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Journal of Perinatology (2009) 29, 89–95

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COMMENTARY
High-risk pregnancy management in women with
hypopituitarism
K Kübler1,2, D Klingmüller2, U Gembruch1 and WM Merz1
1
Department of Obstetrics and Gynecology, University of Bonn, Bonn, Germany and 2Institute for Clinical Chemistry and
Pharmacology, University of Bonn, Bonn, Germany

obstetric complications.1 To assess specific risks during gestation


Pregnancy after complete loss of pituitary function is uncommon. However, and parturition of women lacking pituitary hormones, we
advances in fertility treatment have led to increased pregnancy rates in performed a literature review revealing adverse pregnancy outcome.
hypopituitary women. We hereby present a literature review of pregnancies Furthermore, we compared affected cases with published controls
affected by hypopituitarism, including a comparison with published and identified significantly higher rates of cesarean delivery,
controls; further, we add one case report of severe hypopituitarism where transverse lie and small for gestational age (SGA) neonates,
third-trimester oxytocin supplementation was performed. As only limited indicating the need for close maternal and fetal surveillance.
information is available on management and outcome, our purpose was to We assumed that the adverse pregnancy outcome might reflect
determine obstetric complications associated with deficiency of pituitary uterine dysfunction caused by hormone deficiency, including lack
hormones. The analysis of 31 pregnancies in 27 women revealed that of oxytocin. Oxytocin is a potent uterotonic agent, synthesized in
hypopituitary women are at increased risk: postpartum hemorrhage the hypothalamic nuclei, transported to the posterior pituitary and
occurred in 8.7%, transverse lie in 16%; 42.4% of the newborns were small released into the general circulation in a pulsatile manner.2
for gestational age. These findings are supposedly the result of uterine Oxytocinergic pathways may be adversely affected in hypopituitary
dysfunction caused by hormone deficiency. Oxytocin supplementation was women, resulting in alterations of delivery and lactation. To
performed with the aim to establish physiologic conditions and to prevent compensate for oxytocin deficiency, we performed supplementation
postpartum uterine inertia. In this case substitution may have contributed between the gestational age (GA) of 34 þ 0 weeks and delivery in a
to correct fetal presentation but did not prevent postpartum hemorrhage. patient lacking pituitary hormones. The rationale for this
Further investigations into both oxytocin-dependent and -independent experimental treatment was to enhance uterine function. We
mechanisms regulating uterine contractions and contractility are necessary hypothesized that oxytocin substitution may augment uterine
to develop strategies for prevention of uterine inertia in oxytocin-deficient contractility, thereby preventing fetal malpresentation and
pregnancies. postpartum hemorrhage (PPH). This is the first report of third-
Journal of Perinatology (2009) 29, 89–95; doi:10.1038/jp.2008.116 trimester oxytocin substitution in hypopituitarism because a search
Keywords: oxytocin; hypopituitarism; high-risk pregnancy; malpresen- of Medline (English language; search terms: oxytocin,
tation; postpartum hemorrhage supplementation, substitution, pregnancy) revealed no other cases.

Introduction
Normal functions of the hypothalamic–pituitary-target axes are Methods
important for the regulation of feto-maternal homeostasis. A search was performed using Medline (October 1965 to April 2006)
Consequently, deficiency of pituitary hormones may affect with the following MeSH or keyword terms (single and in
conception, pregnancy and delivery. Although advances in artificial combination): hypopituitarism, oxytocin, pregnancy, delivery and
reproductive techniques (ARTs) provide methods to restore fertility outcome. Titles and abstracts published in English were searched
in hypopituitary women, only few cases of successful pregnancy for relevant information and hard copies retrieved for further
and parturition have been published, reporting high rates of information. References were analyzed by hand to identify
additional publications. From all identified articles, two
Correspondence: Dr WM Merz, Department of Obstetrics and Gynecology, University of Bonn,
investigators selected the reports to be reviewed and extracted data
Sigmund Freud Strasse 25, Bonn 53127, Germany.
E-mail: Waltraut.Merz@ukb.uni-bonn.de from these. As pregnancy in hypopituitarism is rare, we accepted
Received 14 March 2008; revised 25 June 2008; accepted 5 July 2008 case reports as well as retrospective trials. Unpublished data or
Pregnancy management in hypopituitarism
K Kübler et al
90

