Jodi S. Dashe

Subclinical hypothyroidism and pregnancy outcomes.

BACKGROUND: Clinical thyroid dysfunction has been associated with pregnancy complications such as hypertension, preterm birth, low birth weight, placental abruption, and fetal death. The relationship between subclinical hypothyroidism and pregnancy outcomes has not been well studied. We undertook this prospective thyroid screening study to evaluate pregnancy outcomes in women with elevated thyrotropin (thyroid-stimulating hormone, TSH) and normal free thyroxine levels. METHODS: All women who presented to Parkland Hospital for prenatal care between November 1, 2000, and April 14, 2003, had thyroid screening using a chemiluminescent TSH assay. Women with TSH values at or above the 97.5th percentile for gestational age at screening and with free thyroxine more than 0.680 ng/dL were retrospectively identified with subclinical hypothyroidism. Pregnancy outcomes were compared with those in pregnant women with normal TSH values between the 5th and 95th percentiles. RESULTS: A total of 25,756 women underwent thyroid screening and were delivered of a singleton infant. There were 17,298 (67%) women enrolled for prenatal care at 20 weeks of gestation or less, and 404 (2.3%) of these were considered to have subclinical hypothyroidism. Pregnancies in women with subclinical hypothyroidism were 3 times more likely to be complicated by placental abruption (relative risk 3.0, 95% confidence interval 1.1–8.2). Preterm birth, defined as delivery at or before 34 weeks of gestation, was almost 2-fold higher in women with subclinical hypothyroidism (relative risk, 1.8, 95% confidence interval 1.1–2.9). CONCLUSION: We speculate that the previously reported reduction in intelligence quotient of offspring of women with subclinical hypothyroidism may be related to the effects of prematurity. LEVEL OF EVIDENCE: II-2

Subclinical hyperthyroidism and pregnancy outcomes.

OBJECTIVE: Subclinical hyperthyroidism has long-term sequelae that include osteoporosis, cardiovascular morbidity, and progression to overt thyrotoxicosis or thyroid failure. The objective of this study was to evaluate pregnancy outcomes in women with suppressed thyroid-stimulating hormone (TSH) and normal free thyroxine (fT4) levels. METHODS: All women who presented to Parkland Hospital for prenatal care between November 1, 2000, and April 14, 2003, underwent thyroid screening by chemiluminescent TSH assay. Women with TSH values at or below the 2.5th percentile for gestational age and whose serum fT4 levels were 1.75 ng/dL or less were identified to have subclinical hyperthyroidism. Those women screened and delivered of a singleton infant weighing 500 g or more were analyzed. Pregnancy outcomes in women identified with subclinical hyperthyroidism were compared with those in women whose TSH values were between the 5th and 95th percentiles. RESULTS: A total of 25,765 women underwent thyroid screening and were delivered of singleton infants. Of these, 433 (1.7%) were considered to have subclinical hyperthyroidism, which occurred more frequently in African-American and/or parous women. Pregnancies in women with subclinical hyperthyroidism were less likely to be complicated by hypertension (adjusted odds ratio 0.66, 95% confidence interval 0.44–0.98). All other pregnancy complications and perinatal morbidity or mortality were not increased in women with subclinical hyperthyroidism. CONCLUSION: Subclinical hyperthyroidism is not associated with adverse pregnancy outcomes. Our results indicate that identification of subclinical hyperthyroidism and treatment during pregnancy is unwarranted. LEVEL OF EVIDENCE: II-2

Thyroid-stimulating Hormone in Singleton and Twin Pregnancy: Importance of Gestational Age–specific Reference Ranges

