Baha M. Sibai, MD

The authors report no financial relationships relevant to this article.

Thrombosis is hypothesized to be the more common mechanism underlying cerebral palsy in many cases of maternal or fetal thrombophilia; for that reason, understanding the impact of maternal and fetal thrombophilia on pregnancy outcome is of paramount importance when counseling patients.

Is a maternal and fetal thrombophilia work-up needed in women who give birth to a term infant with cerebral palsy? Prospective studies are needed to evaluate whether that is the case. In this article, we review the literature on fetal thrombophilia and its role in explaining some cases of perinatal stroke that lead, ultimately, to cerebral palsy.

The several causes of cerebral palsy

Cerebral palsy is the most common chronic motor disability of childhood. Approximately 2 to 2.5 of every 1,000 children are given a diagnosis of this disorder every year.^1,2 The condition appears early in life; it is not the result of recognized progressive disease.¹ Risk factors for cerebral palsy are multiple and heterogenous^1,3,4-6:

• Prematurity. The risk of developing cerebral palsy correlates inversely with gestational age.^7,8 A premature infant who weighs less than 1,500 g at birth has a risk of cerebral palsy that is 20 to 30 times greater than that of a full-term, normal-weight newborn.^3,4
• Hypoxia and ischemia. These are the conditions most often implicated as the cause of cerebral palsy. Fetal heart-rate monitoring was introduced in the 1960s in the hope that interventions to prevent hypoxia and ischemia would reduce the incidence of cerebral palsy. But monitoring has not had that effect—most likely, because some cases of cerebral palsy are caused by perinatal stroke.⁹ In fact, a large, population-based study has demonstrated that potentially asphyxiating obstetrical conditions account for only about 6% of cases of cerebral palsy.⁶
• Thrombophilia. Several recent studies report an association between fetal thrombophilia and both neonatal stroke and cerebral palsy.^10-14 That association provides a possible explanation for adverse pregnancy outcomes that have otherwise been ascribed to events during delivery.^15-23 Although thrombophilia is a recognized risk factor for cerebral palsy, the strength of the association has still not been fully investigated. TABLE 1 and TABLE 2 summarize studies that have examined this association. Given the rarity of both inherited thrombophilias and cerebral palsy, however, an enormous number of cases would be required to fully establish a causal relationship.

TABLE 1

Case reports reveal an association
between fetal thrombophilias and cerebral palsy

		Thrombophilias present
Study (type)	Cases of CP	Number	Type
Harum et al36 (case report)	1	1	Factor V Leiden
Thorarensen et al37 (case report)	3	3	Factor V Leiden
Lynch et al2 (case series)	8	8	Factor V Leiden
Halliday et al38 (case series)	55	5	Factor V Leiden; prothrombin mutation
Smith et al39 (case series)	38	7	Factor VIIIc
Nelson et al40 (case series)	31	20	Factor V Leiden; protein C deficiency

TABLE 2

How often is a fetal thrombophilia
the likely underlying cause of cerebral palsy?

Thrombophilia*	Prevalence of CP†	Odds ratio
Factor V Leiden	6.3%	0.62 (0.37–1.05)
Prothrombin gene	5.2%	1.11 (0.59–2.06)
MTHFR 677	54.1%	1.27 (0.97–1.66)
MTHFR 1298	39.4%	1.08 (0.69–1.19)
MTHFR 677/1298	15.1%	1.18 (0.82–1.69)
* Heterozygous or homozygous
† Among 354 subjects with thrombophilia studied41
Key: MTHFR, methyltetrahydrofolate reductase

Understanding thrombophilia

“Thrombophilia” describes a spectrum of congenital or acquired coagulation disorders associated with venous and arterial thrombosis.²⁴ These disorders can occur in the mother or in the fetus, or in both concomitantly.

Fetal thrombophilia has a reported incidence of 2.4 to 5.1 cases for every 100,000 births.²⁵ Whereas maternal thrombophilia has a substantially higher incidence, both maternal and fetal thrombophilia can lead to adverse maternal and fetal events.

The incidence of specific inherited fetal thrombophilias is summarized in TABLE 3. Maternal thrombophilia is generally associated with various adverse pregnancy outcomes, particularly cerebral palsy and perinatal stroke.^9,26

TABLE 3

Inherited thrombophilias among the general population

Study	Number	Factor V Leiden	Protein gene mutation	MTHFR
Gibson et al41 (2003)	708	9.8%	4.7%	15.1%*
Dizon-Townson et al42 (2005)	4,033	3.0%	Not reported	Not reported
Infante-Rivard et al43 (2002)	472	3.3%	1.3%	43% to 49%
Stanley-Christian et al44 (2005)	14	0	0	0
Currie et al45 (2002)	46	13.0%	Not reported	Not reported
Livingston et al46 (2001)	92	0	2%	4%
Schlembach et al47 (2003)	28	4.0%	2%	Not reported
Dizon-Townson et al48 (1997)	130	8.6%	Not reported	Not reported
* Heterozygous and homozygous carriers of MTHFR C677T and A1298C
Key: MTHFR, methyltetrahydrofolate reductase

Thrombophilia leads to thrombosis at the maternal or fetal interface (FIGURE):

• When thrombosis occurs on the maternal side, the consequence may be severe preeclampsia, intrauterine growth restriction, abruptio placenta, or fetal loss.^27-29
• Thrombosis on the fetal side can be a source of emboli that bypass hepatic and pulmonary circulation and travel to the fetal brain.³⁰ As a result, the newborn can sustain a catastrophic event such as perinatal arterial stroke via arterial thrombosis, cerebral sinus venous thrombosis, or renal vein thrombosis.²⁵

 

Thrombophilia can lead to thrombosis at the maternal or the fetal interface

Thrombosis on the maternal side may lead to severe preeclampsia, intrauterine growth restriction, abruptio placenta, or fetal loss. Thrombosis on the fetal side can be a source of emboli that bypass hepatic and pulmonary circulation and travel to the fetal brain and cause a catastrophic event, such as perinatal arterial stroke via arterial thrombosis, cerebral sinus venous thrombosis, or renal vein thrombosis.

Perinatal and neonatal stroke

Perinatal stroke is defined as a cerebrovascular event that occurs between 28 weeks of gestation and 28 days of postnatal age.³⁰ Incidence is approximately 17 to 93 cases for every 100,000 live births.⁹

Neonatal stroke occurs in approximately 1 of every 4,000 live births.³⁰ In addition, 1 in every 2,300 to 4,000 newborns is given a diagnosis of ischemic stroke in the nursery.⁹

Stroke and cerebral palsy

Arterial ischemic stroke in the newborn accounts for 50% to 70% of cases of congenital hemiplegic cerebral palsy.¹¹ Factor V Leiden mutation, prothrombin gene mutation, and a deficiency of protein C, protein S, and antithrombin III have, taken together in two studies, been identified in more than 50% of cerebral ischemic strokes.^31,32 In addition to these thrombophilias, important risk factors for perinatal and neonatal stroke include:

• thrombosis in placental villi or vessels
• infection
• use of an intravascular catheter.³³

What causes perinatal stroke?

The mechanism that underlies perinatal stroke is a thromboembolic event that originates from either an intracranial or extracranial vessel, the heart, or the placenta.¹⁰ A recent meta-analysis by Haywood and colleagues found a statistically significant correlation between protein C deficiency, MTHFR C677T (methyltetrahydrofolate reductase), and the first occurrence of arterial ischemic stroke in a pediatric population.³⁴ Associations between specific thrombophilias and perinatal stroke, as well as pediatric stroke, have been demonstrated (TABLE 4), but we want to emphasize that the absolute risks in these populations are very small.^34,35 In addition, the infrequency of these thrombophilias in the general population (TABLE 3) means that their positive predictive value is extremely low.

TABLE 4

Fetal thrombophilia is detected in as many as two thirds of study cases of perinatal and neonatal stroke

			Type of thrombophilia
Study	Infants	Thrombophilia	FVL	APCR	ACA	AT	PC	PS
Golomb et al31	22	14 (63%) *	1 *	3 *	12 *	0	0	0
Bonduel et al32	30	9 (30%) †	n/a	n/a	n/a	2	1	2
deVeber et al49	92	35 (38%) ‡	0	6	23‡	10‡	6‡	3‡
Mercuri et al50	24	10 (42%)	5	n/a	n/a	0	0	0
Günther et al35	91	62 (68%)	17	n/a	3	0	6	0
Govaert et al51	40	3 (8%)	3	n/a	n/a	n/a	n/a	n/a
* FVL, APCR, and ACA diagnoses overlapped.
† Three patients had anticardiolipin antibody and plasminogen deficiency.
‡ Of 35 children, 21 had multiple abnormalities (combined coagulation deficiencies).
Key: ACA, anticardiolipin antibody; APCR, activated protein C resistance; AT, antithrombin deficiency; FVL, factor V Leiden; PC, protein C deficiency; PS, protein S deficiency; n/a, not available or not studied.

Brain injury

The brain is the largest and most vulnerable fetal organ susceptible to thrombi that are formed either in the placenta or elsewhere.¹⁶ A review of cases of cerebral palsy has revealed a pathologic finding, fetal thrombotic vasculopathy (FTV), that has been associated with brain injury.¹⁶ Arias and colleagues¹⁷ and Kraus¹⁸ have observed a correlation among cerebral palsy, a thrombophilic state, and FTV.

Furthermore, Redline found that the presence of severe fetal vascular lesions correlated highly with neurologic impairment and cerebral palsy.¹⁹

What is the take-home message?

Regrettably for patients and their offspring, evidence about the relationship between thrombophilia and an adverse neurologic outcome is insufficiently strong to offer much in the way of definitive recommendations for the obstetrician.

We can, however, make some tentative recommendations on management:

Consider screening. When cerebral palsy occurs in association with perinatal stroke, fetal and maternal screening for thrombophilia can be performed.³⁴ The recommended thrombophilia panel comprises tests for:

• factor V Leiden
• prothrombin G20210
• anticardiolipin antibody
• MTHFR mutation.¹⁰

Family screening has also been suggested in cases of 1) multiple prothrombotic risk factors in an affected newborn and 2) a positive family history.⁹

The cost-effectiveness of screening for thrombophilia has not been evaluated in prospective studies, because the positive predictive value of such screening is extremely low.

Consider offering prophylaxis, with cautions. A mother whose baby has been given a diagnosis of thrombophilia and fetal or neonatal stroke can be offered thromboprophylaxis (heparin and aspirin) during any subsequent pregnancy. The usefulness of this intervention has not been well studied and is based solely on expert opinion, however, so it is imperative to counsel patients on the risks and benefits of prophylactic therapy beforehand.

The authors report no financial relationships relevant to this article.

Thrombosis is hypothesized to be the more common mechanism underlying cerebral palsy in many cases of maternal or fetal thrombophilia; for that reason, understanding the impact of maternal and fetal thrombophilia on pregnancy outcome is of paramount importance when counseling patients.

Is a maternal and fetal thrombophilia work-up needed in women who give birth to a term infant with cerebral palsy? Prospective studies are needed to evaluate whether that is the case. In this article, we review the literature on fetal thrombophilia and its role in explaining some cases of perinatal stroke that lead, ultimately, to cerebral palsy.

The several causes of cerebral palsy

Cerebral palsy is the most common chronic motor disability of childhood. Approximately 2 to 2.5 of every 1,000 children are given a diagnosis of this disorder every year.^1,2 The condition appears early in life; it is not the result of recognized progressive disease.¹ Risk factors for cerebral palsy are multiple and heterogenous^1,3,4-6:

• Prematurity. The risk of developing cerebral palsy correlates inversely with gestational age.^7,8 A premature infant who weighs less than 1,500 g at birth has a risk of cerebral palsy that is 20 to 30 times greater than that of a full-term, normal-weight newborn.^3,4
• Hypoxia and ischemia. These are the conditions most often implicated as the cause of cerebral palsy. Fetal heart-rate monitoring was introduced in the 1960s in the hope that interventions to prevent hypoxia and ischemia would reduce the incidence of cerebral palsy. But monitoring has not had that effect—most likely, because some cases of cerebral palsy are caused by perinatal stroke.⁹ In fact, a large, population-based study has demonstrated that potentially asphyxiating obstetrical conditions account for only about 6% of cases of cerebral palsy.⁶
• Thrombophilia. Several recent studies report an association between fetal thrombophilia and both neonatal stroke and cerebral palsy.^10-14 That association provides a possible explanation for adverse pregnancy outcomes that have otherwise been ascribed to events during delivery.^15-23 Although thrombophilia is a recognized risk factor for cerebral palsy, the strength of the association has still not been fully investigated. TABLE 1 and TABLE 2 summarize studies that have examined this association. Given the rarity of both inherited thrombophilias and cerebral palsy, however, an enormous number of cases would be required to fully establish a causal relationship.

TABLE 1

Case reports reveal an association
between fetal thrombophilias and cerebral palsy

		Thrombophilias present
Study (type)	Cases of CP	Number	Type
Harum et al36 (case report)	1	1	Factor V Leiden
Thorarensen et al37 (case report)	3	3	Factor V Leiden
Lynch et al2 (case series)	8	8	Factor V Leiden
Halliday et al38 (case series)	55	5	Factor V Leiden; prothrombin mutation
Smith et al39 (case series)	38	7	Factor VIIIc
Nelson et al40 (case series)	31	20	Factor V Leiden; protein C deficiency

TABLE 2

How often is a fetal thrombophilia
the likely underlying cause of cerebral palsy?

Thrombophilia*	Prevalence of CP†	Odds ratio
Factor V Leiden	6.3%	0.62 (0.37–1.05)
Prothrombin gene	5.2%	1.11 (0.59–2.06)
MTHFR 677	54.1%	1.27 (0.97–1.66)
MTHFR 1298	39.4%	1.08 (0.69–1.19)
MTHFR 677/1298	15.1%	1.18 (0.82–1.69)
* Heterozygous or homozygous
† Among 354 subjects with thrombophilia studied41
Key: MTHFR, methyltetrahydrofolate reductase

Understanding thrombophilia

“Thrombophilia” describes a spectrum of congenital or acquired coagulation disorders associated with venous and arterial thrombosis.²⁴ These disorders can occur in the mother or in the fetus, or in both concomitantly.

Fetal thrombophilia has a reported incidence of 2.4 to 5.1 cases for every 100,000 births.²⁵ Whereas maternal thrombophilia has a substantially higher incidence, both maternal and fetal thrombophilia can lead to adverse maternal and fetal events.