published abstracts were not included. We did not attempt to group of hypopituitary pregnancies (n ¼ 16) and the ART control
contact authors. group (n ¼ 16),35, respectively.
A total of 28 documents comprising 63 pregnancies in 40 As only few cases were observed in the study group, the
women were identified.1,3–29 Inclusion criteria for the study statistical analysis was obtained by simulation procedure with the
group were as follows: pregnancies conceived by ART, resulting statistical software ‘R’ (version 2.1.0, The R Foundation for
in viable babies. We further evaluated causes of hypopituitarism Statistical Computing, Vienna, Austria). Distributions were
and considered only cases where posterior pituitary damage compared using the Fisher’s exact test. The level of statistical
was likely.30,31 The following cases were excluded: significance was set at P<0.05.
subclinical hypopituitarism (n ¼ 16);4,6,8,11 –13,17,19,25,28,29
cause of hypopituitarism not specified (n ¼ 1);21
first-trimester miscarriages (n ¼ 15).1,4,12,19 Sixteen case Case
reports3,5–7,9,10,14 –16,18,20,22–24,26,27 describing the outcome of A 35-year-old woman had undergone subtotal excision of a
18 pregnancies and one trial1 reporting 13 pregnancies in nine craniopharyngioma at the age of 8 years. The resulting pituitary
women were included in the analysis. The following data were insufficiency was treated with substitution of L-thyroxine,
analyzed: baseline characteristics (age at diagnosis and pregnancy, hydrocortisone, desmopressin and growth hormone. At 12 years of
cause and therapy of hypopituitarism, ovulation induction, age, recurrence was diagnosed and reoperation performed.
obstetric history); course of pregnancy (pregnancy-specific Subsequently, she underwent radiation therapy for residual tumor.
complications, drug substitution); delivery (mode of delivery Post-interventional panhypopituitarism was diagnosed and
(MOD), GA); puerperium (onset of lactation, maternal complete substitution of pituitary hormones initiated. The patient
complications) and fetal outcome (birth weight, perinatal remained disease-free thereafter. At the age of 19, menstrual cycle
morbidity and mortality). Weight centiles corrected for GA and was established by combined oral contraceptives. The patient
singleton versus multiple pregnancy were calculated according to requested fertility treatment at the age of 30 years and ovulation
ethnicity and sex.32–34 In case the sex was not reported, the centile induction with gonadotropins was performed. The third cycle of
was adjusted as a minimum for both sexes. in vitro fertilization (IVF) with intracytoplasmic sperm injection
To determine specific pregnancy-related risks in hypopituitary (ICSI) resulted in a singleton intrauterine pregnancy. Progesterone
women, the study group was compared to published controls.35–37 was substituted until 12 weeks’ GA. Assessment of adequate