OBJECTIVE: To estimate a normal reference range for thyroid-stimulating hormone (TSH) at each point in gestation in singleton and twin pregnancies. METHODS: All women enrolling for prenatal care from December 2000 through November 2001 underwent prospective TSH screening at their first visit. Separate nomograms were constructed for singleton and twin pregnancies using regression analysis. Values were converted to multiples of the median (MoM) for singleton pregnancies at each week of gestation. RESULTS: Thyroid-stimulating hormone was evaluated in 13,599 singleton and 132 twin pregnancies. Thyroid-stimulating hormone decreased significantly during the first trimester, and the decrease was greater in twins (both P < .001). Had a nonpregnant reference (0.4–4.0 mU/L) been used rather than our nomogram, 28% of 342 singletons with TSH greater than 2 standard deviations above the mean would not have been identified. For singleton first-trimester pregnancies, the approximate upper limit of normal TSH was 4.0 MoM, and for twins, 3.5 MoM. Thereafter, the approximate upper limit was 2.5 MoM for singleton and twin pregnancies. CONCLUSION: If thyroid testing is performed during pregnancy, nomograms that adjust for fetal number and gestational age may greatly improve disease detection. Values expressed as multiples of the median may facilitate comparisons across different laboratories and populations. LEVEL OF EVIDENCE: II-2

Perinatal Significance of Isolated Maternal Hypothyroxinemia Identified in the First Half of Pregnancy

OBJECTIVE: To establish pregnancy-specific free thyroxine thresholds and to assess perinatal effects associated with isolated maternal hypothyroxinemia identified in the first half of pregnancy. METHODS: Stored serum samples from 17,298 women who previously underwent thyroid-stimulating hormone (TSH) screening in the first half of pregnancy were analyzed for free thyroxine (T4) concentrations and thyroid peroxidase antibodies. Women with a free T4 below 0.86 ng/dL but a normal-range TSH were identified to have isolated maternal hypothyroxinemia. Pregnancy outcomes in these women were compared to those with a normal TSH and free T4. Thyroid peroxidase antibody status and the relationship between TSH and free T4 were analyzed for these women and women with subclinical hypothyroidism. RESULTS: Isolated maternal hypothyroxinemia was identified in 233 women (1.3%). There were not any excessive adverse pregnancy outcomes in these women. Positive thyroid peroxidase antibody assays (greater than 50 international units/mL) were similar in normal women (4%) and those with isolated hypothyroxinemia (5%) but were greater in women with subclinical hypothyroidism (31%, P<.001). There was a negative correlation between TSH and free T4 in normal women (rs=–0.19, P<.001) and those with subclinical hypothyroidism (rs=–0.11, P=.007). The correlation in women with isolated hypothyroxinemia was not significant. CONCLUSION: Isolated maternal hypothyroxinemia has no adverse effects on perinatal outcome. Moreover, unlike subclinical hypothyroidism, there was a low prevalence of thyroid peroxidase antibodies and no correlation between TSH and free T4 levels in women with hypothyroxinemia, leading us to question its biological significance. LEVEL OF EVIDENCE: II

Relationship between maternal methadone dosage and neonatal withdrawal

OBJECTIVE To determine whether maternal methadone dosage affects duration and degree of neonatal narcotic withdrawal. METHODS This was a retrospective cohort study of pregnant women with opioid addiction who delivered live‐born singletons between April 1990 and April 2001. Inpatient detoxification or outpatient methadone maintenance therapy was offered. Women who had a positive drug screen or whose neonate tested positive for opioids were considered to be supplementing. We evaluated indices of neonatal withdrawal according to the maximum daily methadone dosage in the last week of pregnancy. RESULTS Seventy women with opioid addiction were followed. Median methadone dosage was 20 mg (range 0–150 mg), and 32 infants (46%) were treated for narcotic withdrawal. Among women who received less than 20 mg per day, 20–39 mg per day, and at least 40 mg per day of methadone, treatment for withdrawal occurred in 12%, 44%, and 90% of infants, respectively (P < 0.02). Methadone dosage was also correlated with both duration of neonatal hospitalization and neonatal abstinence score (rs = .70 and .73 respectively, both P < .001). Neonates were more likely to experience withdrawal if their mothers were supplementing with heroin, 68% versus 35% (P = .01). Regardless of supplementation, there was a significant relationship between methadone dosage and neonatal withdrawal (P < .05). CONCLUSION Maternal methadone dosage was associated with duration of neonatal hospitalization, neonatal abstinence score, and treatment for withdrawal. Heroin supplementation did not alter this dose–response relationship. In selected pregnancies, lowering the maternal methadone dosage was associated with both decreased incidence and severity of neonatal withdrawal.

