Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study

Reproductive Toxicology 18 (2004) 93–101

Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study Chamutal Gur a,b,1 , Orna Diav-Citrin a,b,∗ , Svetlana Shechtman a , Judy Arnon a , Asher Ornoy a,b a

b

The Israeli Teratogen Information Service, The Israeli Ministry of Health, Hadassah Medical School and The Israeli Ministry of Health, The Hebrew University, P.O. Box 12272, Jerusalem 91120, Israel Laboratory of Teratology, Dept. of Anatomy and Cell Biology, Hadassah Medical School, The Hebrew University, P.O. Box 12272, Jerusalem 91120, Israel Received 1 May 2003; received in revised form 20 August 2003; accepted 5 September 2003

Abstract Objective: To evaluate the safety of glucocorticosteroids (GCS) in pregnancy. Study design: The Israeli Teratogen Information Service (TIS) prospectively collected and followed 311 pregnancies counseled regarding systemic use of different GCS in the first trimester. The rate of major congenital anomalies was compared to that of 790 controls who were counseled for non-teratogenic exposure. Results: The rate of major anomalies did not significantly differ between the groups [12/262 = 4.6% (GCS), 19/728 = 2.6% (control), P = 0.116]. There was no case of oral cleft and no pattern of anomalies among the GCS exposed group. Higher rates of miscarriages (11.5% versus 7.0%, P = 0.013) and preterm births (22.7% versus 10.8%, P < 0.001) were observed among the GCS exposed group compared to the controls. GCS exposed infants had a lower median birth weight [3080 g versus 3290 g, P < 0.001] and were born at an earlier median gestational age [39 weeks versus 40, P < 0.001] compared to the control. Conclusions: The present study supports that GCS do not represent a major teratogenic risk in humans. The study was powered to find a 2.5-fold increase in the overall rate of major anomalies. © 2003 Elsevier Inc. All rights reserved. Keywords: Glucocorticosteroids; Prednisone; Pregnancy; Congenital anomalies

1. Introduction Glucocorticosteroids (GCS) are used for a variety of conditions common in women of reproductive age (i.e. allergy, asthma, collagen vascular diseases, inflammatory bowel disease, etc.). GCS cross the human placenta [1,2]. Diffusion through the placenta is more rapid for fluorinated GCS [3]. Hydrocortisone is metabolized by 11␤-ol-dehydrogenase, which is abundant in the placenta, to cortisone, while other GCS can cross the placenta unchanged (e.g. dexamethasone). Almost without exception, the GCS were potent teratogens in laboratory animals at doses that were less than or similar to those used in humans. The primary defect induced in most species was cleft palate [4]. The published animal studies raised the question of whether GCS are also human teratogens. Two case reports of neonates with isolated cleft palate after pregnancy exposure to cortisone were published in 1956 [5,6]. Fraser and Sajoo [7] summarized ∗ Corresponding author. Tel.: +972-2-6758430; fax: +972-2-6758430. E-mail address: [email protected] (O. Diav-Citrin). 1 Served as partial fulfillment of the requirements for the MD degree of the Hadassah Medical School, Hebrew University.

0890-6238/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.reprotox.2003.10.007

17 case series including 468 GCS exposed women in early pregnancy and concluded that the teratogenic potential of GCS was so low as to be undetectable from the data available. Prospective cohort studies in humans have not shown a teratogenic effect but had limited power (Table 1) [8–17]. During the 1990s, several large retrospective case control studies have been published supporting the association between oral clefts and GCS in pregnancy (Table 2) [18–21]. In a recent meta-analysis the Mantel–Haenszel summary odds ratio for major malformations with all cohort studies was 1.45 [95% CI, 0.80, 2.60], and 3.03 [95% CI, 1.08, 8.54] when one of the studies [11], which did not separate major and minor malformations, was removed. Summary odds ratio for case control studies examining oral clefts was significant: 3.35 [95% CI, 1.97, 5.69] [17]. With the available data, the safety of GCS in human pregnancy is controversial. The primary objective of our study was to prospectively evaluate the rate of major anomalies after in utero exposure to GCS compared to the rate in a control group of pregnant women who were counseled for non-teratogenic exposure. Secondary endpoints of interest were pregnancy outcome, rate of preterm births, birth weight and gestational age at delivery. We also recalculated a cumulative odds ratio for