The analysis was limited to singleton pregnancies because substitution of pituitary hormones involved both clinical and
complication rates are higher for multiple pregnancies. Owing to biochemical evaluations. Hydrocortisone dosage had to be
the fact that comparisons may be hampered by maternal increased from 5 mg daily preconceptionally to 10 mg per day (17
differences between the groups we tried to adjust as many weeks’ GA), 15 mg per day (24 weeks’ GA) and 25 mg per day (32
confounding factors as possible. Matching criteria for published weeks’ GA) for the remaining pregnancy. L-Thyroxine (125 mg per
epidemiological studies were as follows: singleton pregnancies day) and desmopressin (0.4 mg per day) did not require
received after ART, mean maternal age, proportion of primiparity adjustment. The patient was referred to our department for
p20% and mean GAp1 week difference, date of parturition antenatal care at 16 þ 4 weeks’ GA and was seen monthly until
between 1965 and 2005, delivery in developed countries and 34 þ 0 weeks’ GA. No maternal complications occurred and fetal
definition of adverse outcome. The following pregnancy development was normal.
complications were analyzed: SGA (birth weight p10th centile), As oxytocin-deficiency was presumed, we performed third-
transverse lie at term (confirmed by cesarean section), PPH (blood trimester substitution. After obtaining informed consent
loss requiring blood transfusion and/or blood loss resulting in incremental doses of intravenous (i.v.) oxytocin under
hysterectomy and/or medical treatment to induce uterine cardiotocographic monitoring were administered at 34 þ 0 weeks’
contractions), cesarean delivery (in case of one woman with more GA to define the amount of oxytocin required to induce uterine
than one pregnancy, the repeat cesarean section was excluded1). contractions. Regular contractions were recorded at a dose of 3
Comparing the various indications for cesarean delivery between milliunits per min oxytocin. With nasal bioavailability of one-tenth
the groups, no significant differences were found for the following compared to i.v. application, the patient was started on spray-
criteria: fetal distress (31.25% (5/16) vs 31.25% (5/16); P ¼ 1), administered oxytocin (0.25 U, q.i.d.). Cardiotocography was
lack of progress in labor or failed induction of labor (31.25% performed in regular intervals (34 þ 4, 35 þ 4 and 37 þ 0 weeks’
(5/16) vs 12.5% (2/16); P ¼ 0.4), previous cesarean section or GA) to monitor the effect of spray application. Substitution
scarred uterus (0% (0/16) vs 6.25% (1/16); P ¼ 1), abnormal was well tolerated; the only adverse reaction consisted of
presentation (25% (4/16) vs 18.75% (3/16); P ¼ 1), obstetric deteriorating rhinorrhea. Application was therefore switched
indications (12.5% (2/16) vs 25% (4/16); P ¼ 0.65) and absent to i.v. oxytocin and carried out every second day from 37 þ 1
medical indication (0% (0/16) vs 6.25% (1/16); P ¼ 1) in the to 38 þ 4 weeks’ GA.