Effect of Maternal Obesity on the Ultrasound Detection of Anomalous Fetuses

OBJECTIVE: To estimate the effect of maternal habitus on detection of fetuses with major structural anomalies during second-trimester standard and targeted ultrasound examinations. METHODS: This was a retrospective cohort study of pregnancies 18 to 24 weeks that underwent ultrasonography over a 5-year period. An anomalous fetus was considered detected if a major abnormality of the relevant organ system was identified, regardless of the anticipated ultrasound detection. Anomalies were verified using a prospectively maintained database. Body mass index (BMI) was based on weight at first prenatal visit. RESULTS: There were 10,112 standard examinations in low-risk pregnancies and 1,098 targeted examinations in pregnancies with either high-risk indications or with an abnormality detected during standard ultrasonography. Detection of anomalous fetuses decreased with increasing BMI. For normal BMI, overweight, and class I, II, and III obesity, detection with standard ultrasonography was 66%, 49%, 48%, 42%, and 25%, respectively, and with targeted ultrasonography, 97%, 91%, 75%, 88%, and 75%, respectively, both P≤.03. Residual anomaly risk after a normal ultrasound examination increased with increasing BMI, from 0.4% among women of normal BMI to 1.0% among obese women, P=.001. Anomaly detection was lower among women with pregestational diabetes than in those with other high-risk indications, 38% compared with 88% respectively, P<.001. CONCLUSION: With increasing maternal BMI, we found decreased detection of anomalous fetuses with either standard or targeted ultrasonography, a difference of at least 20% when women of normal BMI were compared with obese women. Anomaly detection was even less in pregnancies complicated by pregestational diabetes. Counseling may need to be modified to reflect the limitations of ultrasonography in obese women. LEVEL OF EVIDENCE: II

The Long-Term Consequences of Thrombotic Microangiopathy (Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome) in Pregnancy

Objective To characterize perinatal outcomes and long-term maternal complications from thrombotic microangiopathy manifested during pregnancy, and to review the clinical course and long-term follow-up of pregnant women with this condition at our institution over the past 25 years. Methods We identified prospectively pregnant women who met clinical and laboratory criteria for thrombotic thrombocytopenic purpura or hemolytic uremic syndrome. Their clinical and laboratory findings, response to treatment, perinatal outcomes, and long-term sequelae were then analyzed. Results Between 1972 and 1997, 11 women had 13 pregnancies complicated by thrombotic microangiopathy, representing an incidence of one per 25,000 births. In three pregnancies (23%), severe and refractory disease developed before midpregnancy. In ten other pregnancies, disease developed either peripartum (62%) or several weeks postpartum (15%). In only two pregnancies with peripartum or postpartum onset of disease was there a clinical picture of severe preeclampsia. In general, the response to treatment was prompt. One woman died of her initial disease in early pregnancy, and mean follow-up of nine survivors was 8.7 years. Disease recurred at least once in 50% of these, two during a subsequent pregnancy. There was at least one serious long-term sequela in all but two survivors; these included recurrence of thrombotic microangiopathy, renal failure, severe hypertension, chronic blood-borne infections, and death. Conclusion Thrombotic microangiopathy complicating pregnancy is rare, and with careful evaluation, it should not be confused with atypical preeclampsia. With prompt and aggressive treatment including plasma exchange, the likelihood of immediate survival is high; however, long-term morbidity and mortality are common.