The incidence of specific inherited fetal thrombophilias is summarized in TABLE 3. Maternal thrombophilia is generally associated with various adverse pregnancy outcomes, particularly cerebral palsy and perinatal stroke.^9,26

TABLE 3

Inherited thrombophilias among the general population

Study	Number	Factor V Leiden	Protein gene mutation	MTHFR
Gibson et al41 (2003)	708	9.8%	4.7%	15.1%*
Dizon-Townson et al42 (2005)	4,033	3.0%	Not reported	Not reported
Infante-Rivard et al43 (2002)	472	3.3%	1.3%	43% to 49%
Stanley-Christian et al44 (2005)	14	0	0	0
Currie et al45 (2002)	46	13.0%	Not reported	Not reported
Livingston et al46 (2001)	92	0	2%	4%
Schlembach et al47 (2003)	28	4.0%	2%	Not reported
Dizon-Townson et al48 (1997)	130	8.6%	Not reported	Not reported
* Heterozygous and homozygous carriers of MTHFR C677T and A1298C
Key: MTHFR, methyltetrahydrofolate reductase

Thrombophilia leads to thrombosis at the maternal or fetal interface (FIGURE):

• When thrombosis occurs on the maternal side, the consequence may be severe preeclampsia, intrauterine growth restriction, abruptio placenta, or fetal loss.^27-29
• Thrombosis on the fetal side can be a source of emboli that bypass hepatic and pulmonary circulation and travel to the fetal brain.³⁰ As a result, the newborn can sustain a catastrophic event such as perinatal arterial stroke via arterial thrombosis, cerebral sinus venous thrombosis, or renal vein thrombosis.²⁵

 

Thrombophilia can lead to thrombosis at the maternal or the fetal interface

Thrombosis on the maternal side may lead to severe preeclampsia, intrauterine growth restriction, abruptio placenta, or fetal loss. Thrombosis on the fetal side can be a source of emboli that bypass hepatic and pulmonary circulation and travel to the fetal brain and cause a catastrophic event, such as perinatal arterial stroke via arterial thrombosis, cerebral sinus venous thrombosis, or renal vein thrombosis.

Perinatal and neonatal stroke

Perinatal stroke is defined as a cerebrovascular event that occurs between 28 weeks of gestation and 28 days of postnatal age.³⁰ Incidence is approximately 17 to 93 cases for every 100,000 live births.⁹

Neonatal stroke occurs in approximately 1 of every 4,000 live births.³⁰ In addition, 1 in every 2,300 to 4,000 newborns is given a diagnosis of ischemic stroke in the nursery.⁹

Stroke and cerebral palsy

Arterial ischemic stroke in the newborn accounts for 50% to 70% of cases of congenital hemiplegic cerebral palsy.¹¹ Factor V Leiden mutation, prothrombin gene mutation, and a deficiency of protein C, protein S, and antithrombin III have, taken together in two studies, been identified in more than 50% of cerebral ischemic strokes.^31,32 In addition to these thrombophilias, important risk factors for perinatal and neonatal stroke include:

• thrombosis in placental villi or vessels
• infection
• use of an intravascular catheter.³³

What causes perinatal stroke?

The mechanism that underlies perinatal stroke is a thromboembolic event that originates from either an intracranial or extracranial vessel, the heart, or the placenta.¹⁰ A recent meta-analysis by Haywood and colleagues found a statistically significant correlation between protein C deficiency, MTHFR C677T (methyltetrahydrofolate reductase), and the first occurrence of arterial ischemic stroke in a pediatric population.³⁴ Associations between specific thrombophilias and perinatal stroke, as well as pediatric stroke, have been demonstrated (TABLE 4), but we want to emphasize that the absolute risks in these populations are very small.^34,35 In addition, the infrequency of these thrombophilias in the general population (TABLE 3) means that their positive predictive value is extremely low.

TABLE 4

Fetal thrombophilia is detected in as many as two thirds of study cases of perinatal and neonatal stroke

			Type of thrombophilia
Study	Infants	Thrombophilia	FVL	APCR	ACA	AT	PC	PS
Golomb et al31	22	14 (63%) *	1 *	3 *	12 *	0	0	0
Bonduel et al32	30	9 (30%) †	n/a	n/a	n/a	2	1	2
deVeber et al49	92	35 (38%) ‡	0	6	23‡	10‡	6‡	3‡
Mercuri et al50	24	10 (42%)	5	n/a	n/a	0	0	0
Günther et al35	91	62 (68%)	17	n/a	3	0	6	0
Govaert et al51	40	3 (8%)	3	n/a	n/a	n/a	n/a	n/a
* FVL, APCR, and ACA diagnoses overlapped.
† Three patients had anticardiolipin antibody and plasminogen deficiency.
‡ Of 35 children, 21 had multiple abnormalities (combined coagulation deficiencies).
Key: ACA, anticardiolipin antibody; APCR, activated protein C resistance; AT, antithrombin deficiency; FVL, factor V Leiden; PC, protein C deficiency; PS, protein S deficiency; n/a, not available or not studied.

Brain injury

The brain is the largest and most vulnerable fetal organ susceptible to thrombi that are formed either in the placenta or elsewhere.¹⁶ A review of cases of cerebral palsy has revealed a pathologic finding, fetal thrombotic vasculopathy (FTV), that has been associated with brain injury.¹⁶ Arias and colleagues¹⁷ and Kraus¹⁸ have observed a correlation among cerebral palsy, a thrombophilic state, and FTV.

Furthermore, Redline found that the presence of severe fetal vascular lesions correlated highly with neurologic impairment and cerebral palsy.¹⁹

What is the take-home message?

Regrettably for patients and their offspring, evidence about the relationship between thrombophilia and an adverse neurologic outcome is insufficiently strong to offer much in the way of definitive recommendations for the obstetrician.

We can, however, make some tentative recommendations on management:

Consider screening. When cerebral palsy occurs in association with perinatal stroke, fetal and maternal screening for thrombophilia can be performed.³⁴ The recommended thrombophilia panel comprises tests for:

• factor V Leiden
• prothrombin G20210
• anticardiolipin antibody
• MTHFR mutation.¹⁰

Family screening has also been suggested in cases of 1) multiple prothrombotic risk factors in an affected newborn and 2) a positive family history.⁹

The cost-effectiveness of screening for thrombophilia has not been evaluated in prospective studies, because the positive predictive value of such screening is extremely low.

Consider offering prophylaxis, with cautions. A mother whose baby has been given a diagnosis of thrombophilia and fetal or neonatal stroke can be offered thromboprophylaxis (heparin and aspirin) during any subsequent pregnancy. The usefulness of this intervention has not been well studied and is based solely on expert opinion, however, so it is imperative to counsel patients on the risks and benefits of prophylactic therapy beforehand.

The authors report no financial relationships relevant to this article.

Thrombosis is hypothesized to be the more common mechanism underlying cerebral palsy in many cases of maternal or fetal thrombophilia; for that reason, understanding the impact of maternal and fetal thrombophilia on pregnancy outcome is of paramount importance when counseling patients.

Is a maternal and fetal thrombophilia work-up needed in women who give birth to a term infant with cerebral palsy? Prospective studies are needed to evaluate whether that is the case. In this article, we review the literature on fetal thrombophilia and its role in explaining some cases of perinatal stroke that lead, ultimately, to cerebral palsy.

The several causes of cerebral palsy

Cerebral palsy is the most common chronic motor disability of childhood. Approximately 2 to 2.5 of every 1,000 children are given a diagnosis of this disorder every year.^1,2 The condition appears early in life; it is not the result of recognized progressive disease.¹ Risk factors for cerebral palsy are multiple and heterogenous^1,3,4-6:

• Prematurity. The risk of developing cerebral palsy correlates inversely with gestational age.^7,8 A premature infant who weighs less than 1,500 g at birth has a risk of cerebral palsy that is 20 to 30 times greater than that of a full-term, normal-weight newborn.^3,4
• Hypoxia and ischemia. These are the conditions most often implicated as the cause of cerebral palsy. Fetal heart-rate monitoring was introduced in the 1960s in the hope that interventions to prevent hypoxia and ischemia would reduce the incidence of cerebral palsy. But monitoring has not had that effect—most likely, because some cases of cerebral palsy are caused by perinatal stroke.⁹ In fact, a large, population-based study has demonstrated that potentially asphyxiating obstetrical conditions account for only about 6% of cases of cerebral palsy.⁶
• Thrombophilia. Several recent studies report an association between fetal thrombophilia and both neonatal stroke and cerebral palsy.^10-14 That association provides a possible explanation for adverse pregnancy outcomes that have otherwise been ascribed to events during delivery.^15-23 Although thrombophilia is a recognized risk factor for cerebral palsy, the strength of the association has still not been fully investigated. TABLE 1 and TABLE 2 summarize studies that have examined this association. Given the rarity of both inherited thrombophilias and cerebral palsy, however, an enormous number of cases would be required to fully establish a causal relationship.

TABLE 1

Case reports reveal an association
between fetal thrombophilias and cerebral palsy

		Thrombophilias present
Study (type)	Cases of CP	Number	Type
Harum et al36 (case report)	1	1	Factor V Leiden
Thorarensen et al37 (case report)	3	3	Factor V Leiden
Lynch et al2 (case series)	8	8	Factor V Leiden
Halliday et al38 (case series)	55	5	Factor V Leiden; prothrombin mutation
Smith et al39 (case series)	38	7	Factor VIIIc
Nelson et al40 (case series)	31	20	Factor V Leiden; protein C deficiency

TABLE 2

How often is a fetal thrombophilia
the likely underlying cause of cerebral palsy?

Thrombophilia*	Prevalence of CP†	Odds ratio
Factor V Leiden	6.3%	0.62 (0.37–1.05)
Prothrombin gene	5.2%	1.11 (0.59–2.06)
MTHFR 677	54.1%	1.27 (0.97–1.66)
MTHFR 1298	39.4%	1.08 (0.69–1.19)
MTHFR 677/1298	15.1%	1.18 (0.82–1.69)
* Heterozygous or homozygous
† Among 354 subjects with thrombophilia studied41
Key: MTHFR, methyltetrahydrofolate reductase

Understanding thrombophilia

“Thrombophilia” describes a spectrum of congenital or acquired coagulation disorders associated with venous and arterial thrombosis.²⁴ These disorders can occur in the mother or in the fetus, or in both concomitantly.

Fetal thrombophilia has a reported incidence of 2.4 to 5.1 cases for every 100,000 births.²⁵ Whereas maternal thrombophilia has a substantially higher incidence, both maternal and fetal thrombophilia can lead to adverse maternal and fetal events.

The incidence of specific inherited fetal thrombophilias is summarized in TABLE 3. Maternal thrombophilia is generally associated with various adverse pregnancy outcomes, particularly cerebral palsy and perinatal stroke.^9,26

TABLE 3

Inherited thrombophilias among the general population

Study	Number	Factor V Leiden	Protein gene mutation	MTHFR
Gibson et al41 (2003)	708	9.8%	4.7%	15.1%*
Dizon-Townson et al42 (2005)	4,033	3.0%	Not reported	Not reported
Infante-Rivard et al43 (2002)	472	3.3%	1.3%	43% to 49%
Stanley-Christian et al44 (2005)	14	0	0	0
Currie et al45 (2002)	46	13.0%	Not reported	Not reported
Livingston et al46 (2001)	92	0	2%	4%
Schlembach et al47 (2003)	28	4.0%	2%	Not reported
Dizon-Townson et al48 (1997)	130	8.6%	Not reported	Not reported
* Heterozygous and homozygous carriers of MTHFR C677T and A1298C
Key: MTHFR, methyltetrahydrofolate reductase

Thrombophilia leads to thrombosis at the maternal or fetal interface (FIGURE):

• When thrombosis occurs on the maternal side, the consequence may be severe preeclampsia, intrauterine growth restriction, abruptio placenta, or fetal loss.^27-29
• Thrombosis on the fetal side can be a source of emboli that bypass hepatic and pulmonary circulation and travel to the fetal brain.³⁰ As a result, the newborn can sustain a catastrophic event such as perinatal arterial stroke via arterial thrombosis, cerebral sinus venous thrombosis, or renal vein thrombosis.²⁵

 

Thrombophilia can lead to thrombosis at the maternal or the fetal interface

Thrombosis on the maternal side may lead to severe preeclampsia, intrauterine growth restriction, abruptio placenta, or fetal loss. Thrombosis on the fetal side can be a source of emboli that bypass hepatic and pulmonary circulation and travel to the fetal brain and cause a catastrophic event, such as perinatal arterial stroke via arterial thrombosis, cerebral sinus venous thrombosis, or renal vein thrombosis.

Perinatal and neonatal stroke

Perinatal stroke is defined as a cerebrovascular event that occurs between 28 weeks of gestation and 28 days of postnatal age.³⁰ Incidence is approximately 17 to 93 cases for every 100,000 live births.⁹

Neonatal stroke occurs in approximately 1 of every 4,000 live births.³⁰ In addition, 1 in every 2,300 to 4,000 newborns is given a diagnosis of ischemic stroke in the nursery.⁹

Stroke and cerebral palsy

Arterial ischemic stroke in the newborn accounts for 50% to 70% of cases of congenital hemiplegic cerebral palsy.¹¹ Factor V Leiden mutation, prothrombin gene mutation, and a deficiency of protein C, protein S, and antithrombin III have, taken together in two studies, been identified in more than 50% of cerebral ischemic strokes.^31,32 In addition to these thrombophilias, important risk factors for perinatal and neonatal stroke include:

• thrombosis in placental villi or vessels
• infection
• use of an intravascular catheter.³³

What causes perinatal stroke?

The mechanism that underlies perinatal stroke is a thromboembolic event that originates from either an intracranial or extracranial vessel, the heart, or the placenta.¹⁰ A recent meta-analysis by Haywood and colleagues found a statistically significant correlation between protein C deficiency, MTHFR C677T (methyltetrahydrofolate reductase), and the first occurrence of arterial ischemic stroke in a pediatric population.³⁴ Associations between specific thrombophilias and perinatal stroke, as well as pediatric stroke, have been demonstrated (TABLE 4), but we want to emphasize that the absolute risks in these populations are very small.^34,35 In addition, the infrequency of these thrombophilias in the general population (TABLE 3) means that their positive predictive value is extremely low.

TABLE 4

Fetal thrombophilia is detected in as many as two thirds of study cases of perinatal and neonatal stroke

			Type of thrombophilia
Study	Infants	Thrombophilia	FVL	APCR	ACA	AT	PC	PS
Golomb et al31	22	14 (63%) *	1 *	3 *	12 *	0	0	0
Bonduel et al32	30	9 (30%) †	n/a	n/a	n/a	2	1	2
deVeber et al49	92	35 (38%) ‡	0	6	23‡	10‡	6‡	3‡
Mercuri et al50	24	10 (42%)	5	n/a	n/a	0	0	0
Günther et al35	91	62 (68%)	17	n/a	3	0	6	0
Govaert et al51	40	3 (8%)	3	n/a	n/a	n/a	n/a	n/a
* FVL, APCR, and ACA diagnoses overlapped.
† Three patients had anticardiolipin antibody and plasminogen deficiency.
‡ Of 35 children, 21 had multiple abnormalities (combined coagulation deficiencies).
Key: ACA, anticardiolipin antibody; APCR, activated protein C resistance; AT, antithrombin deficiency; FVL, factor V Leiden; PC, protein C deficiency; PS, protein S deficiency; n/a, not available or not studied.