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Table 1 Summary of published prospective cohort studies on GCS in pregnancy Study

Design

Sample size∗

[8] [9] [10] [11] [12] [13] [14] [15] [16] [17]

PCC PCC PUC PCC PCC PCC PUC PCC PCC PCC

n n n n n n n n n n

= 21 = 34 = 55 = 151 = 148 = 102 = 29 = 28 = 101 = 122

Defects

Association

Indication

Comments

1 2 2 6 3 0 0 1 0 4

Difficult to interpret No No No No No No No No No

RA, SLE, AS Various Asthma N/A IBD SLE Asthma APLA Recurrent fetal loss Various

Cleft palate 1 Cleft palate Major and minor defects not separated 1 Cleft palate and microglossia

Primary outcome not birth defects Primary outcome not birth defects 1 with cleft palate and hypospadias

PCC: prospective controlled cohort; PUC: prospective uncontrolled cohort; ∗ : the number of pregnancies after first trimester exposure; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; AS: ankylosing spondylitis; N/A: not available; IBD: inflammatory bowel disease; APLA: antiphospholipid antibodies.

Table 2 Summary of published retrospective case control studies on oral clefts and GCS in pregnancy Study

Design

Cases of OC

Association

OR (95% CI)

[18] [19]

RCC RCC

n = 132 n = 1223

Yes Yes

2.58 (1.10–6.02) 5.88 (1.70–20.32)

[20] [21]

RCC RCC

n = 1184 n = 622

Yes Yes

6.55 (1.44–29.76) 4.3 (1.1–17.2) CL ± palate 5.3 (1.1–26.5) CP

Comments Only in the group exposed till week 4 post-LMP, CL ± palate CL ± palate

RCC: retrospective case control; OC: oral clefts; OR: odds ratio; CI: confidence interval; CL: cleft lip; CP: cleft palate; LMP: last menstrual period.

the published controlled cohort studies [8,9,11–13,17] with our study using similar criteria as described in the previous meta-analysis [17].

2. Methods All women who contacted (directly or through their health care providers) the Israeli Teratogen Information Service (TIS) between the years 1988 and 2001 for information about gestational systemic exposure to different GCS in the first trimester of pregnancy or to non-teratogenic agents were prospectively enrolled in the study. Details of exposure were collected during pregnancy, using a structured questionnaire. Standardized data collection forms were used to record the following information by telephone: maternal demographics, medical and obstetric histories, exposure details (dose, duration, route of administration, timing in pregnancy and indication for therapy) and concurrent exposures. Our inclusion criteria were as follows: systemic administration (PO, IV, IM), exposure at least during the first trimester of pregnancy to prednisone, prednisolone, methylprednisolone, cortisone, dexamethasone, hydrocortisone, fluocortolone, betamethasone, or triamcinolone for any indication, duration or dosage. Exclusion criteria were as follows: topical or inhalational exposure, first exposure beyond 13 weeks, or only in the “all or none” period (less than 4 weeks’ gestation), exposure to agents with mainly min-

eralocorticoid activity (i.e. fludrocortisone), or when GCS eventually were not taken in pregnancy. After the expected date of delivery, follow up was conducted by a telephone interview with the woman using a structured questionnaire to obtain details on the pregnancy outcome, gestational age at delivery, birth weight, major or minor birth anomalies, and additional exposures. When the mother reported a malformation, she was asked to send medical documents verifying the diagnosis. Alternatively, an attempt was made to contact the child’s physician for verification. Follow up of offspring in the index and control group was performed between the neonatal period and 8 years of age. However, in most cases, it was carried out within the first two and a half years of life. The control women had been counseled in regard to exposures not known to be teratogenic such as: antibiotics (i.e. penicillins, cephalosporins, erythromycin), topical preparations not containing retinoids, oral contraceptives taken prior to pregnancy and no later than the first 4–5 weeks of pregnancy, hair dye and house-cleaning agents, low-dose diagnostic irradiation, vitamin supplementation, analgesics, antacids, and thyroxine replacement. The Israeli TIS had 550 calls that met the inclusion criteria in regard to GCS exposure in pregnancy in the defined time frame. Follow up was obtained on 311 (56.5%) GCS first trimester exposed women and 790 (28.2%) control women. Part of the present control group has been previously used [22]. We aimed at a 1:3 ratio between the steroid and control groups among live births.