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Elective cesarean delivery on request was performed without Compared to the current cesarean delivery rate in ART
complications under combined spinal–epidural anesthesia at pregnancies, the incidence of operative deliveries in women with
38 þ 6 weeks’ GA and a viable fetus was delivered (cephalic hypopituitarism is striking (Table 3). Indications were
presentation, female, 2950 g (25th centile), Apgar score 9/10/10, heterogeneous; of note however is the high malpresentation rate of
umbilical artery blood pH 7.34). For surgery, the patient received a 25% (10% breech lie, 15% transverse lie) in singleton pregnancies.
single stress-dose of hydrocortisone (200 mg) that was tapered to Transverse lie in particular was significantly more common
the maintenance level of 25 mg per day. After the delivery of fetus (Table 3). However, we cannot exclude that the high cesarean
and placenta, uterine atony occurred that responded to i.v. oxytocin section rate is due to obstetricians’ recommendations rather than
(cumulative dose 39 U) and i.v. prostaglandin-E2 analog medical necessity.
sulprostone (cumulative dose 525 mg). Estimated blood loss was Our review also revealed a higher trend in PPH compared to the
800 ml. After delivery, the patient was started on methylergometrin given incidence, although this did not reach statistical significance
(0.75 mg per day, p.o.), prostaglandin-E1 analog misoprostol (Table 3).
(2 mg per day, p.r.) and oxytocin (48 U, nasal per day) to promote Thus, pregnancies in women with hypopituitarism require
uterine involution. However, subinvolution was diagnosed the fifth special antenatal care. Serial ultrasound for fetal growth
postoperative day by clinical and sonographic examination (soft, assessment is recommended. In case of malpresentation, the
tender uterus with retained blood clots in the uterine cavity); it was decision on external cephalic version versus cesarean delivery needs
successfully treated by a single infusion of 23 U oxytocin and to be taken after considering additional risk factors. Regarding
0.4 mg methylergometrin. The further course was normal with PPH, active management may be beneficial.
daily doses of methylergometrin (0.75 mg) and misoprostol Altogether, we hypothesized oxytocin to be involved in the
(0.6 mg) until the 18th day after delivery. following mechanisms: Braxton–Hicks contractions of late
Despite regular intake of desmopressin, diabetes insipidus gestation contributing to correct fetal presentation; and increased
developed on postpartal day 5, manifesting with polydipsia and myometrial contractility preventing uterine inertia and PPH. These
polyuria (intake 7500 ml, output 8750 ml). Symptoms responded considerations were the rationale for oxytocin supplementation in
well to an increase of desmopressin dosage (0.6 mg per day) with our patient.
gradual normalization of serum osmolality. Lactation never The biological function of oxytocin was demonstrated in
commenced. monkeys, where increased oxytocin concentrations were related to
Neonatal adaptation was unremarkable; the newborn was rising levels of nocturnal uterine activity.38 In the uterine smooth
discharged home together with the mother on the 11th day of life. muscle oxytocin has a direct uterotonic effect, whereas in the
choriodecidual tissue it releases prostaglandins PGE2 and PGF2a.39
Membrane-bound oxytocin receptor (OT-R) transduces the
Results oxytocin effect.40 OT-R density within the myometrium increases
towards term. In addition, oxytocin itself controls its receptor with a
We evaluated 31 pregnancies in 27 women (25 singleton, 5 twin
blunted effect on binding sites after prolonged exposure.41 Both
and 1 triplet pregnancy).
myometrial receptor density and receptor susceptibility to induce
Details on medical history, pregnancy, delivery and postpartum
contractile responses are involved in uterine tone. In guinea pigs,
course are listed in Table 1. A summary of maternal characteristics
contractility increased gestation dependent due to not yet defined
in hypopituitary and published control pregnancies is presented in
cell-signaling processes despite unchanged oxytocin-binding
Table 2. Comparison of complication rates in hypopituitary and
characteristics.42 Accordingly, enhanced smooth muscle
control pregnancies is given in Table 3. No neonatal complication
contractility has been demonstrated after repetitive oxytocin
or congenital anomaly was reported.
stimulation, presumably mediated by increased sensitivity of OT-R.43
Still the role of oxytocin in parturition has been questioned as
delivery proceeds normally in oxytocin-deficient mice.44 This
Discussion finding could be peculiar to mice; however, in our review, five
Our literature review revealed pregnancies in women with vaginal deliveries were reported suggesting that parturition in
hypopituitarism to be high risk for mother and fetus. humans may be regarded as being independent from circulating
On the fetal side, the high SGA rate is in contrast to the oxytocin. Accordingly, it has been postulated that oxytocin from
published incidence in singleton ART pregnancies (Table 3) and different sources contributes to the various stages of labor, with
supposedly the result of poor placental function. Whether this uterine oxytocin supporting the initiation of parturition and
uteroplacental dysfunction is due to lack in uterine preparedness1 pituitary oxytocin the expulsive phase.39 In the postpartum course,
or lack in responsiveness of neuroendocrine feedback mechanisms pituitary oxytocin is involved in uterine involution, whereas the
remains to be elucidated. relevance of locally produced oxytocin in puerperium is unknown.