Brain injury

The brain is the largest and most vulnerable fetal organ susceptible to thrombi that are formed either in the placenta or elsewhere.¹⁶ A review of cases of cerebral palsy has revealed a pathologic finding, fetal thrombotic vasculopathy (FTV), that has been associated with brain injury.¹⁶ Arias and colleagues¹⁷ and Kraus¹⁸ have observed a correlation among cerebral palsy, a thrombophilic state, and FTV.

Furthermore, Redline found that the presence of severe fetal vascular lesions correlated highly with neurologic impairment and cerebral palsy.¹⁹

What is the take-home message?

Regrettably for patients and their offspring, evidence about the relationship between thrombophilia and an adverse neurologic outcome is insufficiently strong to offer much in the way of definitive recommendations for the obstetrician.

We can, however, make some tentative recommendations on management:

Consider screening. When cerebral palsy occurs in association with perinatal stroke, fetal and maternal screening for thrombophilia can be performed.³⁴ The recommended thrombophilia panel comprises tests for:

• factor V Leiden
• prothrombin G20210
• anticardiolipin antibody
• MTHFR mutation.¹⁰

Family screening has also been suggested in cases of 1) multiple prothrombotic risk factors in an affected newborn and 2) a positive family history.⁹

The cost-effectiveness of screening for thrombophilia has not been evaluated in prospective studies, because the positive predictive value of such screening is extremely low.

Consider offering prophylaxis, with cautions. A mother whose baby has been given a diagnosis of thrombophilia and fetal or neonatal stroke can be offered thromboprophylaxis (heparin and aspirin) during any subsequent pregnancy. The usefulness of this intervention has not been well studied and is based solely on expert opinion, however, so it is imperative to counsel patients on the risks and benefits of prophylactic therapy beforehand.

The authors report no financial relationships relevant to this article.

CASE Life on the line

A 32-year-old woman in the 24th week of her fourth pregnancy arrives at the emergency department complaining of cough and congestion, shortness of breath, and swelling in her face, hands, and feet. The swelling has become worse over the past 2 weeks, and she had several episodes of bloody vomiting the day before her visit. The patient says she has not experienced any leakage of fluid, vaginal bleeding, or contractions. She reports good fetal movement.

The patient’s medical history is unremarkable, but a review of systems reveals a 15-lb weight loss over the past 2 weeks, racing heart, worsening edema and shortness of breath, and diarrhea.

Physical findings include exophthalmia and an enlarged thyroid with a nodule on the right side, as well as bilateral rales, tachycardia, tremor, and increased deep tendon reflexes. There is no evidence of fetal cardiac failure or goiter.

A computed tomography (CT) scan of the mother shows bilateral pleural effusions indicative of high-output cardiac failure. Thyroid ultrasonography (US) reveals a diffusely enlarged thyroid gland with a right-sided mass.

The thyroid-stimulating hormone (TSH) level is undetectable. Fetal heart rate is in the 160s, with normal variability and occasional variable deceleration. Fetal US is consistent with the estimated gestational age and shows adequate amniotic fluid and no gross fetal anomalies.

What is the likely diagnosis?

This is a classic example of undiagnosed hyperthyroidism in pregnancy manifesting as thyroid storm.

As the case illustrates, uncontrolled hyperthyroidism in pregnancy poses a significant challenge for the obstetrician. The condition can cause miscarriage, preterm delivery, intrauterine growth restriction, preeclampsia, and—at its most dangerous—thyroid storm.¹ Thyroid storm is a life-threatening emergency, and treatment must be initiated even before hyperthyroidism is confirmed by thyroid function testing.² The good news is that these complications can be successfully avoided with adequate control of thyroid function.

Overt hyperthyroidism, seen in 0.2% of pregnancies, requires active intervention to avert adverse pregnancy outcome and neurologic damage to the fetus. Subclinical disease, seen in 1.7% of pregnancies, can also create serious obstetrical problems.¹

The effects of hyperthyroidism in pregnancy vary in severity, ranging from the fairly innocuous, transient, and self-limited state called gestational transient thyrotoxicosis to the life-threatening emergency of thyroid storm. This review will update you on how to manage this disorder for optimal pregnancy outcome.

To screen or not to screen

Routine screening for thyroid dysfunction has been recommended for women who have infertility, menstrual disorders, or type 1 diabetes mellitus, and for pregnant women who have signs and symptoms of the disorder. Some authors recommend screening all pregnant women, but routine screening is not endorsed by the American College of Obstetricians and Gynecologists.^2,3

Thyroid testing in pregnancy is recommended in women who:

• have a family history of autoimmune thyroid disease
• are on thyroid therapy
• have a goiter or
• have insulin-dependent diabetes mellitus.

Pregnant women who have a history of high-dose neck radiation, thyroid therapy, postpartum thyroiditis, or an infant born with thyroid disease should also be tested at the first prenatal visit.⁴

Telltale signs and laboratory tests

The signs and symptoms of hyperthyroidism can include nervousness, heat intolerance, tachycardia, palpitations, goiter, weight loss, thyromegaly, exophthalmia, increased appetite, nausea and vomiting, sweating, and tremor.¹ The difficulty here? Many of these symptoms are also seen in pregnant women who have normal thyroid function, so that symptoms alone are not a reliable guide.

Instead, the diagnosis of overt hyperthyroidism is made on the basis of laboratory tests indicating suppressed TSH and elevated levels of free thyroxine (FT₄) and free triiodothyronine (FT₃). Subclinical hyperthyroidism is defined as a suppressed TSH level with normal FT₄ and FT₃ levels.²

The effects of hyperthyroidism on laboratory values are shown in TABLE 1. A form of hyperthyroidism called the T₃– toxicosis syndrome is diagnosed by suppressed TSH, normal FT₄, and elevated FT₃ levels.⁴

TABLE 1

Is your pregnant patient hyperthyroid? Five-test lab panel offers a guide

TEST AND RESULT
THYROID-STIMULATING HORMONE	FREE TRI-IODOTHYRONINE	FREE THYROXINE	TOTAL TRI-IODOTHYRONINE	TOTAL THYROXINE	THEN THE MOTHER’S CONDITION IS …
No change	No change	↑	↑	↑	Pregnancy
↓	↑	↑	↑	↑	Hyperthyroidism
↓	No change	No change	No change	No change	Subclinical hyperthyroidism

What are the causes?

The most common cause of hyperthyroidism in pregnancy—accounting for some 95% of cases—is Graves’ disease.² This autoimmune disorder is characterized by autoantibodies that activate the TSH receptor. These autoantibodies cross the placenta and can cause fetal and neonatal thyroid dysfunction even when the mother herself is in a euthyroid condition.⁴

 

Far less often, hyperthyroidism in pregnancy has a cause other than Graves’ disease; TABLE 2 summarizes the possibilities.¹ Other causes of hyperthyroidism in early pregnancy include choriocarcinoma and gestational trophoblastic disease (partial and complete moles) (TABLE 3).

TABLE 2

Causes of hyperthyroidism in pregnancy

Graves’ disease
Adenoma
Toxic nodular goiter
Thyroiditis
Excessive thyroid hormone intake
Choriocarcinoma
Molar pregnancy

TABLE 3

What causes severe hyperthyroidism before 20 weeks’ gestation?

Gestational transient thyrotoxicosis
Choriocarcinoma
Gestational trophoblastic disease Partial hydatidiform mole Complete hydatidiform mole

Signs and symptoms of Graves’ disease

Women who have Graves’ disease usually have thyroid nodules and may have exophthalmia, pretibial myxedema, and tachycardia. They also display other classic signs and symptoms of hyperthyroidism, such as muscle weakness, tremor, and warm and moist skin.

During pregnancy, Graves’ disease usually becomes worse during the first trimester and postpartum period; symptoms resolve during the second and third trimesters.¹

Thyrotoxin receptor and antithyroid antibodies

Antithyroid antibodies are common in patients with autoimmune thyroid disease, as a response to thyroid antigens. The two most common antithyroid antibodies are thyroglobulin and thyroid peroxidase (anti-TPO). Anti-TPO antibodies are associated with postpartum thyroiditis and fetal and neonatal hyperthyroidism. TSH-receptor antibodies include thyroid-stimulating immunoglobulin (TSI) and TSH-receptor antibody. TSI is associated with Graves’ disease. TSH-receptor antibody is associated with fetal goiter, congenital hypothyroidism, and chronic thyroiditis without goiter.⁴

Who do you test for antibodies? Test for maternal thyroid antibodies in patients who:

• had Graves’ disease with fetal or neonatal hyperthyroidism in a previous pregnancy
• have active Graves’ disease being treated with antithyroid drugs
• are euthyroid or have undergone ablative therapy and have fetal tachycardia or intrauterine growth restriction
• have chronic thyroiditis without goiter
• have fetal goiter on ultrasound.

Newborns who have congenital hypothyroidism should also be screened for thyroid antibodies.⁴

What are the consequences?

Hyperthyroidism can have multiple effects on the pregnant patient and her fetus, ranging in severity from the minimal to the catastrophic.

Gestational transient thyrotoxicosis

This condition is presumably related to high levels of human chorionic gonadotropin, a substance known to stimulate TSH receptors. Unhappily for your patient, the condition is usually heralded by severe bouts of nausea and vomiting starting at 4 to 8 weeks’ gestation. Laboratory tests show significantly elevated levels of FT₄ and FT₃ and suppressed TSH. Despite this significant derangement, patients generally have no evidence of a hypermetabolic state.

This condition resolves by 14 to 20 weeks of gestation, is not associated with poor pregnancy outcomes, and does not require treatment with antithyroid medication.¹

Adverse pregnancy outcomes

Pregnant women who have uncontrolled hyperthyroidism are at increased risk of spontaneous miscarriage, congestive heart failure, preterm delivery, intrauterine growth restriction, and preeclampsia.¹ Studies that evaluated pregnancy outcomes in 239 women with overt hyperthyroidism showed increased risk of adverse pregnancy outcomes, compared with treated, euthyroid women (FIGURE 1).^5-7

FIGURE 1 Consequences of uncontrolled hyperthyroidism

Several studies have found a much higher risk of pregnancy complications in women who have uncontrolled hyperthyroidism, compared with their treated and euthyroid peers.^5-7

PTD=preterm delivery; FGR=fetal growth restrictions.

Fetal and neonatal hyperthyroidism

Hyperthyroidism in the fetus or newborn is caused by placental transfer of maternal immunoglobulin antibodies (TSI) to the fetus and is associated with maternal Graves’ disease. The incidence of neonatal hyperthyroidism is less than 1%. It can be predicted by rising levels of maternal TSI antibodies, to the point where levels in the third trimester are three to five times higher than they were at the beginning of pregnancy.⁴

Fetal hyperthyroidism develops at about 22 to 24 weeks’ gestation in mothers with a history of Graves’ disease who have been treated surgically or with ablative therapy prior to pregnancy. Even when these therapies achieve a euthyroid state in the mother, TSI levels may remain elevated and lead to fetal hyperthyroidism.

Characteristics of hyperthyroidism in the fetus include tachycardia, intrauterine growth restriction, congestive heart failure, oligohydramnios, and goiter. Treating the mother with antithyroid medications will ameliorate symptoms in the fetus.⁴

Thyroid storm

This is the worst-case scenario—a rare but potentially lethal complication of uncontrolled hyperthyroidism. Thyroid storm is a hypermetabolic state characterized by fever, nausea, vomiting, diarrhea, tachycardia, altered mental status, restlessness, nervousness, seizures, coma, and cardiac arrhythmias. It occurs in 1% to 2% of patients receiving thioamide therapy.⁸

In most instances, thyroid storm is a complication of uncontrolled hyperthyroidism, but it can also be precipitated by infection, surgery, thromboembolism, preeclampsia, labor, and delivery.

Thyroid storm is a medical emergency

This manifestation of uncontrolled hyperthyroidism is so urgent that treatment should be initiated before the results of TSH, FT₄, and FT₃ tests are available.^2,8 Delivery should be avoided, if possible, until the mother’s condition can be stabilized but, if the status of the fetus is compromised, delivery is indicated.

 

Treatment of thyroid storm begins with stabilization of the patient, followed by initiation of a stepwise management approach (FIGURE 2).

FIGURE 2 Management of thyroid storm

Aggressive management of thyroid storm is indicated, following a stepwise approach. Each medication used to treat thyroid storm plays a specific role in suppressing thyroid function. Propylthiouracil (PTU) blocks additional synthesis of thyroid hormone and inhibits the conversion of thyroxine (T₄) to triiodothyronine (T₃). Methimazole blocks additional synthesis of thyroid hormones. Saturated solution of potassium iodide (SSKI), Lugol’s solution, and sodium iodide block the release of thyroid hormone from the gland. Dexamethasone is used to decrease thyroid hormone release and peripheral conversion of T₄ to T₃. Propranolol is used to treat maternal tachycardia by inhibiting the adrenergic effects of excessive thyroid hormones. Finally, phenobarbital is used to treat maternal agitation and restlessness caused by the increased catabolism of thyroid hormones.

SOURCE: Adapted from ACOG.²

Treatment of hyperthyroidism in pregnancy

Two medications are available to treat hyperthyroidism in pregnancy: propylthiouracil (PTU) and methimazole. These medications are known as thioamides.^1,2

PTU blocks the oxidation of iodine in the thyroid gland, thereby preventing the synthesis of T₄ and T₃. The initial dosage for hyperthyroid women who are not pregnant is usually 300 to 450 mg/day in three divided doses every 8 hours, and this dosing strategy can also be applied to the pregnant patient. Maintenance therapy is usually achieved with 100 to 150 mg/day in divided doses every 8 to 12 hours.⁹

Methimazole works by blocking the organification of iodide, which decreases thyroid hormone production. The usual dosing, given in three divided doses every 8 hours, is 15 mg/day for mild hyperthyroidism, 30 to 40 mg/day for moderately severe hyperthyroidism, and 60 mg/day for severe hyperthyroidism. Maintenance therapy with methimazole is usually given at a dosage of 5 to 15 mg/day.⁹

In the past, PTU was considered the drug of choice for treatment of hyperthyroidism in pregnancy because clinicians believed it crossed the placenta to a lesser degree than did methimazole, and because methimazole was associated with fetal esophageal and choanal atresia and fetal cutis aplasia (congenital skin defect of the scalp).^1,2 Available evidence does not, however, support these conclusions.^8,10 Whatever medication regimen you choose, thyroid function should be monitored 1) every 4 weeks until TSH and FT₄ levels are within normal limits and 2) every trimester thereafter. FIGURE 3 presents an algorithm for managing hyperthyroidism in pregnancy.