Persistence of placenta Previa according to Gestational age at ultrasound detection

OBJECTIVE To evaluate gestational age at ultrasound detection of placenta previa as a predictor of previa persistence until delivery, and to estimate the effects of previa type, parity, and prior cesarean delivery on previa persistence. METHODS This was a retrospective cohort study of pregnancies with placenta previa detected during transabdominal or endovaginal ultrasound examination. Previa was categorized as complete if the placenta completely covered the internal cervical os or incomplete if the inferior placental edge partially covered or reached the margin of the os. Gestational age was grouped into 4‐week intervals from 15 to 36 weeks. The outcome was cesarean delivery for persistent previa. RESULTS Previa was detected during 940 ultrasound examinations in 714 pregnancies. Of those with placenta previa at 15–19 weeks, 20–23 weeks, 24–27 weeks, 28–31 weeks, and 32–35 weeks, previa persisted until delivery in 12%, 34%, 49%, 62%, and 73%, respectively. At each interval, complete previa was more likely to persist than incomplete previa, all P < .001. Prior cesarean delivery was an independent risk factor for persistent previa among women diagnosed with previa in the second trimester, P < .05. However, parity was not an independent risk factor for persistence at any gestational age interval after adjusting for prior cesarean delivery. CONCLUSION Gestational age at ultrasound detection of placenta previa may be used to predict likelihood of previa persistence. After midpregnancy, risk of persistence appears to be higher than previously reported. Type of placentation and prior cesarean delivery are important factors that modify the risk that previa will complicate delivery.

Epidural analgesia and intrapartum fever: placental findings

OBJECTIVE To assess whether epidural analgesia is associated with fever, independent of maternal infection, by evaluating the relationship between epidural analgesia and inflammation of the placenta. METHODS Placentas collected prospectively from women with singleton gestations, who delivered 6 hours or more after membrane rupture, were evaluated systematically for histologic inflammation by an investigator blinded to all clinical information. Maternal and neonatal markers of infection were assessed in the cohorts who did and did not receive epidural analgesia. RESULTS One hundred forty-nine consecutive placentas were analyzed, and 80 (54%) of these women received epidural analgesia. On univariate analysis, significant differences between epidural and no epidural groups were found with respect to maternal fever 38C or greater (46% versus 26%, P = .01), placenta inflammation (61% versus 36%, P = .002), and length of labor (11.8 hours versus 9.6 hours, P = .03). The combination of maternal fever plus placental inflammation was significantly more common in the epidural group (35% versus 17% P = .02). However, maternal fever in the absence of supporting evidence of infection, in the form of placental inflammation, was not increased after epidural analgesia (11% versus 9%, P = .61). CONCLUSION Epidural analgesia is associated with intrapartum fever, but only in the presence of placental inflammation. This suggests that the fever reported with epidural analgesia is due to infection rather than the analgesia itself.

Opioid detoxification in pregnancy

Objective Opioid withdrawal has been associated with poor fetal growth, preterm delivery, and fetal death. We sought to evaluate the safety of antepartum opioid detoxification in selected gravidas. Methods Between 1990 and 1996, women with singleton gestations who reported opioid use were offered inpatient detoxification. Predetoxification sonography was performed to confirm gestational age and to exclude fetuses with growth restriction and oligohydramnios. Women with mild withdrawal symptoms were given clonidine initially, and methadone was substituted if symptoms persisted. Objective signs of withdrawal were treated with methadone from the outset. Antenatal testing was performed once gestations reached 24 weeks. Newborns were observed for signs of neonatal abstinence syndrome and were treated as necessary. Obstetric and neonatal outcome data were collected. Results Thirty-four gravidas elected to undergo opioid detoxification at a mean gestational age of 24 weeks. The median maximum dose of methadone was 20 mg per day (range 10–85 mg), and the median time to detoxification was 12 days (range 3–39 days). Overall, 20 women (59%) successfully underwent detoxification and did not relapse, ten (29%) resumed antenatal opioid use, and four (12%) did not complete detoxification and opted for methadone maintenance. There was no evidence of fetal distress during detoxification, no fetal death, and no delivery before 36 weeks. Fifteen percent of neonates were treated for narcotic withdrawal. Conclusion In selected patients, opioid detoxification can be accomplished safely during pregnancy.