C. Gur et al. / Reproductive Toxicology 18 (2004) 93–101

The primary outcome of interest was the rate of major malformations [i.e. those having a structural abnormality that has serious medical, surgical or cosmetic consequences [23], we included all structural-morphological, functional, biochemical-molecular genetic abnormalities]. In cases of multiple births, each live-born was included in the analysis. We did not include children with minor anomalies, functional problems without any morphological changes (i.e. systolic heart murmur with normal echocardiography, developmental delay), or complications of preterm birth. Abnormalities detected by prenatal ultrasonography (if verified postnatally or by autopsy) are included in our study since antenatal screening for major anomalies is routinely performed in Israel. The analysis of major congenital anomalies was performed on live-born infants and elective terminations of pregnancy due to prenatally diagnosed anomalies. Exclusion of elective terminations due to prenatally diagnosed anomalies would cause under-reporting of anomalies. The analysis was also done in a prednisone subgroup, as the various GCS have different pharmacology and, therefore, may have different effects. Gestational age in the present study applies to weeks post last menstrual period. Secondary endpoints were the rates of live birth, miscarriage, pregnancy termination, stillbirth and ectopic pregnancy, the rate of preterm births (≤37 weeks gestational age), gestational age at delivery and birth weight. 2.1. Statistical analysis Dichotomous data were compared by chi-square or Fisher’s exact tests, when appropriate. Data are expressed as ratios or percentages for dichotomous data. Continuous data were not normally distributed, and were compared using the Mann–Whitney test. Continuous data are expressed

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as median with interquartile range (IQR). Relative risk and power calculations were performed using Epi Info 2000 software. Linear and logistic regression was performed post hoc to analyse the relative contribution of various predictors to differences in dependent variables. A cumulative odds ratio (OR) was calculated using the Cochrane Review Manager version 4.1 software.

3. Results We prospectively collected and followed up 311 pregnancies exposed to systemic GCS at least in the first trimester of pregnancy. Most women were exposed only during the first trimester (65.4%), 8.4% were treated during the first and second trimesters, while 26.2% were treated throughout pregnancy. The majority of the women in our cohort were exposed to prednisone (70.0%). The distribution of the various GCS is presented in Fig. 1 and the indications for treatment in Fig. 2. The majority of patients in our cohort (86.2%) used the medication orally, while 13.8% used it by intravenous or intramuscular routes. The median daily GCS dose is expressed in the relative glucocorticosteroid activity compared to prednisone (prednisone = 1, cortisone = 0.2, hydrocortisone = 0.25, prednisolone methylprednisolone and triamcinolone 1.25 each, fluocortolone = 2.5, dexamethasone and betamethasone 7.5 each) was 20 mg (10.0–30.0 IQR). The median duration of exposure was 8.5 weeks (2.0–36.0 IQR). Maternal characteristics and obstetrical history. A comparison of maternal characteristics between the GCS and control groups is presented in Table 3. The median gestational age at initial call was 9 weeks (7–13 IQR) in the GCS group and 10 weeks (7–18 IQR) in the controls (P < 0.001).

Triamcinolone 2.6% Hydrocortisone 2.9%

Prednisone 70.0%

Prednisolone 2.9% Methylprednisolone 2.9% Fluocortolone 3.5% Dexamethasone 3.5% Cortisone 3.9% Betamethasone 7.7% Fig. 1. Distribution of the various GCS.