FIGURE 3 Management of hyperthyroidism in pregnancy

CASE Resolved

The patient in thyroid storm described at the beginning of this article requires aggressive management, as outlined in the algorithm in FIGURE 2. As her symptoms diminish, fetal tachycardia resolves. The patient’s FT₄ level begins to decline, consistent with appropriate treatment, and she is discharged home and instructed to continue PTU and labetalol and to follow up at the endocrinology and high-risk obstetrics clinics as soon as possible.

The patient does not follow this advice. Consequently, she presents at 33 5/7 weeks in a hypertensive crisis, with symptoms similar to those she first exhibited plus acute pulmonary edema. Fetal heart rate is initially in the 130s, with good variability and occasional decelerations (FIGURE 4A), but decelerations then become worse (FIGURE 4B) and emergency cesarean section is performed.

A male infant is delivered, weighing 2,390 g. Apgar scores are 0 at 1 minute and 9 at 5 minutes. A 25% placental abruption is noted at the time of delivery.

Mother and fetus are stabilized and discharged.

FIGURE 4 Weakening fetal status in a mother who is in thyroid storm

Fetal heart rate is initially in the 130s with good variability and occasional decelerations (A), but then deteriorates, with increasing decelerations (B), an indication for immediate delivery.

The authors report no financial relationships relevant to this article.

CASE Life on the line

A 32-year-old woman in the 24th week of her fourth pregnancy arrives at the emergency department complaining of cough and congestion, shortness of breath, and swelling in her face, hands, and feet. The swelling has become worse over the past 2 weeks, and she had several episodes of bloody vomiting the day before her visit. The patient says she has not experienced any leakage of fluid, vaginal bleeding, or contractions. She reports good fetal movement.

The patient’s medical history is unremarkable, but a review of systems reveals a 15-lb weight loss over the past 2 weeks, racing heart, worsening edema and shortness of breath, and diarrhea.

Physical findings include exophthalmia and an enlarged thyroid with a nodule on the right side, as well as bilateral rales, tachycardia, tremor, and increased deep tendon reflexes. There is no evidence of fetal cardiac failure or goiter.

A computed tomography (CT) scan of the mother shows bilateral pleural effusions indicative of high-output cardiac failure. Thyroid ultrasonography (US) reveals a diffusely enlarged thyroid gland with a right-sided mass.

The thyroid-stimulating hormone (TSH) level is undetectable. Fetal heart rate is in the 160s, with normal variability and occasional variable deceleration. Fetal US is consistent with the estimated gestational age and shows adequate amniotic fluid and no gross fetal anomalies.

What is the likely diagnosis?

This is a classic example of undiagnosed hyperthyroidism in pregnancy manifesting as thyroid storm.

As the case illustrates, uncontrolled hyperthyroidism in pregnancy poses a significant challenge for the obstetrician. The condition can cause miscarriage, preterm delivery, intrauterine growth restriction, preeclampsia, and—at its most dangerous—thyroid storm.¹ Thyroid storm is a life-threatening emergency, and treatment must be initiated even before hyperthyroidism is confirmed by thyroid function testing.² The good news is that these complications can be successfully avoided with adequate control of thyroid function.

Overt hyperthyroidism, seen in 0.2% of pregnancies, requires active intervention to avert adverse pregnancy outcome and neurologic damage to the fetus. Subclinical disease, seen in 1.7% of pregnancies, can also create serious obstetrical problems.¹

The effects of hyperthyroidism in pregnancy vary in severity, ranging from the fairly innocuous, transient, and self-limited state called gestational transient thyrotoxicosis to the life-threatening emergency of thyroid storm. This review will update you on how to manage this disorder for optimal pregnancy outcome.

To screen or not to screen

Routine screening for thyroid dysfunction has been recommended for women who have infertility, menstrual disorders, or type 1 diabetes mellitus, and for pregnant women who have signs and symptoms of the disorder. Some authors recommend screening all pregnant women, but routine screening is not endorsed by the American College of Obstetricians and Gynecologists.^2,3

Thyroid testing in pregnancy is recommended in women who:

• have a family history of autoimmune thyroid disease
• are on thyroid therapy
• have a goiter or
• have insulin-dependent diabetes mellitus.

Pregnant women who have a history of high-dose neck radiation, thyroid therapy, postpartum thyroiditis, or an infant born with thyroid disease should also be tested at the first prenatal visit.⁴

Telltale signs and laboratory tests

The signs and symptoms of hyperthyroidism can include nervousness, heat intolerance, tachycardia, palpitations, goiter, weight loss, thyromegaly, exophthalmia, increased appetite, nausea and vomiting, sweating, and tremor.¹ The difficulty here? Many of these symptoms are also seen in pregnant women who have normal thyroid function, so that symptoms alone are not a reliable guide.

Instead, the diagnosis of overt hyperthyroidism is made on the basis of laboratory tests indicating suppressed TSH and elevated levels of free thyroxine (FT₄) and free triiodothyronine (FT₃). Subclinical hyperthyroidism is defined as a suppressed TSH level with normal FT₄ and FT₃ levels.²

The effects of hyperthyroidism on laboratory values are shown in TABLE 1. A form of hyperthyroidism called the T₃– toxicosis syndrome is diagnosed by suppressed TSH, normal FT₄, and elevated FT₃ levels.⁴

TABLE 1

Is your pregnant patient hyperthyroid? Five-test lab panel offers a guide

TEST AND RESULT
THYROID-STIMULATING HORMONE	FREE TRI-IODOTHYRONINE	FREE THYROXINE	TOTAL TRI-IODOTHYRONINE	TOTAL THYROXINE	THEN THE MOTHER’S CONDITION IS …
No change	No change	↑	↑	↑	Pregnancy
↓	↑	↑	↑	↑	Hyperthyroidism
↓	No change	No change	No change	No change	Subclinical hyperthyroidism

What are the causes?

The most common cause of hyperthyroidism in pregnancy—accounting for some 95% of cases—is Graves’ disease.² This autoimmune disorder is characterized by autoantibodies that activate the TSH receptor. These autoantibodies cross the placenta and can cause fetal and neonatal thyroid dysfunction even when the mother herself is in a euthyroid condition.⁴

 

Far less often, hyperthyroidism in pregnancy has a cause other than Graves’ disease; TABLE 2 summarizes the possibilities.¹ Other causes of hyperthyroidism in early pregnancy include choriocarcinoma and gestational trophoblastic disease (partial and complete moles) (TABLE 3).

TABLE 2

Causes of hyperthyroidism in pregnancy

Graves’ disease
Adenoma
Toxic nodular goiter
Thyroiditis
Excessive thyroid hormone intake
Choriocarcinoma
Molar pregnancy

TABLE 3

What causes severe hyperthyroidism before 20 weeks’ gestation?

Gestational transient thyrotoxicosis
Choriocarcinoma
Gestational trophoblastic disease Partial hydatidiform mole Complete hydatidiform mole

Signs and symptoms of Graves’ disease

Women who have Graves’ disease usually have thyroid nodules and may have exophthalmia, pretibial myxedema, and tachycardia. They also display other classic signs and symptoms of hyperthyroidism, such as muscle weakness, tremor, and warm and moist skin.

During pregnancy, Graves’ disease usually becomes worse during the first trimester and postpartum period; symptoms resolve during the second and third trimesters.¹

Thyrotoxin receptor and antithyroid antibodies

Antithyroid antibodies are common in patients with autoimmune thyroid disease, as a response to thyroid antigens. The two most common antithyroid antibodies are thyroglobulin and thyroid peroxidase (anti-TPO). Anti-TPO antibodies are associated with postpartum thyroiditis and fetal and neonatal hyperthyroidism. TSH-receptor antibodies include thyroid-stimulating immunoglobulin (TSI) and TSH-receptor antibody. TSI is associated with Graves’ disease. TSH-receptor antibody is associated with fetal goiter, congenital hypothyroidism, and chronic thyroiditis without goiter.⁴

Who do you test for antibodies? Test for maternal thyroid antibodies in patients who:

• had Graves’ disease with fetal or neonatal hyperthyroidism in a previous pregnancy
• have active Graves’ disease being treated with antithyroid drugs
• are euthyroid or have undergone ablative therapy and have fetal tachycardia or intrauterine growth restriction
• have chronic thyroiditis without goiter
• have fetal goiter on ultrasound.

Newborns who have congenital hypothyroidism should also be screened for thyroid antibodies.⁴

What are the consequences?

Hyperthyroidism can have multiple effects on the pregnant patient and her fetus, ranging in severity from the minimal to the catastrophic.

Gestational transient thyrotoxicosis

This condition is presumably related to high levels of human chorionic gonadotropin, a substance known to stimulate TSH receptors. Unhappily for your patient, the condition is usually heralded by severe bouts of nausea and vomiting starting at 4 to 8 weeks’ gestation. Laboratory tests show significantly elevated levels of FT₄ and FT₃ and suppressed TSH. Despite this significant derangement, patients generally have no evidence of a hypermetabolic state.

This condition resolves by 14 to 20 weeks of gestation, is not associated with poor pregnancy outcomes, and does not require treatment with antithyroid medication.¹

Adverse pregnancy outcomes

Pregnant women who have uncontrolled hyperthyroidism are at increased risk of spontaneous miscarriage, congestive heart failure, preterm delivery, intrauterine growth restriction, and preeclampsia.¹ Studies that evaluated pregnancy outcomes in 239 women with overt hyperthyroidism showed increased risk of adverse pregnancy outcomes, compared with treated, euthyroid women (FIGURE 1).^5-7

FIGURE 1 Consequences of uncontrolled hyperthyroidism

Several studies have found a much higher risk of pregnancy complications in women who have uncontrolled hyperthyroidism, compared with their treated and euthyroid peers.^5-7

PTD=preterm delivery; FGR=fetal growth restrictions.

Fetal and neonatal hyperthyroidism

Hyperthyroidism in the fetus or newborn is caused by placental transfer of maternal immunoglobulin antibodies (TSI) to the fetus and is associated with maternal Graves’ disease. The incidence of neonatal hyperthyroidism is less than 1%. It can be predicted by rising levels of maternal TSI antibodies, to the point where levels in the third trimester are three to five times higher than they were at the beginning of pregnancy.⁴

Fetal hyperthyroidism develops at about 22 to 24 weeks’ gestation in mothers with a history of Graves’ disease who have been treated surgically or with ablative therapy prior to pregnancy. Even when these therapies achieve a euthyroid state in the mother, TSI levels may remain elevated and lead to fetal hyperthyroidism.

Characteristics of hyperthyroidism in the fetus include tachycardia, intrauterine growth restriction, congestive heart failure, oligohydramnios, and goiter. Treating the mother with antithyroid medications will ameliorate symptoms in the fetus.⁴

Thyroid storm

This is the worst-case scenario—a rare but potentially lethal complication of uncontrolled hyperthyroidism. Thyroid storm is a hypermetabolic state characterized by fever, nausea, vomiting, diarrhea, tachycardia, altered mental status, restlessness, nervousness, seizures, coma, and cardiac arrhythmias. It occurs in 1% to 2% of patients receiving thioamide therapy.⁸

In most instances, thyroid storm is a complication of uncontrolled hyperthyroidism, but it can also be precipitated by infection, surgery, thromboembolism, preeclampsia, labor, and delivery.

Thyroid storm is a medical emergency

This manifestation of uncontrolled hyperthyroidism is so urgent that treatment should be initiated before the results of TSH, FT₄, and FT₃ tests are available.^2,8 Delivery should be avoided, if possible, until the mother’s condition can be stabilized but, if the status of the fetus is compromised, delivery is indicated.

 

Treatment of thyroid storm begins with stabilization of the patient, followed by initiation of a stepwise management approach (FIGURE 2).

FIGURE 2 Management of thyroid storm

Aggressive management of thyroid storm is indicated, following a stepwise approach. Each medication used to treat thyroid storm plays a specific role in suppressing thyroid function. Propylthiouracil (PTU) blocks additional synthesis of thyroid hormone and inhibits the conversion of thyroxine (T₄) to triiodothyronine (T₃). Methimazole blocks additional synthesis of thyroid hormones. Saturated solution of potassium iodide (SSKI), Lugol’s solution, and sodium iodide block the release of thyroid hormone from the gland. Dexamethasone is used to decrease thyroid hormone release and peripheral conversion of T₄ to T₃. Propranolol is used to treat maternal tachycardia by inhibiting the adrenergic effects of excessive thyroid hormones. Finally, phenobarbital is used to treat maternal agitation and restlessness caused by the increased catabolism of thyroid hormones.

SOURCE: Adapted from ACOG.²

Treatment of hyperthyroidism in pregnancy

Two medications are available to treat hyperthyroidism in pregnancy: propylthiouracil (PTU) and methimazole. These medications are known as thioamides.^1,2

PTU blocks the oxidation of iodine in the thyroid gland, thereby preventing the synthesis of T₄ and T₃. The initial dosage for hyperthyroid women who are not pregnant is usually 300 to 450 mg/day in three divided doses every 8 hours, and this dosing strategy can also be applied to the pregnant patient. Maintenance therapy is usually achieved with 100 to 150 mg/day in divided doses every 8 to 12 hours.⁹

Methimazole works by blocking the organification of iodide, which decreases thyroid hormone production. The usual dosing, given in three divided doses every 8 hours, is 15 mg/day for mild hyperthyroidism, 30 to 40 mg/day for moderately severe hyperthyroidism, and 60 mg/day for severe hyperthyroidism. Maintenance therapy with methimazole is usually given at a dosage of 5 to 15 mg/day.⁹

In the past, PTU was considered the drug of choice for treatment of hyperthyroidism in pregnancy because clinicians believed it crossed the placenta to a lesser degree than did methimazole, and because methimazole was associated with fetal esophageal and choanal atresia and fetal cutis aplasia (congenital skin defect of the scalp).^1,2 Available evidence does not, however, support these conclusions.^8,10 Whatever medication regimen you choose, thyroid function should be monitored 1) every 4 weeks until TSH and FT₄ levels are within normal limits and 2) every trimester thereafter. FIGURE 3 presents an algorithm for managing hyperthyroidism in pregnancy.

