pregnancy. In: Martin RJ, Fanaroff AA, Walsh MC (eds). Fanaroff and Martin's Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant, 11th edition. 2020. Elsevier, Philadelphia, PA, pp. 288-303.
12. Backes CH, Markham K, Moorehead P, Cordero L, Nankervis CA, Giannone PJ. Maternal preeclampsia and neonatal outcomes. J Pregnancy. 2011;2011:214365. doi:10.1155/2011/214365
13. Blickstein, I, et al. Chapter 18. Pregnancy Complicated by Diabetes Mellitus. In: Martin RJ, Fanaroff AA, Walsh MC (eds). Fanaroff and Martin's Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant, 11th edition. 2020. Elsevier, Philadelphia, PA, pp. 304-311.
14. Hudak ML. Chapter 46. Infants of Substance-Using Mothers. In: Martin RJ, Fanaroff AA, Walsh MC (eds). Fanaroff and Martin's Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant, 11th edition. 2020. Elsevier, Philadelphia, PA, pp. 735-750.
15. Metz TD, Borgelt LM. Marijuana Use in Pregnancy and While Breastfeeding. Obstet Gynecol. 2018;132(5):1198-1210. doi: 10.1097/AOG.0000000000002878. PMID: 30234728; PMCID: PMC6370295.
16. Kilpatrick, SJ, Papil, L (eds). Guidelines for Perinatal Care, 8th edition. 2017, American Academy of Pediatrics and The American College of Obstetricians and Gynecologists.
17. Centers for Disease Control and Prevention. Fetal Alcohol Spectrum Disorders (FASDs). Data and Statistics. https://www.cdc.gov/ncbddd/fasd/data.html accessed on March 2, 2022 .
18. National Institute on Alcohol Abuse and Alcoholism. Drinking Levels Defined. https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/moderate-binge-drinking accessed on March 2, 2022.
19. Falck, AJ, et al. Chapter 14. Adverse Exposures to the Fetus and Neonate. In: Martin RJ, Fanaroff AA, Walsh MC (eds). Fanaroff and Martin's Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant, 11th edition. 2020. Elsevier, Philadelphia, PA, pp. 239-259.
Answers to questions
1.False, 2.D, 3.B, 4.C, 5.D, 6.False