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Allergy 17.7%

Not specified 20.6%

Asthma 16.1%

Other 23.9% Arthritis 3.2%

RA 4.8%

SLE 6.8%

IBD 6.8%

Fig. 2. Indications for treatment in the GCS group. IBD: inflammatory bowel disease; SLE: systemic lupus erythematosus; RA: rheumatoid arthritis, Other: less common indication (<1.5% each) i.e. recurrent fetal loss, APLA: antiphospholipid antibody syndrome, erythema nodosum, transplantation.

No significant differences were found between the group taking GCS and the controls in maternal age, pregnancy order, parity, history of miscarriages, therapeutic abortions, years of schooling and cigarette smoking. Data on the latter two were only partially available (on schooling since 1996). Cigarette smoking was reported by 9.2% of the women in the GCS group and 7.0% in the control group.

Table 3 Maternal characteristics and obstetrical history GCS

Control

Median age (year) (interquartile range)

30 (27–34)

30 (27–34)

Gestational age at call weeks (interquartile range)

9 (7–13)

10 (7–18)

P-value 0.232 <0.001

Pregnancy order (%) PO1 PO2–6 ≥PO7

74 (24.6) 214 (71.1) 13 (4.3)

185 (24.4) 535 (70.6) 38 (5.0)

0.893

Parity (%) P0 P1 ≥P2

90 (30.4) 79 (26.7) 127 (42.9)

219 (29.1) 201 (26.7) 333 (44.2)

0.900

Miscarriages (%) None One Two Three or more

217 56 19 9

(72.1) (18.6) (6.3) (3.0)

602 104 39 13

(79.4) (13.7) (5.1) (1.7)

0.068

ETOP (%) None One Two Three or more

264 26 5 1

(89.2) (8.8) (1.7) (0.3)

669 59 17 5

(89.2) (7.9) (2.3) (0.6)

0.812

21 (4.7) 165 (37.2) 257 (58)

0.367

Maternal schooling∗ (year) <12 12 >12

4 (2.9) 60 (42.9) 76 (54.3)

PO: pregnancy order; P: parity; ETOP: elective termination of pregnancy; ∗ : data on schooling known only since 1996.

3.1. Pregnancy outcome A comparison between the GCS and control groups as well as between the prednisone subgroup and control group is presented in Table 4. There was no increase in the rate of major anomalies among live births plus elective terminations of pregnancy due to prenatally diagnosed anomalies between the GCS group compared to controls (Table 4) [12/262 (4.6%) versus 19/728 (2.6%), respectively; relative risk (RR) 1.75; 95% confidence interval (CI), 0.86–3.57]. This calculation was repeated considering only congenital anomalies that could be caused by environmental exposure without chromosomal abnormalities and genetic or familial disorders (see ∗ in Tables 5 and 6) [10/262 (3.8%) (GCS) versus 14/725 (1.9%) (control); RR, 1.98; 95% CI, 0.89–4.40, Table 4]. The rate of cardiac anomalies, although higher, did not significantly differ between the groups [5/262 (1.9%) (GCS) versus 4/728 (0.5%) (control); RR, 3.47; 95% CI, 0.94–12.84]. A cumulative OR was recalculated for six controlled cohort studies [8,9,11–13,17] (excluding two studies in which the primary outcome was not birth defects) and the present one using similar criteria as described in a previous meta-analysis [17]. The Mantel–Haenszel summary odds ratio for major anomalies was 1.57; 95% CI, 0.99–2.49 (exposed n1 /N1 = 28/810 versus non-exposed n2 /N2 = 2294/53,848; z = 1.93, P = 0.054) and the trials were homogenous [heterogeneity chi square 4.45 (d.f. = 5), P = 0.492]. The reported major anomalies in the GCS and control groups in the prospective study are listed in Tables 5 and 6, respectively. As can be seen in Table 5, there was no case of oral cleft in the GCS exposed group. In the exposed group, an infant diagnosed with lacrimal duct stenosis, which resolved after dilatations, was excluded. Another infant in the GSC group, who was diagnosed with bicuspid aortic valve was considered as having a minor anomaly, as this anomaly is estimated to be present in 2–3% of the population [24], and it is usually asymptomatic in early life. The same infant was diagnosed at 6 months with neuroblastoma, which