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Table 1 Clinical data of women with hypopituitarism
Baseline characteristics Pregnancy Delivery Postpartum course

Case Age at Age at Cause of Therapy Pregestational Ovulation Gravida/ Complications Substitution MOD Indications GA Sex, weight Lactation Maternal
number, diagnosis pregnancy pituitary substitution induction para/ (centile) complications
reference (years) (years) insufficiency abortus

116 22 28 CP S, Rx NR GnRH pump III/0/II None NR CD Obstetric NR NR NR NR

Pregnancy management in hypopituitarism


29 19 27 NR NR C, L-T4, EP HMG, HCG I/0/0 Hyperlipemia, C, L-T4, CD Preeclampsia, 36 F 1800 g (5), NR PPH (TAH),
preeclampsia, progestative triplets F 1800 g (5), status epilepticus,
triplets agents M 1800 g (5) diabetes insipidus
314 35 37 P S Bromocriptine HMG III/0/II None Progesterone NR NR 31 M NR NR NR
410 23 29 Sh F C, L-T4, EP HMG, HCG III/II/0 None C, L-T4 ECD Transverse lie, 35 F 2200 g (25) AG None
PROM
55 24 28 CP S C, L-T4, V, EP HMG, HCG I/0/0 None C, L-T4, V Forceps NR 40 M 2500 g (8) NR NR
66 18 28 A S, Rx L-T4, estrogen HMG, HCG I/0/0 Twins L-T4 CD Failed IOL 40 NR 2800 g AG None
(min 25),
NR 2500 g

K Kübler et al
(min 10)
76 32 34 A S, Rx C, L-T4, CDr HPG, HCG III/0/II Threatened C, L-T4, CDr CD Transverse lie 40 M 3500 g (50) AG None
abortion
86 25 29 A S, Rx C, L-T4 HMG, HCG I/0/0 Twins L-T4 CD NR 39 NR 2700 g AG None
(min 25),
NR 2800 g
(min 40)
915 25 29 A S, Rx C, L-T4, V HMG, HCG III/I/I None C, L-T4, CDr CD Failed IOL 42 M 3750 g (50) NR Diabetes
insipidus
1022 19 27 CP S C, L-T4 HMG, HCG, estrogen I/0/0 Hyperemesis NR CD Fetal distress 40 F 2764 g (8) NR None
117 18 27 A S, Rx, rS C, L-T4 HMG, HCG I/0/0 Hyperemesis C, L-T4 Vacuum History of 38 NR 4010 g AG PPH (transfusion,
brain surgery (min 95) methergin)
1224 22 27 G Rx C, L-T4, D, HMG, HCG I/0/0 Twins C, L-T4, D CD Breech lie, 37 M 2080 g (5), NR None
terguride transverse lie F 2380 g (25)
131 NR 32 P Rx NR HMG I/0/0 None C, L-T4, V, ECD Fetal distress 38 F 2040 g (3) AG None
bromocriptine
141 NR 29 CP S NR HMG III/0/II None C, L-T4 ECD PROM, 34 M 2540 g (50) AG None
transverse lie,
arm prolapse
151 NR NR CP S NR HMG IV/I /II None C, L-T4 ECD PROM, breech lie 35 F 2650 g (50) AG None
161 8 34 CP S NR HMG I/0/0 None C, L-T4, V ECD Failure to progress 38 M 3450 g (50) LA None
171 8 NR CP S NR HMG II/I/0 None C, L-T4, V CD Previous CD 38 F 2620 g (10) LA None
181 13 38 T NR NR GnRH pump I/0/0 None C, L-T4, V CD Failure to progress 38 M 3245 g (50) LA None
191 NR 42 Sh F NR HMG NR NR C, L-T4 NR NR NR NR NR Psychotic reaction
201 NR 31 A S NR HMG II/0/I Nausea and C, L-T4 CD Fetal growth 38 M 2560 g (3) AG None
vomiting restriction
Table 1 Continued
Baseline characteristics Pregnancy Delivery Postpartum course

Case Age at Age at Cause of Therapy Pregestational Ovulation Gravida/ Complications Substitution MOD Indications GA Sex, weight Lactation Maternal
number, diagnosis pregnancy pituitary substitution induction para/ (centile) complications
reference (years) (years) insufficiency abortus