FIGURE 3 Management of hyperthyroidism in pregnancy

CASE Resolved

The patient in thyroid storm described at the beginning of this article requires aggressive management, as outlined in the algorithm in FIGURE 2. As her symptoms diminish, fetal tachycardia resolves. The patient’s FT₄ level begins to decline, consistent with appropriate treatment, and she is discharged home and instructed to continue PTU and labetalol and to follow up at the endocrinology and high-risk obstetrics clinics as soon as possible.

The patient does not follow this advice. Consequently, she presents at 33 5/7 weeks in a hypertensive crisis, with symptoms similar to those she first exhibited plus acute pulmonary edema. Fetal heart rate is initially in the 130s, with good variability and occasional decelerations (FIGURE 4A), but decelerations then become worse (FIGURE 4B) and emergency cesarean section is performed.

A male infant is delivered, weighing 2,390 g. Apgar scores are 0 at 1 minute and 9 at 5 minutes. A 25% placental abruption is noted at the time of delivery.

Mother and fetus are stabilized and discharged.

FIGURE 4 Weakening fetal status in a mother who is in thyroid storm

Fetal heart rate is initially in the 130s with good variability and occasional decelerations (A), but then deteriorates, with increasing decelerations (B), an indication for immediate delivery.

The authors report no financial relationships relevant to this article.

CASE Life on the line

A 32-year-old woman in the 24th week of her fourth pregnancy arrives at the emergency department complaining of cough and congestion, shortness of breath, and swelling in her face, hands, and feet. The swelling has become worse over the past 2 weeks, and she had several episodes of bloody vomiting the day before her visit. The patient says she has not experienced any leakage of fluid, vaginal bleeding, or contractions. She reports good fetal movement.

The patient’s medical history is unremarkable, but a review of systems reveals a 15-lb weight loss over the past 2 weeks, racing heart, worsening edema and shortness of breath, and diarrhea.

Physical findings include exophthalmia and an enlarged thyroid with a nodule on the right side, as well as bilateral rales, tachycardia, tremor, and increased deep tendon reflexes. There is no evidence of fetal cardiac failure or goiter.

A computed tomography (CT) scan of the mother shows bilateral pleural effusions indicative of high-output cardiac failure. Thyroid ultrasonography (US) reveals a diffusely enlarged thyroid gland with a right-sided mass.

The thyroid-stimulating hormone (TSH) level is undetectable. Fetal heart rate is in the 160s, with normal variability and occasional variable deceleration. Fetal US is consistent with the estimated gestational age and shows adequate amniotic fluid and no gross fetal anomalies.

What is the likely diagnosis?

This is a classic example of undiagnosed hyperthyroidism in pregnancy manifesting as thyroid storm.

As the case illustrates, uncontrolled hyperthyroidism in pregnancy poses a significant challenge for the obstetrician. The condition can cause miscarriage, preterm delivery, intrauterine growth restriction, preeclampsia, and—at its most dangerous—thyroid storm.¹ Thyroid storm is a life-threatening emergency, and treatment must be initiated even before hyperthyroidism is confirmed by thyroid function testing.² The good news is that these complications can be successfully avoided with adequate control of thyroid function.

Overt hyperthyroidism, seen in 0.2% of pregnancies, requires active intervention to avert adverse pregnancy outcome and neurologic damage to the fetus. Subclinical disease, seen in 1.7% of pregnancies, can also create serious obstetrical problems.¹

The effects of hyperthyroidism in pregnancy vary in severity, ranging from the fairly innocuous, transient, and self-limited state called gestational transient thyrotoxicosis to the life-threatening emergency of thyroid storm. This review will update you on how to manage this disorder for optimal pregnancy outcome.

To screen or not to screen

Routine screening for thyroid dysfunction has been recommended for women who have infertility, menstrual disorders, or type 1 diabetes mellitus, and for pregnant women who have signs and symptoms of the disorder. Some authors recommend screening all pregnant women, but routine screening is not endorsed by the American College of Obstetricians and Gynecologists.^2,3

Thyroid testing in pregnancy is recommended in women who:

• have a family history of autoimmune thyroid disease
• are on thyroid therapy
• have a goiter or
• have insulin-dependent diabetes mellitus.

Pregnant women who have a history of high-dose neck radiation, thyroid therapy, postpartum thyroiditis, or an infant born with thyroid disease should also be tested at the first prenatal visit.⁴

Telltale signs and laboratory tests

The signs and symptoms of hyperthyroidism can include nervousness, heat intolerance, tachycardia, palpitations, goiter, weight loss, thyromegaly, exophthalmia, increased appetite, nausea and vomiting, sweating, and tremor.¹ The difficulty here? Many of these symptoms are also seen in pregnant women who have normal thyroid function, so that symptoms alone are not a reliable guide.

Instead, the diagnosis of overt hyperthyroidism is made on the basis of laboratory tests indicating suppressed TSH and elevated levels of free thyroxine (FT₄) and free triiodothyronine (FT₃). Subclinical hyperthyroidism is defined as a suppressed TSH level with normal FT₄ and FT₃ levels.²

The effects of hyperthyroidism on laboratory values are shown in TABLE 1. A form of hyperthyroidism called the T₃– toxicosis syndrome is diagnosed by suppressed TSH, normal FT₄, and elevated FT₃ levels.⁴

TABLE 1

Is your pregnant patient hyperthyroid? Five-test lab panel offers a guide

TEST AND RESULT
THYROID-STIMULATING HORMONE	FREE TRI-IODOTHYRONINE	FREE THYROXINE	TOTAL TRI-IODOTHYRONINE	TOTAL THYROXINE	THEN THE MOTHER’S CONDITION IS …
No change	No change	↑	↑	↑	Pregnancy
↓	↑	↑	↑	↑	Hyperthyroidism
↓	No change	No change	No change	No change	Subclinical hyperthyroidism

What are the causes?

The most common cause of hyperthyroidism in pregnancy—accounting for some 95% of cases—is Graves’ disease.² This autoimmune disorder is characterized by autoantibodies that activate the TSH receptor. These autoantibodies cross the placenta and can cause fetal and neonatal thyroid dysfunction even when the mother herself is in a euthyroid condition.⁴

 

Far less often, hyperthyroidism in pregnancy has a cause other than Graves’ disease; TABLE 2 summarizes the possibilities.¹ Other causes of hyperthyroidism in early pregnancy include choriocarcinoma and gestational trophoblastic disease (partial and complete moles) (TABLE 3).

TABLE 2

Causes of hyperthyroidism in pregnancy

Graves’ disease
Adenoma
Toxic nodular goiter
Thyroiditis
Excessive thyroid hormone intake
Choriocarcinoma
Molar pregnancy

TABLE 3

What causes severe hyperthyroidism before 20 weeks’ gestation?

Gestational transient thyrotoxicosis
Choriocarcinoma
Gestational trophoblastic disease Partial hydatidiform mole Complete hydatidiform mole

Signs and symptoms of Graves’ disease

Women who have Graves’ disease usually have thyroid nodules and may have exophthalmia, pretibial myxedema, and tachycardia. They also display other classic signs and symptoms of hyperthyroidism, such as muscle weakness, tremor, and warm and moist skin.

During pregnancy, Graves’ disease usually becomes worse during the first trimester and postpartum period; symptoms resolve during the second and third trimesters.¹

Thyrotoxin receptor and antithyroid antibodies

Antithyroid antibodies are common in patients with autoimmune thyroid disease, as a response to thyroid antigens. The two most common antithyroid antibodies are thyroglobulin and thyroid peroxidase (anti-TPO). Anti-TPO antibodies are associated with postpartum thyroiditis and fetal and neonatal hyperthyroidism. TSH-receptor antibodies include thyroid-stimulating immunoglobulin (TSI) and TSH-receptor antibody. TSI is associated with Graves’ disease. TSH-receptor antibody is associated with fetal goiter, congenital hypothyroidism, and chronic thyroiditis without goiter.⁴

Who do you test for antibodies? Test for maternal thyroid antibodies in patients who:

• had Graves’ disease with fetal or neonatal hyperthyroidism in a previous pregnancy
• have active Graves’ disease being treated with antithyroid drugs
• are euthyroid or have undergone ablative therapy and have fetal tachycardia or intrauterine growth restriction
• have chronic thyroiditis without goiter
• have fetal goiter on ultrasound.

Newborns who have congenital hypothyroidism should also be screened for thyroid antibodies.⁴

What are the consequences?

Hyperthyroidism can have multiple effects on the pregnant patient and her fetus, ranging in severity from the minimal to the catastrophic.

Gestational transient thyrotoxicosis

This condition is presumably related to high levels of human chorionic gonadotropin, a substance known to stimulate TSH receptors. Unhappily for your patient, the condition is usually heralded by severe bouts of nausea and vomiting starting at 4 to 8 weeks’ gestation. Laboratory tests show significantly elevated levels of FT₄ and FT₃ and suppressed TSH. Despite this significant derangement, patients generally have no evidence of a hypermetabolic state.

This condition resolves by 14 to 20 weeks of gestation, is not associated with poor pregnancy outcomes, and does not require treatment with antithyroid medication.¹

Adverse pregnancy outcomes

Pregnant women who have uncontrolled hyperthyroidism are at increased risk of spontaneous miscarriage, congestive heart failure, preterm delivery, intrauterine growth restriction, and preeclampsia.¹ Studies that evaluated pregnancy outcomes in 239 women with overt hyperthyroidism showed increased risk of adverse pregnancy outcomes, compared with treated, euthyroid women (FIGURE 1).^5-7

FIGURE 1 Consequences of uncontrolled hyperthyroidism

Several studies have found a much higher risk of pregnancy complications in women who have uncontrolled hyperthyroidism, compared with their treated and euthyroid peers.^5-7

PTD=preterm delivery; FGR=fetal growth restrictions.

Fetal and neonatal hyperthyroidism

Hyperthyroidism in the fetus or newborn is caused by placental transfer of maternal immunoglobulin antibodies (TSI) to the fetus and is associated with maternal Graves’ disease. The incidence of neonatal hyperthyroidism is less than 1%. It can be predicted by rising levels of maternal TSI antibodies, to the point where levels in the third trimester are three to five times higher than they were at the beginning of pregnancy.⁴

Fetal hyperthyroidism develops at about 22 to 24 weeks’ gestation in mothers with a history of Graves’ disease who have been treated surgically or with ablative therapy prior to pregnancy. Even when these therapies achieve a euthyroid state in the mother, TSI levels may remain elevated and lead to fetal hyperthyroidism.

Characteristics of hyperthyroidism in the fetus include tachycardia, intrauterine growth restriction, congestive heart failure, oligohydramnios, and goiter. Treating the mother with antithyroid medications will ameliorate symptoms in the fetus.⁴

Thyroid storm

This is the worst-case scenario—a rare but potentially lethal complication of uncontrolled hyperthyroidism. Thyroid storm is a hypermetabolic state characterized by fever, nausea, vomiting, diarrhea, tachycardia, altered mental status, restlessness, nervousness, seizures, coma, and cardiac arrhythmias. It occurs in 1% to 2% of patients receiving thioamide therapy.⁸

In most instances, thyroid storm is a complication of uncontrolled hyperthyroidism, but it can also be precipitated by infection, surgery, thromboembolism, preeclampsia, labor, and delivery.

Thyroid storm is a medical emergency

This manifestation of uncontrolled hyperthyroidism is so urgent that treatment should be initiated before the results of TSH, FT₄, and FT₃ tests are available.^2,8 Delivery should be avoided, if possible, until the mother’s condition can be stabilized but, if the status of the fetus is compromised, delivery is indicated.

 

Treatment of thyroid storm begins with stabilization of the patient, followed by initiation of a stepwise management approach (FIGURE 2).

FIGURE 2 Management of thyroid storm

Aggressive management of thyroid storm is indicated, following a stepwise approach. Each medication used to treat thyroid storm plays a specific role in suppressing thyroid function. Propylthiouracil (PTU) blocks additional synthesis of thyroid hormone and inhibits the conversion of thyroxine (T₄) to triiodothyronine (T₃). Methimazole blocks additional synthesis of thyroid hormones. Saturated solution of potassium iodide (SSKI), Lugol’s solution, and sodium iodide block the release of thyroid hormone from the gland. Dexamethasone is used to decrease thyroid hormone release and peripheral conversion of T₄ to T₃. Propranolol is used to treat maternal tachycardia by inhibiting the adrenergic effects of excessive thyroid hormones. Finally, phenobarbital is used to treat maternal agitation and restlessness caused by the increased catabolism of thyroid hormones.

SOURCE: Adapted from ACOG.²

Treatment of hyperthyroidism in pregnancy

Two medications are available to treat hyperthyroidism in pregnancy: propylthiouracil (PTU) and methimazole. These medications are known as thioamides.^1,2

PTU blocks the oxidation of iodine in the thyroid gland, thereby preventing the synthesis of T₄ and T₃. The initial dosage for hyperthyroid women who are not pregnant is usually 300 to 450 mg/day in three divided doses every 8 hours, and this dosing strategy can also be applied to the pregnant patient. Maintenance therapy is usually achieved with 100 to 150 mg/day in divided doses every 8 to 12 hours.⁹

Methimazole works by blocking the organification of iodide, which decreases thyroid hormone production. The usual dosing, given in three divided doses every 8 hours, is 15 mg/day for mild hyperthyroidism, 30 to 40 mg/day for moderately severe hyperthyroidism, and 60 mg/day for severe hyperthyroidism. Maintenance therapy with methimazole is usually given at a dosage of 5 to 15 mg/day.⁹

In the past, PTU was considered the drug of choice for treatment of hyperthyroidism in pregnancy because clinicians believed it crossed the placenta to a lesser degree than did methimazole, and because methimazole was associated with fetal esophageal and choanal atresia and fetal cutis aplasia (congenital skin defect of the scalp).^1,2 Available evidence does not, however, support these conclusions.^8,10 Whatever medication regimen you choose, thyroid function should be monitored 1) every 4 weeks until TSH and FT₄ levels are within normal limits and 2) every trimester thereafter. FIGURE 3 presents an algorithm for managing hyperthyroidism in pregnancy.

FIGURE 3 Management of hyperthyroidism in pregnancy

CASE Resolved

The patient in thyroid storm described at the beginning of this article requires aggressive management, as outlined in the algorithm in FIGURE 2. As her symptoms diminish, fetal tachycardia resolves. The patient’s FT₄ level begins to decline, consistent with appropriate treatment, and she is discharged home and instructed to continue PTU and labetalol and to follow up at the endocrinology and high-risk obstetrics clinics as soon as possible.

The patient does not follow this advice. Consequently, she presents at 33 5/7 weeks in a hypertensive crisis, with symptoms similar to those she first exhibited plus acute pulmonary edema. Fetal heart rate is initially in the 130s, with good variability and occasional decelerations (FIGURE 4A), but decelerations then become worse (FIGURE 4B) and emergency cesarean section is performed.