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Table 4 Pregnancy outcome (%) GCS, n = 311

Prednisone subgroup, n = 217

Live-born infants

260 (5 sets of twins)

183 (4 sets of twins)

Delivery Miscarriages ETOP Stillbirths Ectopic pregnancies Major congenital anomalies∗ (%) Non-genetic major congenital anomalies∗,∗∗ (%) Congenital heart defects∗ (%) Median GA (week) (interquartile range) Preterm birth (≤37 weeks) (%) Median birth weight (g) (interquartile range) Median birth weight of term infants (weeks 38–42) (g) (interquartile range)

256a (82.1) 36 (11.5) 18a (5.8) 1 (0.3) 1 (0.3) 12/262+ (4.6) 10/262+ (3.8)

179a (82.1) 26 (11.9) 12a (5.5) 1 (0.5) 0 (0.0) 9/184+ (4.9) 8/184+ (4.3)

5/262+ (1.9) 39 (38–40)

4/184+ (2.2) 39 (37–40)

56 (22.7) 3080 (2650–3500)+

46 (26.9) 3000 (2504–3458)+

3250 (2900–3560)+

3200 (2875–3500)+

Control, n = 790 722 (14 sets of twins and 1 triplet) 706 (89.4) 55 (7.0) 27 (3.4) 1 (0.1) 1 (0.1) 19/728+ (2.6) 14/725+ (1.9) 4/728+ (0.5) 40 (38–41) 74 (10.8) 3290 (2946–3610)+ 3350 (3100-3650)+

P-value (p1 , p2 )

0.001, 0.013, 0.076, 0.486, 0.486, 0.116, 0.089,

0.004 0.017 0.157 0.386 1.000 0.109 0.064

0.060, 0.057 <0.001, <0.001 <0.001, <0.001 <0.001, <0.001 0.002, 0.002

ETOP: elective termination of pregnancy; GA: gestational age at delivery; a : one twin pregnancy considered twice (one fetus reduced due to spina bifida and one delivered); ∗ : including ETOP due to prenatally diagnosed anomalies/stillbirth with anomalies; ∗∗ : genetic refers to chromosomal, genetic and familial disorders; + : including multiple gestations; p1 : comparison of GCS and control groups, p2 : comparison of prednisone subgroup and control group.

was resected. Similarly, the following anomalies were excluded in the control group: suspected closed fontanelles at birth with normal head circumference increase in the first year, and facial hemangiomas. In both groups cases with suspected hydronephrosis detected by prenatal sonography were not included if followed by a normal postnatal kidney ultrasound. In addition, cases of umbilical hernia without surgical intervention were also excluded. A higher miscarriage rate was reported in the GCS group of mothers compared with that in the controls (36/312, 11.5% versus 55/790, 7.0%, respectively, P = 0.013, Table 4). The median gestational age at delivery was lower in the GCS group compared to the control [39 weeks (38–40 IQR) versus 40 (38–41) (control), P < 0.001]. A two-fold increase in the rate of preterm births (≤37 weeks gestational age) was found in the GCS exposed group [22.7% (GCS) versus 10.8% (control), P < 0.001]. The median birth weight was approximately 200 g lower in the GCS group compared to the controls [3080 g (2650–3500) versus 3290 g (2946–3610), respectively, P < 0.001, Table 4]. Table 7 describes a subgroup analysis of birth weight. When the median birth weight was compared in a subgroup of term infants, a 100 g decrease in birth weight was still detected in the GCS group [3250 g (2900–3569) (GCS) versus 3350 g (3100–3650) (controls), P = 0.002]. In the subgroup of preterm infants the decrease in birth weight was more pronounced [2300 g (1797–2701) (GCS) versus 2550 g (2300–2900) (control), P = 0.003]. The birth weight was also analyzed according to trimester of exposure to GCS. In the subgroup of patients exposed to GCS throughout pregnancy the birth weight was approximately 400 g lower compared to patients exposed in