211 NR NR A S NR HMG IV/I/II Twins, IUFD, C, L-T4 NVD (IOL) F 26 F 660 g (10), NR NR
APH (abruptio F 740 g (25)
placentae)
221 NR 34 Sh F NR HMG NR Twins, PROM, C, L-T4 NVD (IOL) F 26 NR NR NR
IUFD
231 NR 33 CP S NR FSH I/0/0 Ovarian C, L-T4, V ECD Fetal distress 39 M 2580 g (3) AG NR
hyperstimulation (abruptio
syndrome, PIH placentae)
241 NR NR CP S NR HMG II/I/0 None C, L-T4, V CD Previous CD 39 M 2960 g (10) AG NR
251 NR 42 A S NR HMG I/0/0 None C, L-T4 CD Failed IOL 40 M 3980 g (90) AG NR
263 20 24 Sh F C, L-T4, EP HMG, HCG II/I/0 Preeclampsia, C, L-T4 CD Fetal distress NR M 2170g AG None
placental
insufficiency
2720 26 32 A S C, L-T4, EP GH, HMG, HCG NR None C, L-T4 NR NR 39 M 3780 g (75) NR None
2826 23 32 A S, Rx L-T4 HMG, HCG I/0/0 None L-T4 CD PTL, PROM, 33 F 2000 g (50) NR None
fetal distress

K Kübler et al
Pregnancy management in hypopituitarism
2927 25 34 A S, rS C, L-T4, D, EP HMG II/0/0 None C, L-T4, D CD Breech lie 39 F 3200 g (50) AG None
(extra-uterine
gravidity)
3018 26 31 L S C, L-T4, D, EP HMG, HCG I/0/0 Oligohydramnios C, L-T4, D CD IOL, failure to 38 F 2490 g (5) LA None
progress
3123 8 34 CP S, Rx C, L-T4, D, GH, EP HMG, HCG I/0/0 None C, L-T4, D NVD F 37 F 3450 g (90) AG None

Abbreviations: A, adenoma; AG, agalactosis; APH, antepartum hemorrhage; C, cortisone; CP, craniopharyngioma; CD, cesarean delivery; CDr, controlled drinking; D, desmopressin; ECD, emergency cesarean delivery; EP, estrogen–progestin
combination; F, female; FSH, follicle stimulating hormone; G, germinoma; GA, gestational age; GH, growth hormone; GnRH, gonadotropin-releasing hormone; HCG, human chorionic gonadotropin; HMG, human menopausal gonadotropin; HPG,
human pituitary gonadotropin; IOL, induction of labor; IUFD, intrauterine fetal demise; L, lymphocytic hypophysis; LA, lactation; L-T4, L-thyroxine; M, male; NR, not reported; NVD, normal vaginal delivery; P, prolactinoma; PIH, pregnancy-
induced hypertension; PPH, postpartum hemorrhage; PROM, premature rupture of membranes; PTL, preterm labor; rS, recurrent surgery; Rx, radiotherapy; S, pituitary surgery; Sh, Sheehan’s syndrome; T, tuberculoma; TAH, total abdominal
hysterectomy; V, arg-vasopressin.
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Table 2 Maternal characteristics in hypopituitary and published control pregnancies

Mean maternal age (year) Primipara (%) Mean GA (week) Date of parturition Location of parturition

Hypopituitary pregnancies n ¼ 25 32 68 38 1965–2002 Developed countries (94%)

Control pregnancies, reference


n ¼ 26036 32 NR 39 1983–1993 Israel
n ¼ 14035 32 84 39 1988–1994 Belgium
n ¼ 18537 NR 69 38 1995–2002 Hungary
Abbreviations: GA, gestational age; NR, not reported.

Table 3 Comparison of obstetric complications in hypopituitary and published control pregnancies

Hypopituitary pregnancies Control pregnancies, reference P-value

SGA 8/21 (38%) 33/260 (12.7%)36 0.005


Cesarean delivery 16/18 (89%) 16/140 (11.4%)35 0.00000000002
Transverse lie 3/20 (15%) 3/140 (2.1%)35 0.03
Postpartum hemorrhage 1/19 (5.26%) 2/185 (1%)37 0.26
Abbreviation: SGA, small for gestational age.

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