A male infant is delivered, weighing 2,390 g. Apgar scores are 0 at 1 minute and 9 at 5 minutes. A 25% placental abruption is noted at the time of delivery.

Mother and fetus are stabilized and discharged.

FIGURE 4 Weakening fetal status in a mother who is in thyroid storm

Fetal heart rate is initially in the 130s with good variability and occasional decelerations (A), but then deteriorates, with increasing decelerations (B), an indication for immediate delivery.

The authors report no financial relationships relevant to this article.

A pregnant woman whose thyroid gland isn’t doing its job presents a serious management problem for her obstetrician. If she has overt hypothyroidism, seen in between 0.3% and 2.5% of pregnancies, active intervention is required to prevent serious damage to the fetus.^1,2 Even if she has subclinical disease, seen in 2% to 3% of pregnancies, current research indicates that intervention may be indicated.

Fetal thyroxine requirements increase as early as 5 weeks of gestation, when the fetus is still dependent on maternal thyroxine. A deficiency of maternal thyroxine can have severe adverse outcomes, affecting the course of the pregnancy and the neurologic development of the fetus. To prevent such sequelae, patients who were on thyroid medication before pregnancy should increase the dosage by 30% once pregnancy is confirmed, and hypothyroidism that develops in pregnancy should be managed aggressively and meticulously.

Here, we’ll examine the published research to advise you on evidence-based approaches for diagnosis and management of this complex condition.

Maternal thyroid function

An elaborate negative-feedback loop prevails before pregnancy

In a nonpregnant woman, thyroid function is controlled by a negative-feedback loop that works like this:

• The hypothalamus releases thyroid-releasing hormone (TRH)
• TRH acts on the pituitary gland to release thyroid-stimulating hormone (TSH)
• TSH, in turn, acts on the thyroid gland to release the thyroid hormones iodothyronine (T₃) and thyroxine (T₄) that regulate metabolism
• TRH and TSH concentrations are inversely related to T₃ and T₄ concentrations. That is, the more TRH and TSH circulating in the blood stream, the less T₃ and T₄ will be produced by the thyroid gland³
• Almost all (approximately 99%) circulating T₃ and T₄ is bound to a protein called thyroxine-binding globulin (TBG). Only 1% of these hormones circulate in the free form, and only the free forms are biologically active.³

This relationship is illustrated in FIGURE 1.

FIGURE 1 Thyroid physiology and the impact of pregnancy

Pregnancy reduces free forms of T₃ and T₄, and increases TSH slightly

Pregnancy alters thyroid function in significant ways:

• Increases in circulating estrogen lead to the production of more TBG
• When TBG increases, more T₃ and T₄ are bound and fewer free forms of these hormones are available
• Because the total T₃ (TT₃) and total free T₄ (TT₄) are decreased in pregnancy, they are not good measures of thyroid function. Maternal thyroid function in pregnancy should be monitored using free T₄ (FT₄) and TSH levels
• Increased TBG also leads to a slight increase in TSH between the first trimester and term
• Human chorionic gonadotropin (hCG) concentrations also increase in pregnancy. Because hCG has thyrotropin-like activity, these higher levels cause a transient decrease in TSH by suppression of TSH production between approximately 8 and 14 weeks of gestation.

Fetal thyroid function

During early gestation, the fetus receives thyroid hormone from the mother.¹ Maternal T₄ crosses the placenta actively—the only hormone that does so.⁴ The fetus’s need for thyroxine starts to increase as early as 5 weeks of gestation.⁵

Fetal thyroid development does not begin until 10 to 12 weeks of gestation, and then continues until term. The fetus relies on maternal T₄ exclusively before 12 weeks and partially thereafter for normal fetal neurologic development. It follows that maternal hypothyroidism could be detrimental to fetal development if not detected and corrected very early in gestation.

How (and whom) to screen for maternal hypothyroidism

Routine screening has been recommended for women who have infertility, menstrual disorders, or type 1 diabetes mellitus, and for pregnant women who have signs and symptoms of deficient thyroid function.⁶ In recent years, some authors have recommended screening all pregnant women for thyroid dysfunction, but such recommendations remain controversial.^3,7,8 Routine screening is not endorsed by the American College of Obstetricians and Gynecologists.⁶

Symptoms overlap typical conditions of pregnancy

The difficulty here is that the characteristic signs and symptoms of hypothyroidism are very similar to physiologic conditions seen in most pregnancies. They include fatigue, constipation, cold intolerance, muscle cramps, hair loss, dry skin, brittle nails, weight gain, intellectual slowness, bradycardia, depression, insomnia, periorbital edema, myxedema, and myxedema coma.⁶ A side-by-side comparison of pregnancy conditions and hypothyroidism symptoms is provided in TABLE 1.

TABLE 1

Distinguishing hypothyroidism from a normal gestation can be challenging

SYMPTOM	HYPOTHYROIDISM	PREGNANCY
Fatigue	•	•
Constipation	•	•
Hair loss	•
Dry skin	•
Brittle nails	•
Weight gain	•	•
Fluid retention	•	•
Bradycardia	•	•
Goiter	•
Carpal tunnel syndrome	•	•

Which laboratory tests are informative?

Because screening is controversial and symptomatology does not reliably distinguish hypothyroidism from normal pregnancy, laboratory tests are the standard for diagnosis. Overt hypothyroidism is diagnosed in a symptomatic patient by elevated TSH level and low levels of FT₄ and free T₃ (FT₃). Subclinical hypothyroidism is defined as elevated TSH with normal FT₄ and FT₃ in an asymptomatic patient. Level changes characteristic of normal pregnancy, overt hypothyroidism, and subclinical hypothyroidism are given in TABLE 2.⁶

 

TABLE 2

Laboratory diagnosis of hypothyroidism

MATERNAL CONDITION	TSH	FREE T3	FREE T4	TOTAL T3	TOTAL T4
Normal pregnancy	No change	No change	↑	↑	↑
Hypothyroidism	↑	↓	↓	↓	↓
Subclinical hypothyroidism	↑	No change	No change	↓	↓
Adapted from American College of Obstetricians and Gynecologists6

What causes hypothyroidism?

The most common cause of hypothyroidism in most of the world is iodine deficiency. In developed countries, however, where lack of iodine in the diet is not a problem, Hashimoto’s thyroiditis, also known as chronic autoimmune thyroiditis, is the most common cause. Hashimoto’s thyroiditis is characterized by the presence of antithyroid antibodies, including both thyroid antimicrosomial and antithyroglobulin antibodies. Both iodine deficiency and Hashimoto’s thyroiditis are associated with goiter.⁵ Other causes of hypothyroidism include radioactive iodine therapy for Graves’ disease, a condition we will discuss in Part 2 of this series in February; thyroidectomy; viral thyroiditis; pituitary tumors; Sheehan’s syndrome; and a number of medications.

Causes of hypothyroidism are summarized in TABLE 3.³

TABLE 3

Causes of hypothyroidism

Iodine deficiency
Hashimoto’s thyroiditis
Radioactive iodine therapy
Thyroidectomy
Viral thyroiditis
Sheehan’s syndrome
Medications Thionamides Lithium Drugs that inhibit absorption of thyroid medication - Ferrous sulfate - Sucrafate - Cholestyramine - Antacids (aluminum hydroxide)

Effects vary by medication

Medications alter thyroid function in different ways. Iodine and lithium inhibit thyroid function and, along with dopamine antagonists, increase TSH levels. Conversely, thioamides, glucocorticoids, dopamine agonists, and somatostatins decrease TSH levels. Finally, ferrous sulfate, sucrafate, cholestyramine, and aluminum hydroxide antacids all inhibit gastrointestinal absorption of thyroid hormone and therefore should not be taken within 4 hours of thyroid medication.⁶

Maternal hypothyroidism: Effects on fetus, newborn

The impact of maternal hypothyroidism on the fetus depends on the severity of the condition.

• Uncontrolled hypothyroidism. The consequences of this condition can be dire. The possibilities include intrauterine fetal demise and stillbirth, preterm delivery, low birth weight, preeclampsia, and developmental anomalies including reduced intelligence quotient (IQ).^1,2,4,6 Blazer and colleagues correlated intrauterine growth with maternal TSH and fetal FT₄ and concluded that impaired intrauterine growth is related to abnormal thyroid function and might reflect an insufficient level of hormone production by hypothyroid mothers during pregnancy.⁹ Maternal and congenital hypothyroidism resulting from severe iodine deficiency are associated with profound neurologic impairment and mental retardation.^1,3,10 If the condition is left untreated, cretinism can occur. Congenital cretinism is associated with growth failure, mental retardation, and other neuropsychologic deficits including deaf-mutism.^3,4 However, if cretinism is identified and treated in the first 3 months of life, near-normal growth and intelligence can be expected.⁶ For this reason, all 50 states and the District of Columbia require newborn screening for congenital hypothyroidism.⁶
• Asymptomatic overt hypothyroidism. Several studies have evaluated neonatal outcomes in pregnancy complicated by asymptomatic overt hypothyroidism—that is, women who had previously been diagnosed with hypothyroidism, who have abnormal TSH and FT₄ levels, but who do not have symptoms. Pop and colleagues have shown impaired psychomotor development at 10 months in infants born to mothers who had low T₄ during the first 12 weeks of gestation.⁷ Haddow and colleagues correlated elevated maternal TSH levels at less than 17 weeks’ gestation with low IQ scores in the offspring at 7 to 9 years of age.⁸ Klein and colleagues demonstrated an inverse correlation between a woman’s TSH level during pregnancy and the IQ of her offspring.¹¹ Kooistra and colleagues confirmed that maternal hypothyroxinemia is a risk for neurodevelopmental abnormalities that can be identified as early as 3 weeks of age.¹² Studies of this relationship are summarized in TABLE 4.
• Subclinical hypothyroidism. During the past decade, researchers have focused attention on neonatal neurologic function in infants born to mothers who had subclinical disease. Mitchell and Klein evaluated the prevalence of subclinical hypothyroidism at less than 17 weeks’ gestation and subsequently compared the IQs in these children with those of controls.⁴ They found the mean and standard-deviation IQs of the children in the control and treated groups to be significantly higher than those of the children whose mothers were not treated. Casey and colleagues evaluated pregnancy outcomes in women who had undiagnosed subclinical hypothyroidism.¹⁰ They found that such pregnancies were more likely to be complicated by placental abruption and preterm birth, and speculated that the reduced IQ demonstrated in the Mitchell and Klein study might have been related to the effects of prematurity.

TABLE 4

Fetal and neonatal effects of asymptomatic overt hypothyroidism

STUDY	LABORATORY FINDINGS	OUTCOMES AND RECOMMENDATIONS
Kooistra et al12	↓ FT4	Maternal hypothyroxinemia is a risk for neurodevelopmental abnormalities as early as 3 weeks of age
Casey et al10	↑ TSH	Pregnancies with undiagnosed subclinical hypothyroidism were more likely to be complicated by placental abruption and preterm birth. The reduced IQ seen in a prior study (Mitchell and Klein4) may be related to effects of prematurity
Mitchell and Klein4	↑ TSH	The mean and standard deviation of IQs of the children of treated mothers with hypothyroidism and the control group were significantly higher than those for children of untreated hypothyroid women
Blazer et al9	↑ maternal TSH, ↑ fetal FT4	Impaired intrauterine growth may reflect insufficient levels of hormone replacement therapy in hypothyroid mothers during pregnancy
Pop et al7	↓ FT4	Impaired psychomotor development at 10 months of age in offspring of mothers with low T4 at ≤12 weeks
Haddow et al8	↑ TSH, ↓ FT4	Elevated TSH levels at <17 weeks’ gestation are associated with low IQ scores at 7 to 9 years of age. Routine screening for thyroid deficiency may be warranted
Klein et al11	↑ TSH, ↓ FT4, ↓ TT4	Inverse correlation between TSH during pregnancy and IQ of offspring
FT4=free thyroxine, TSH=thyroid-stimulating hormone, TT4=total thyroxine

 

Managing hypothyroidism in pregnancy

The treatment of choice for correction of hypothyroidism is synthetic T₄, or levothyroxine (Levothyroid, Levoxyl, Synthroid, and Unithroid). Initial treatment in the nonpregnant patient is 1.7 μg/kg/day or 12.5 to 25 μg/day adjusted by 25 μg/day every 2 to 4 weeks until a euthyroid state is achieved.¹³

Patients who were on thyroxine therapy before pregnancy should increase the dose by 30% once pregnancy is confirmed.^1,5 Serum thyrotropin levels should be monitored every 4 weeks to maintain a TSH level between 1 and 2 mU/L and FT₄ in upper third of normal.¹ Once a euthyroid state has been achieved, thyrotropin levels should be monitored every trimester until delivery. FIGURE 2 provides an algorithm for management of hypothyroidism in pregnancy.

FIGURE 2 During pregnancy, thyroid function merits regular monitoring, fine-tuning of treatment

Postpartum thyroiditis

About 5% of all obstetrical patients develop postpartum thyroiditis. Approximately 45% of these women present with hypothyroidism, with the rest evenly divided between thyrotoxicosis (hyperthyroidism) and thyrotoxicosis followed by hypothyroidism. Unfortunately, the signs and symptoms of hypo- and hyperthyroidism are similar to the postpartum state. Many of these patients are not diagnosed. A high index of suspicion warrants thyroid function testing. Women who have a history of type 1 diabetes mellitus have a 25% chance of developing postpartum thyroid dysfunction.

The diagnosis is made by documenting abnormal levels of TSH and FT₄. Postpartum hyperthyroidism may be diagnosed by the presence of antimicrosomal or thyroperoxidase antithyroid peroxidase antibodies. Goiter may be present in up to 50% of patients.

Postpartum thyroiditis has two phases

The first phase, also known as the thyrotoxic phase, occurs 1 to 4 months after delivery when transient thyrotoxicosis develops from excessive release of thyroid hormones. The most common symptoms with early postpartum thyroiditis are fatigue and palpitations. Approximately 67% of these women will return to a euthyroid state, and thioamide therapy is generally considered ineffective. Hypothyroidism can develop within 1 month of the onset of thyroiditis.

The second phase occurs between 4 and 8 months postpartum, and these women present with hypothyroidism. Thyromegaly and associated symptoms are common. Unlike the first (thyrotoxic) phase, medical treatment is recommended. Thyroxine treatment should be initiated and maintained for 6 to 12 months. Postpartum thyroiditis carries a 30% risk of recurrence.¹⁴

Postpartum thyroiditis may be associated with depression or aggravate symptoms of depression, although the data on this association are conflicting. The largest study addressing this issue concluded that there was no difference in the clinical and psychiatric signs and symptoms between postpartum thyroiditis and controls.¹⁵ Nevertheless, it would seem prudent to evaluate thyroid function in postpartum depression if other signs of thyroid dysfunction are present.