the first and second trimesters (P = 0.005). The birth weight was approximately 600 g lower in the subgroup of patients exposed throughout pregnancy to GCS compared to the whole control group (P < 0.001). Moreover, there was no significant difference in birth weight between those exposed in the first and second trimesters compared to the whole control group [3140 g (2800–3535) versus 3290 g (2946–3610), P = 0.211]. In order to evaluate the relative contribution of various predictors to the differences in miscarriage rate, rate of preterm births, and birth weight, logistic regression analysis was performed for miscarriage and rate of preterm births while linear regression analysis was performed for birth weight. History of miscarriages, gestational age at call, maternal age, presence of chronic systemic disease, and GCS mean daily dosage were entered to the model for miscarriage. The only significant predictor found was gestational age at call (P < 0.001). The exposed group was divided into two subgroups of patients, with or without chronic systemic disease. In an attempt to assess whether the basic disease, trimester of exposure (1st/1st + 2nd trimesters versus throughout pregnancy), and/or GCS exposure correlated with a higher rate of preterm births, trimester of exposure, presence of chronic systemic disease and GCS mean daily dosage were entered to the model for preterm births. The model was significant (P < 0.001) and the only significant predictor was trimester of exposure (P = 0.012). The following predictors were entered to the model for birth weight: gestational age at delivery, trimester of exposure, GCS mean daily dosage, smoking, presence of chronic systemic disease, and parity. The model was found significant (P < 0.001) and the predictors that had a major contribution

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Table 5 Major congenital anomalies in the GCS exposed group Details of exposure to GCS, indication

Additional pregnancy exposures

Follow up

VSD

Prednisone 60 mg per day, till week 13, asthma

Roxithromycin, beclomethasone

VSD + peripheral artery stenosis VSD

Prednisone 10 mg per day, throughout pregnancy, arthritis Betamethasone, weeks 4–5, allergy

Aspirin, naproxen

VSD

Prednisone, 5 mg per day, weeks 10–14, hyperemesis gravidarum

None

Asymptomatic, present at 3.5 years (minimal) Spontaneously closed at several weeks Spontaneously closed at 1.5 years Surgically corrected at 4 months

PDA Severe unilateral hearing impairment Bilateral hearing loss∗

Prednisone, 7.5 mg per day, weeks 11–41, AIHA Prednisone, 7.5 mg per day, throughout pregnancy, RA

None None

Spontaneously closed at 1 year No history of recurrent AOM

Cortisone week 5, infectious mononucleosis

None

Hearing aid

EA + TE fistula

Prednisone, 10 mg per day, throughout pregnancy

Tacrolimus, azathioprine, ganciclovir, insulin, pancrease, CMV, DM

Operated after birth

CDH Fragile × syndrome∗ Spina bifida

Prednisone, 35 mg per day, weeks 5–6, CD Prednisone, 7.5 mg per day, till week 15, CD Prednisone, 10 mg per day, throughout pregnancy, RA

Bilateral agenesis of kidneys

Betamethasone dipropionate 5 mg IV, week 10

∗ The

None

Treated with braces 5-ASA Aspirin, thyroxine Bethametasone (topical) throughout pregnancy

Prenatally diagnosed by U/S, reduced at 21 weeks ETOP at 20 weeks, following prenatal diagnosis

Comments

CHF after birth, treated by digoxin, furosemide and captopril till surgery Term (41 weeks) Negative family history, negative TORCH Positive family history (another sibling and on paternal side) Mother has CF, underwent lung transplantation 2 years prior to pregnancy Female Male One of twin pregnancy

marked anomalies were not included in the repeated calculation on non-genetic major congenital anomalies, genetic refers to chromosomal, genetic and familial disorders; VSD: ventricular septal defect; PDA: patent ductus arteriosus; AOM: acute otitis media; EA + TE fistula: esophageal atresia with tracheoesphageal fistula; DM: diabetes mellitus; CF: cystic fibrosis; CDH: congenital dysplasia of the hip; 5-ASA: 5-aminosalicylic acid; AIHA: autoimmune hemolytic anemia; RA: rheumatoid arthritis; CD: Crohn’s disease; CHF: congestive heart failure.

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Type of anomaly

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Table 6 Major congenital anomalies in the control group Type of anomaly

Details of exposure

Comments

Urinary tract anomaly Bilateral dilatation of renal pelvis (reflux) Transposition of great arteries

Dental X-ray, week 2 Diclofenac, propoxyphene and paracetamol, contraceptive sponge, till week 7 Famotidine, paracetamol, metoclopramide (months 2–3) Detergent Medroxy-progesterone, till weeks 8–9

Surgery required

Trimethoprim and sulphametoxazole, week 4

Congestive heart failure after birth, treated by digoxin and furosemide, improved with time Positive family history Prenatal diagnosis Term, operated at 10 month

Pulmonic regurgitation, VSD Urinary tract obstruction with left hydronephrosis VSD, ASD X-linked ichthyosis∗ Unilateral agenesis of kidney Inguinal hernia Russel–Silver syndrome∗ CDH CDH VSD Anencephaly Chromosomal aberration∗ Hydrocephalus Omphalocele 21 trisomy∗ 21 trisomy∗

Cefuroxime, week 24 Activated charcoal, week 30 Paracetamol, phenylpropanolamine, diphenhydramine Salbutamol Chlorpheniramine Chest X-ray

Neonatal death Spontaneous closure of VSD at several months Prenatal diagnosis, operation at 10 month of age

Hypotonia, developmental delay Casting Braces till 8 months

Amoxycillin clavulanate Cephalexin, amoxycillin, cloxacillin, week 9 5-ASA throughout pregnancy Miconazole Laxative tea

ETOP at 20 weeks, following prenatal diagnosis History of mosaicism in a previous pregnancy, ETOP at 22 weeks, following prenatal diagnosis ETOP at 23 weeks, following prenatal diagnosis ETOP at 20 weeks, following prenatal diagnosis ETOP at 21 weeks, following amniocentesis results ETOP at 21 weeks, following amniocentesis results

∗ The

marked anomalies were not included in the repeated calculation on non-genetic major congenital anomalies, genetic refers to chromosomal, genetic and familial disorders; ETOP: elective termination of pregnancy, VSD: ventricular septal defect, ASD: atrial septal defect; CDH: congenital dysplasia of the hip. Table 7 Subgroup analysis of birth weight

Median birth weight (g) (interquartile range)

GCS

Control

P-value

Preterm infants GCS subgroup exposed in the first and second trimesters versus controls GCS subgroup exposed throughout pregnancy versus controls

2300 (1797–2701) 3140 (2800–3535), n = 164 2703 (2192–3266), n = 78

2550 (2300–2900) 3290 (2946–3610), n = 707 3290 (2946–3610), n = 707

0.003 0.211 <0.001

were gestational age at delivery (R2 change = 40.4%, P < 0.001) and trimester of exposure (R2 change = 3.5%, P = 0.002). The other predictors mentioned were not significant.

4. Discussion The present study, which is the largest prospective controlled cohort on systemic GCS exposure in gestational weeks 4–13, followed-up 311 pregnancies to examine the rate of major malformations. Both the GCS exposed cases and their controls had malformation rates within the expected baseline risk for the general population. The incidence of major anomalies recognized at birth among live-born infants is 1–3% [11]. The incidence is as high as 5% if one includes malformations detected later at childhood [25], this also includes mental retardation. It is consistent with most previous prospective studies not associating GCS exposure during pregnancy with a teratogenic risk in humans (Table 1). No specific pattern of anomalies among

the GCS-exposed infants was found, supporting lack of a teratogenic effect. In contrast to the above, most retrospective case control studies support the association between oral clefts and in utero exposure to GCS. This discrepancy may be explained by a higher sensitivity of the retrospective case control design to detect low frequency defects, or by the potential biases (recall and publication bias) inherent in this type of design. The latter argument does not explain why the association was with oral clefts and not with other defects that were evaluated [19,21]. A sample size of 260 live-births in the GCS exposed group with a ratio of 1:3 to the control group, power of 80%, assuming a baseline risk of 3% for major anomalies, enables detection of a 2.5-fold increase in the rate of major anomalies (with 95% confidence interval). The cumulative OR recalculated for seven controlled cohort studies including the results of the present study did not show a significant increased risk for major anomalies associated with GCS first trimester exposure. It shows, however, a trend for a slight increased risk of major anomalies after