The authors report no financial relationships relevant to this article.

A pregnant woman whose thyroid gland isn’t doing its job presents a serious management problem for her obstetrician. If she has overt hypothyroidism, seen in between 0.3% and 2.5% of pregnancies, active intervention is required to prevent serious damage to the fetus.^1,2 Even if she has subclinical disease, seen in 2% to 3% of pregnancies, current research indicates that intervention may be indicated.

Fetal thyroxine requirements increase as early as 5 weeks of gestation, when the fetus is still dependent on maternal thyroxine. A deficiency of maternal thyroxine can have severe adverse outcomes, affecting the course of the pregnancy and the neurologic development of the fetus. To prevent such sequelae, patients who were on thyroid medication before pregnancy should increase the dosage by 30% once pregnancy is confirmed, and hypothyroidism that develops in pregnancy should be managed aggressively and meticulously.

Here, we’ll examine the published research to advise you on evidence-based approaches for diagnosis and management of this complex condition.

Maternal thyroid function

An elaborate negative-feedback loop prevails before pregnancy

In a nonpregnant woman, thyroid function is controlled by a negative-feedback loop that works like this:

• The hypothalamus releases thyroid-releasing hormone (TRH)
• TRH acts on the pituitary gland to release thyroid-stimulating hormone (TSH)
• TSH, in turn, acts on the thyroid gland to release the thyroid hormones iodothyronine (T₃) and thyroxine (T₄) that regulate metabolism
• TRH and TSH concentrations are inversely related to T₃ and T₄ concentrations. That is, the more TRH and TSH circulating in the blood stream, the less T₃ and T₄ will be produced by the thyroid gland³
• Almost all (approximately 99%) circulating T₃ and T₄ is bound to a protein called thyroxine-binding globulin (TBG). Only 1% of these hormones circulate in the free form, and only the free forms are biologically active.³

This relationship is illustrated in FIGURE 1.

FIGURE 1 Thyroid physiology and the impact of pregnancy

Pregnancy reduces free forms of T₃ and T₄, and increases TSH slightly

Pregnancy alters thyroid function in significant ways:

• Increases in circulating estrogen lead to the production of more TBG
• When TBG increases, more T₃ and T₄ are bound and fewer free forms of these hormones are available
• Because the total T₃ (TT₃) and total free T₄ (TT₄) are decreased in pregnancy, they are not good measures of thyroid function. Maternal thyroid function in pregnancy should be monitored using free T₄ (FT₄) and TSH levels
• Increased TBG also leads to a slight increase in TSH between the first trimester and term
• Human chorionic gonadotropin (hCG) concentrations also increase in pregnancy. Because hCG has thyrotropin-like activity, these higher levels cause a transient decrease in TSH by suppression of TSH production between approximately 8 and 14 weeks of gestation.

Fetal thyroid function

During early gestation, the fetus receives thyroid hormone from the mother.¹ Maternal T₄ crosses the placenta actively—the only hormone that does so.⁴ The fetus’s need for thyroxine starts to increase as early as 5 weeks of gestation.⁵

Fetal thyroid development does not begin until 10 to 12 weeks of gestation, and then continues until term. The fetus relies on maternal T₄ exclusively before 12 weeks and partially thereafter for normal fetal neurologic development. It follows that maternal hypothyroidism could be detrimental to fetal development if not detected and corrected very early in gestation.

How (and whom) to screen for maternal hypothyroidism

Routine screening has been recommended for women who have infertility, menstrual disorders, or type 1 diabetes mellitus, and for pregnant women who have signs and symptoms of deficient thyroid function.⁶ In recent years, some authors have recommended screening all pregnant women for thyroid dysfunction, but such recommendations remain controversial.^3,7,8 Routine screening is not endorsed by the American College of Obstetricians and Gynecologists.⁶

Symptoms overlap typical conditions of pregnancy

The difficulty here is that the characteristic signs and symptoms of hypothyroidism are very similar to physiologic conditions seen in most pregnancies. They include fatigue, constipation, cold intolerance, muscle cramps, hair loss, dry skin, brittle nails, weight gain, intellectual slowness, bradycardia, depression, insomnia, periorbital edema, myxedema, and myxedema coma.⁶ A side-by-side comparison of pregnancy conditions and hypothyroidism symptoms is provided in TABLE 1.

TABLE 1

Distinguishing hypothyroidism from a normal gestation can be challenging

SYMPTOM	HYPOTHYROIDISM	PREGNANCY
Fatigue	•	•
Constipation	•	•
Hair loss	•
Dry skin	•
Brittle nails	•
Weight gain	•	•
Fluid retention	•	•
Bradycardia	•	•
Goiter	•
Carpal tunnel syndrome	•	•

Which laboratory tests are informative?

Because screening is controversial and symptomatology does not reliably distinguish hypothyroidism from normal pregnancy, laboratory tests are the standard for diagnosis. Overt hypothyroidism is diagnosed in a symptomatic patient by elevated TSH level and low levels of FT₄ and free T₃ (FT₃). Subclinical hypothyroidism is defined as elevated TSH with normal FT₄ and FT₃ in an asymptomatic patient. Level changes characteristic of normal pregnancy, overt hypothyroidism, and subclinical hypothyroidism are given in TABLE 2.⁶

 

TABLE 2

Laboratory diagnosis of hypothyroidism

MATERNAL CONDITION	TSH	FREE T3	FREE T4	TOTAL T3	TOTAL T4
Normal pregnancy	No change	No change	↑	↑	↑
Hypothyroidism	↑	↓	↓	↓	↓
Subclinical hypothyroidism	↑	No change	No change	↓	↓
Adapted from American College of Obstetricians and Gynecologists6

What causes hypothyroidism?

The most common cause of hypothyroidism in most of the world is iodine deficiency. In developed countries, however, where lack of iodine in the diet is not a problem, Hashimoto’s thyroiditis, also known as chronic autoimmune thyroiditis, is the most common cause. Hashimoto’s thyroiditis is characterized by the presence of antithyroid antibodies, including both thyroid antimicrosomial and antithyroglobulin antibodies. Both iodine deficiency and Hashimoto’s thyroiditis are associated with goiter.⁵ Other causes of hypothyroidism include radioactive iodine therapy for Graves’ disease, a condition we will discuss in Part 2 of this series in February; thyroidectomy; viral thyroiditis; pituitary tumors; Sheehan’s syndrome; and a number of medications.

Causes of hypothyroidism are summarized in TABLE 3.³

TABLE 3

Causes of hypothyroidism

Iodine deficiency
Hashimoto’s thyroiditis
Radioactive iodine therapy
Thyroidectomy
Viral thyroiditis
Sheehan’s syndrome
Medications Thionamides Lithium Drugs that inhibit absorption of thyroid medication - Ferrous sulfate - Sucrafate - Cholestyramine - Antacids (aluminum hydroxide)

Effects vary by medication

Medications alter thyroid function in different ways. Iodine and lithium inhibit thyroid function and, along with dopamine antagonists, increase TSH levels. Conversely, thioamides, glucocorticoids, dopamine agonists, and somatostatins decrease TSH levels. Finally, ferrous sulfate, sucrafate, cholestyramine, and aluminum hydroxide antacids all inhibit gastrointestinal absorption of thyroid hormone and therefore should not be taken within 4 hours of thyroid medication.⁶

Maternal hypothyroidism: Effects on fetus, newborn

The impact of maternal hypothyroidism on the fetus depends on the severity of the condition.

• Uncontrolled hypothyroidism. The consequences of this condition can be dire. The possibilities include intrauterine fetal demise and stillbirth, preterm delivery, low birth weight, preeclampsia, and developmental anomalies including reduced intelligence quotient (IQ).^1,2,4,6 Blazer and colleagues correlated intrauterine growth with maternal TSH and fetal FT₄ and concluded that impaired intrauterine growth is related to abnormal thyroid function and might reflect an insufficient level of hormone production by hypothyroid mothers during pregnancy.⁹ Maternal and congenital hypothyroidism resulting from severe iodine deficiency are associated with profound neurologic impairment and mental retardation.^1,3,10 If the condition is left untreated, cretinism can occur. Congenital cretinism is associated with growth failure, mental retardation, and other neuropsychologic deficits including deaf-mutism.^3,4 However, if cretinism is identified and treated in the first 3 months of life, near-normal growth and intelligence can be expected.⁶ For this reason, all 50 states and the District of Columbia require newborn screening for congenital hypothyroidism.⁶
• Asymptomatic overt hypothyroidism. Several studies have evaluated neonatal outcomes in pregnancy complicated by asymptomatic overt hypothyroidism—that is, women who had previously been diagnosed with hypothyroidism, who have abnormal TSH and FT₄ levels, but who do not have symptoms. Pop and colleagues have shown impaired psychomotor development at 10 months in infants born to mothers who had low T₄ during the first 12 weeks of gestation.⁷ Haddow and colleagues correlated elevated maternal TSH levels at less than 17 weeks’ gestation with low IQ scores in the offspring at 7 to 9 years of age.⁸ Klein and colleagues demonstrated an inverse correlation between a woman’s TSH level during pregnancy and the IQ of her offspring.¹¹ Kooistra and colleagues confirmed that maternal hypothyroxinemia is a risk for neurodevelopmental abnormalities that can be identified as early as 3 weeks of age.¹² Studies of this relationship are summarized in TABLE 4.
• Subclinical hypothyroidism. During the past decade, researchers have focused attention on neonatal neurologic function in infants born to mothers who had subclinical disease. Mitchell and Klein evaluated the prevalence of subclinical hypothyroidism at less than 17 weeks’ gestation and subsequently compared the IQs in these children with those of controls.⁴ They found the mean and standard-deviation IQs of the children in the control and treated groups to be significantly higher than those of the children whose mothers were not treated. Casey and colleagues evaluated pregnancy outcomes in women who had undiagnosed subclinical hypothyroidism.¹⁰ They found that such pregnancies were more likely to be complicated by placental abruption and preterm birth, and speculated that the reduced IQ demonstrated in the Mitchell and Klein study might have been related to the effects of prematurity.

TABLE 4

Fetal and neonatal effects of asymptomatic overt hypothyroidism

STUDY	LABORATORY FINDINGS	OUTCOMES AND RECOMMENDATIONS
Kooistra et al12	↓ FT4	Maternal hypothyroxinemia is a risk for neurodevelopmental abnormalities as early as 3 weeks of age
Casey et al10	↑ TSH	Pregnancies with undiagnosed subclinical hypothyroidism were more likely to be complicated by placental abruption and preterm birth. The reduced IQ seen in a prior study (Mitchell and Klein4) may be related to effects of prematurity
Mitchell and Klein4	↑ TSH	The mean and standard deviation of IQs of the children of treated mothers with hypothyroidism and the control group were significantly higher than those for children of untreated hypothyroid women
Blazer et al9	↑ maternal TSH, ↑ fetal FT4	Impaired intrauterine growth may reflect insufficient levels of hormone replacement therapy in hypothyroid mothers during pregnancy
Pop et al7	↓ FT4	Impaired psychomotor development at 10 months of age in offspring of mothers with low T4 at ≤12 weeks
Haddow et al8	↑ TSH, ↓ FT4	Elevated TSH levels at <17 weeks’ gestation are associated with low IQ scores at 7 to 9 years of age. Routine screening for thyroid deficiency may be warranted
Klein et al11	↑ TSH, ↓ FT4, ↓ TT4	Inverse correlation between TSH during pregnancy and IQ of offspring
FT4=free thyroxine, TSH=thyroid-stimulating hormone, TT4=total thyroxine

 

Managing hypothyroidism in pregnancy

The treatment of choice for correction of hypothyroidism is synthetic T₄, or levothyroxine (Levothyroid, Levoxyl, Synthroid, and Unithroid). Initial treatment in the nonpregnant patient is 1.7 μg/kg/day or 12.5 to 25 μg/day adjusted by 25 μg/day every 2 to 4 weeks until a euthyroid state is achieved.¹³

Patients who were on thyroxine therapy before pregnancy should increase the dose by 30% once pregnancy is confirmed.^1,5 Serum thyrotropin levels should be monitored every 4 weeks to maintain a TSH level between 1 and 2 mU/L and FT₄ in upper third of normal.¹ Once a euthyroid state has been achieved, thyrotropin levels should be monitored every trimester until delivery. FIGURE 2 provides an algorithm for management of hypothyroidism in pregnancy.

FIGURE 2 During pregnancy, thyroid function merits regular monitoring, fine-tuning of treatment

Postpartum thyroiditis

About 5% of all obstetrical patients develop postpartum thyroiditis. Approximately 45% of these women present with hypothyroidism, with the rest evenly divided between thyrotoxicosis (hyperthyroidism) and thyrotoxicosis followed by hypothyroidism. Unfortunately, the signs and symptoms of hypo- and hyperthyroidism are similar to the postpartum state. Many of these patients are not diagnosed. A high index of suspicion warrants thyroid function testing. Women who have a history of type 1 diabetes mellitus have a 25% chance of developing postpartum thyroid dysfunction.

The diagnosis is made by documenting abnormal levels of TSH and FT₄. Postpartum hyperthyroidism may be diagnosed by the presence of antimicrosomal or thyroperoxidase antithyroid peroxidase antibodies. Goiter may be present in up to 50% of patients.

Postpartum thyroiditis has two phases

The first phase, also known as the thyrotoxic phase, occurs 1 to 4 months after delivery when transient thyrotoxicosis develops from excessive release of thyroid hormones. The most common symptoms with early postpartum thyroiditis are fatigue and palpitations. Approximately 67% of these women will return to a euthyroid state, and thioamide therapy is generally considered ineffective. Hypothyroidism can develop within 1 month of the onset of thyroiditis.

The second phase occurs between 4 and 8 months postpartum, and these women present with hypothyroidism. Thyromegaly and associated symptoms are common. Unlike the first (thyrotoxic) phase, medical treatment is recommended. Thyroxine treatment should be initiated and maintained for 6 to 12 months. Postpartum thyroiditis carries a 30% risk of recurrence.¹⁴

Postpartum thyroiditis may be associated with depression or aggravate symptoms of depression, although the data on this association are conflicting. The largest study addressing this issue concluded that there was no difference in the clinical and psychiatric signs and symptoms between postpartum thyroiditis and controls.¹⁵ Nevertheless, it would seem prudent to evaluate thyroid function in postpartum depression if other signs of thyroid dysfunction are present.

The authors report no financial relationships relevant to this article.