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first trimester exposure to GCS, which did not reach statistical significance. The absence of a case of oral cleft in our GCS exposed group, does not rule out a weak association between these defects and in utero exposure to GCS. The baseline risk for cleft palate in the general population is 1:2500 and for cleft lip with or without cleft palate 1:500–1000 [26]. In order to detect a small increase in the incidence of these defects a larger sample size is needed. Among the major anomalies reported in the GCS group cardiac defects were the most common. The relative high frequency of cardiac defects may be explained by the fact that these defects are the most common defects in the general population (0.8%). Although the rate of cardiac defects was approximately twice the expected, it was not statistically significant compared to the controls [1.9% (GCS), 0.5% (control), P = 0.60]. Furthermore, as many of the detected cardiac defects (2 of the 4 VSDs and the 1 PDA) in the exposed group spontaneously resolved, it does not seem to be clinically significant. Previous studies [17] did not support an association between cardiac defects and prenatal exposure to GCS. A larger sample size is needed to verify such an association. A two-fold increase in the rate of preterm births in the GCS group was observed and partly explained by the trimester of exposure. GCS treatment throughout pregnancy was correlated with a higher rate of preterm births. We lacked data on two important risk factors for prematurity: history of previous preterm births and premature rupture of membranes. Partial data on smoking habits did not allow evaluation of the contribution of this predictor on the rate of preterm births and birth weight. The neonatal birth weight was significantly reduced in the GCS exposed group in comparison to that of controls. The birth weight reduction in the GCS group was partly explained by an earlier gestational age at delivery and a higher rate of preterm births. In the subgroup analysis the difference in birth weight was still noticeable comparing term neonates only. The decrease in birth weight was more pronounced in a subgroup of patients exposed throughout pregnancy to GCS. The most important predictor explaining 40.4% of the birth weight difference between the GCS exposed group and the controls was gestational age at delivery. Another important predictor was timing of exposure (R2 change = 3.5%), the longer the duration of GCS treatment (and especially exposure in the third trimester of pregnancy when most of fetal weight gain occurs), the lower the median neonatal birth weight. Duration of treatment is closely related to disease severity, so both factors might have played a role in the effect on birth weight. Data available from both animal experiments and clinical observations suggest that prenatal exposure to GCS is associated with a lower birth weight in the offspring and a higher rate of preterm births [9,14,27–31]. In some cases these outcome measures have been attributed to the underlying disease for which the GCS were given [14,27,31]. Others have attributed these findings to a direct drug effect

[9,30]. Our study supports that both variables contribute to the observed effects. A higher miscarriage rate was observed in the GCS group (11.5%) compared to the control group (7.0%). The reported rate in the GCS group is within the baseline miscarriage risk of the general population (10–12%) [32]. Some of the underlying diseases may be associated with an increased miscarriage risk (e.g. systemic lupus erythematosus [3]). Logistic regression analysis in our study showed that the only significant predictor that correlated with a higher miscarriage rate in the GCS group was an earlier gestational age at call, as most miscarriages occur during the first 3 months of pregnancy. Disease state or GCS mean daily dosage were not significant predictors. The present prospective controlled cohort study, despite its limitations (i.e. reliance on self-reported drug exposure and maternal interview as a source for outcome data), is a valid approach to the question of the safety of GCS in human pregnancy. The same procedure, applied to both arms of the study, and the prospective nature of the study minimize the potential biases. The present study supports that GCS do not represent a major teratogenic risk in humans. The study was powered to find a 2.5-fold increase in the overall rate of major anomalies. Despite the fact that a sample size of 311 pregnancies is the largest published to date, it cannot rule out a weak association between oral clefts and GCS. In utero exposure to GCS seems to contribute to a higher rate of preterm births and a lower birth weight, particularly when the exposure continues throughout the entire pregnancy.

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