A pregnant woman whose thyroid gland isn’t doing its job presents a serious management problem for her obstetrician. If she has overt hypothyroidism, seen in between 0.3% and 2.5% of pregnancies, active intervention is required to prevent serious damage to the fetus.^1,2 Even if she has subclinical disease, seen in 2% to 3% of pregnancies, current research indicates that intervention may be indicated.

Fetal thyroxine requirements increase as early as 5 weeks of gestation, when the fetus is still dependent on maternal thyroxine. A deficiency of maternal thyroxine can have severe adverse outcomes, affecting the course of the pregnancy and the neurologic development of the fetus. To prevent such sequelae, patients who were on thyroid medication before pregnancy should increase the dosage by 30% once pregnancy is confirmed, and hypothyroidism that develops in pregnancy should be managed aggressively and meticulously.

Here, we’ll examine the published research to advise you on evidence-based approaches for diagnosis and management of this complex condition.

Maternal thyroid function

An elaborate negative-feedback loop prevails before pregnancy

In a nonpregnant woman, thyroid function is controlled by a negative-feedback loop that works like this:

• The hypothalamus releases thyroid-releasing hormone (TRH)
• TRH acts on the pituitary gland to release thyroid-stimulating hormone (TSH)
• TSH, in turn, acts on the thyroid gland to release the thyroid hormones iodothyronine (T₃) and thyroxine (T₄) that regulate metabolism
• TRH and TSH concentrations are inversely related to T₃ and T₄ concentrations. That is, the more TRH and TSH circulating in the blood stream, the less T₃ and T₄ will be produced by the thyroid gland³
• Almost all (approximately 99%) circulating T₃ and T₄ is bound to a protein called thyroxine-binding globulin (TBG). Only 1% of these hormones circulate in the free form, and only the free forms are biologically active.³

This relationship is illustrated in FIGURE 1.

FIGURE 1 Thyroid physiology and the impact of pregnancy

Pregnancy reduces free forms of T₃ and T₄, and increases TSH slightly

Pregnancy alters thyroid function in significant ways:

• Increases in circulating estrogen lead to the production of more TBG
• When TBG increases, more T₃ and T₄ are bound and fewer free forms of these hormones are available
• Because the total T₃ (TT₃) and total free T₄ (TT₄) are decreased in pregnancy, they are not good measures of thyroid function. Maternal thyroid function in pregnancy should be monitored using free T₄ (FT₄) and TSH levels
• Increased TBG also leads to a slight increase in TSH between the first trimester and term
• Human chorionic gonadotropin (hCG) concentrations also increase in pregnancy. Because hCG has thyrotropin-like activity, these higher levels cause a transient decrease in TSH by suppression of TSH production between approximately 8 and 14 weeks of gestation.

Fetal thyroid function

During early gestation, the fetus receives thyroid hormone from the mother.¹ Maternal T₄ crosses the placenta actively—the only hormone that does so.⁴ The fetus’s need for thyroxine starts to increase as early as 5 weeks of gestation.⁵

Fetal thyroid development does not begin until 10 to 12 weeks of gestation, and then continues until term. The fetus relies on maternal T₄ exclusively before 12 weeks and partially thereafter for normal fetal neurologic development. It follows that maternal hypothyroidism could be detrimental to fetal development if not detected and corrected very early in gestation.

How (and whom) to screen for maternal hypothyroidism

Routine screening has been recommended for women who have infertility, menstrual disorders, or type 1 diabetes mellitus, and for pregnant women who have signs and symptoms of deficient thyroid function.⁶ In recent years, some authors have recommended screening all pregnant women for thyroid dysfunction, but such recommendations remain controversial.^3,7,8 Routine screening is not endorsed by the American College of Obstetricians and Gynecologists.⁶

Symptoms overlap typical conditions of pregnancy

The difficulty here is that the characteristic signs and symptoms of hypothyroidism are very similar to physiologic conditions seen in most pregnancies. They include fatigue, constipation, cold intolerance, muscle cramps, hair loss, dry skin, brittle nails, weight gain, intellectual slowness, bradycardia, depression, insomnia, periorbital edema, myxedema, and myxedema coma.⁶ A side-by-side comparison of pregnancy conditions and hypothyroidism symptoms is provided in TABLE 1.

TABLE 1

Distinguishing hypothyroidism from a normal gestation can be challenging

SYMPTOM	HYPOTHYROIDISM	PREGNANCY
Fatigue	•	•
Constipation	•	•
Hair loss	•
Dry skin	•
Brittle nails	•
Weight gain	•	•
Fluid retention	•	•
Bradycardia	•	•
Goiter	•
Carpal tunnel syndrome	•	•

Which laboratory tests are informative?

Because screening is controversial and symptomatology does not reliably distinguish hypothyroidism from normal pregnancy, laboratory tests are the standard for diagnosis. Overt hypothyroidism is diagnosed in a symptomatic patient by elevated TSH level and low levels of FT₄ and free T₃ (FT₃). Subclinical hypothyroidism is defined as elevated TSH with normal FT₄ and FT₃ in an asymptomatic patient. Level changes characteristic of normal pregnancy, overt hypothyroidism, and subclinical hypothyroidism are given in TABLE 2.⁶

 

TABLE 2

Laboratory diagnosis of hypothyroidism

MATERNAL CONDITION	TSH	FREE T3	FREE T4	TOTAL T3	TOTAL T4
Normal pregnancy	No change	No change	↑	↑	↑
Hypothyroidism	↑	↓	↓	↓	↓
Subclinical hypothyroidism	↑	No change	No change	↓	↓
Adapted from American College of Obstetricians and Gynecologists6

What causes hypothyroidism?

The most common cause of hypothyroidism in most of the world is iodine deficiency. In developed countries, however, where lack of iodine in the diet is not a problem, Hashimoto’s thyroiditis, also known as chronic autoimmune thyroiditis, is the most common cause. Hashimoto’s thyroiditis is characterized by the presence of antithyroid antibodies, including both thyroid antimicrosomial and antithyroglobulin antibodies. Both iodine deficiency and Hashimoto’s thyroiditis are associated with goiter.⁵ Other causes of hypothyroidism include radioactive iodine therapy for Graves’ disease, a condition we will discuss in Part 2 of this series in February; thyroidectomy; viral thyroiditis; pituitary tumors; Sheehan’s syndrome; and a number of medications.

Causes of hypothyroidism are summarized in TABLE 3.³

TABLE 3

Causes of hypothyroidism

Iodine deficiency
Hashimoto’s thyroiditis
Radioactive iodine therapy
Thyroidectomy
Viral thyroiditis
Sheehan’s syndrome
Medications Thionamides Lithium Drugs that inhibit absorption of thyroid medication - Ferrous sulfate - Sucrafate - Cholestyramine - Antacids (aluminum hydroxide)

Effects vary by medication

Medications alter thyroid function in different ways. Iodine and lithium inhibit thyroid function and, along with dopamine antagonists, increase TSH levels. Conversely, thioamides, glucocorticoids, dopamine agonists, and somatostatins decrease TSH levels. Finally, ferrous sulfate, sucrafate, cholestyramine, and aluminum hydroxide antacids all inhibit gastrointestinal absorption of thyroid hormone and therefore should not be taken within 4 hours of thyroid medication.⁶

Maternal hypothyroidism: Effects on fetus, newborn

The impact of maternal hypothyroidism on the fetus depends on the severity of the condition.

• Uncontrolled hypothyroidism. The consequences of this condition can be dire. The possibilities include intrauterine fetal demise and stillbirth, preterm delivery, low birth weight, preeclampsia, and developmental anomalies including reduced intelligence quotient (IQ).^1,2,4,6 Blazer and colleagues correlated intrauterine growth with maternal TSH and fetal FT₄ and concluded that impaired intrauterine growth is related to abnormal thyroid function and might reflect an insufficient level of hormone production by hypothyroid mothers during pregnancy.⁹ Maternal and congenital hypothyroidism resulting from severe iodine deficiency are associated with profound neurologic impairment and mental retardation.^1,3,10 If the condition is left untreated, cretinism can occur. Congenital cretinism is associated with growth failure, mental retardation, and other neuropsychologic deficits including deaf-mutism.^3,4 However, if cretinism is identified and treated in the first 3 months of life, near-normal growth and intelligence can be expected.⁶ For this reason, all 50 states and the District of Columbia require newborn screening for congenital hypothyroidism.⁶
• Asymptomatic overt hypothyroidism. Several studies have evaluated neonatal outcomes in pregnancy complicated by asymptomatic overt hypothyroidism—that is, women who had previously been diagnosed with hypothyroidism, who have abnormal TSH and FT₄ levels, but who do not have symptoms. Pop and colleagues have shown impaired psychomotor development at 10 months in infants born to mothers who had low T₄ during the first 12 weeks of gestation.⁷ Haddow and colleagues correlated elevated maternal TSH levels at less than 17 weeks’ gestation with low IQ scores in the offspring at 7 to 9 years of age.⁸ Klein and colleagues demonstrated an inverse correlation between a woman’s TSH level during pregnancy and the IQ of her offspring.¹¹ Kooistra and colleagues confirmed that maternal hypothyroxinemia is a risk for neurodevelopmental abnormalities that can be identified as early as 3 weeks of age.¹² Studies of this relationship are summarized in TABLE 4.
• Subclinical hypothyroidism. During the past decade, researchers have focused attention on neonatal neurologic function in infants born to mothers who had subclinical disease. Mitchell and Klein evaluated the prevalence of subclinical hypothyroidism at less than 17 weeks’ gestation and subsequently compared the IQs in these children with those of controls.⁴ They found the mean and standard-deviation IQs of the children in the control and treated groups to be significantly higher than those of the children whose mothers were not treated. Casey and colleagues evaluated pregnancy outcomes in women who had undiagnosed subclinical hypothyroidism.¹⁰ They found that such pregnancies were more likely to be complicated by placental abruption and preterm birth, and speculated that the reduced IQ demonstrated in the Mitchell and Klein study might have been related to the effects of prematurity.

TABLE 4

Fetal and neonatal effects of asymptomatic overt hypothyroidism

STUDY	LABORATORY FINDINGS	OUTCOMES AND RECOMMENDATIONS
Kooistra et al12	↓ FT4	Maternal hypothyroxinemia is a risk for neurodevelopmental abnormalities as early as 3 weeks of age
Casey et al10	↑ TSH	Pregnancies with undiagnosed subclinical hypothyroidism were more likely to be complicated by placental abruption and preterm birth. The reduced IQ seen in a prior study (Mitchell and Klein4) may be related to effects of prematurity
Mitchell and Klein4	↑ TSH	The mean and standard deviation of IQs of the children of treated mothers with hypothyroidism and the control group were significantly higher than those for children of untreated hypothyroid women
Blazer et al9	↑ maternal TSH, ↑ fetal FT4	Impaired intrauterine growth may reflect insufficient levels of hormone replacement therapy in hypothyroid mothers during pregnancy
Pop et al7	↓ FT4	Impaired psychomotor development at 10 months of age in offspring of mothers with low T4 at ≤12 weeks
Haddow et al8	↑ TSH, ↓ FT4	Elevated TSH levels at <17 weeks’ gestation are associated with low IQ scores at 7 to 9 years of age. Routine screening for thyroid deficiency may be warranted
Klein et al11	↑ TSH, ↓ FT4, ↓ TT4	Inverse correlation between TSH during pregnancy and IQ of offspring
FT4=free thyroxine, TSH=thyroid-stimulating hormone, TT4=total thyroxine

 

Managing hypothyroidism in pregnancy

The treatment of choice for correction of hypothyroidism is synthetic T₄, or levothyroxine (Levothyroid, Levoxyl, Synthroid, and Unithroid). Initial treatment in the nonpregnant patient is 1.7 μg/kg/day or 12.5 to 25 μg/day adjusted by 25 μg/day every 2 to 4 weeks until a euthyroid state is achieved.¹³

Patients who were on thyroxine therapy before pregnancy should increase the dose by 30% once pregnancy is confirmed.^1,5 Serum thyrotropin levels should be monitored every 4 weeks to maintain a TSH level between 1 and 2 mU/L and FT₄ in upper third of normal.¹ Once a euthyroid state has been achieved, thyrotropin levels should be monitored every trimester until delivery. FIGURE 2 provides an algorithm for management of hypothyroidism in pregnancy.

FIGURE 2 During pregnancy, thyroid function merits regular monitoring, fine-tuning of treatment

Postpartum thyroiditis

About 5% of all obstetrical patients develop postpartum thyroiditis. Approximately 45% of these women present with hypothyroidism, with the rest evenly divided between thyrotoxicosis (hyperthyroidism) and thyrotoxicosis followed by hypothyroidism. Unfortunately, the signs and symptoms of hypo- and hyperthyroidism are similar to the postpartum state. Many of these patients are not diagnosed. A high index of suspicion warrants thyroid function testing. Women who have a history of type 1 diabetes mellitus have a 25% chance of developing postpartum thyroid dysfunction.

The diagnosis is made by documenting abnormal levels of TSH and FT₄. Postpartum hyperthyroidism may be diagnosed by the presence of antimicrosomal or thyroperoxidase antithyroid peroxidase antibodies. Goiter may be present in up to 50% of patients.

Postpartum thyroiditis has two phases

The first phase, also known as the thyrotoxic phase, occurs 1 to 4 months after delivery when transient thyrotoxicosis develops from excessive release of thyroid hormones. The most common symptoms with early postpartum thyroiditis are fatigue and palpitations. Approximately 67% of these women will return to a euthyroid state, and thioamide therapy is generally considered ineffective. Hypothyroidism can develop within 1 month of the onset of thyroiditis.

The second phase occurs between 4 and 8 months postpartum, and these women present with hypothyroidism. Thyromegaly and associated symptoms are common. Unlike the first (thyrotoxic) phase, medical treatment is recommended. Thyroxine treatment should be initiated and maintained for 6 to 12 months. Postpartum thyroiditis carries a 30% risk of recurrence.¹⁴

Postpartum thyroiditis may be associated with depression or aggravate symptoms of depression, although the data on this association are conflicting. The largest study addressing this issue concluded that there was no difference in the clinical and psychiatric signs and symptoms between postpartum thyroiditis and controls.¹⁵ Nevertheless, it would seem prudent to evaluate thyroid function in postpartum depression if other signs of thyroid dysfunction are present.

Thrombophilia has been widely investigated—and that may be one of the main challenges in detecting and managing it during pregnancy: Numerous studies have yielded different estimates of the incidence of various clotting disorders in pregnancy—itself a hypercoagulable state—and conflicting screening and prevention recommendations. The authors offer whatever recommendations have emerged.

Why thrombophilia matters

During pregnancy, clotting factors I, VII, VIII, IX, and X rise; protein S and fibrinolytic activity diminish; and resistance to activated protein C develops.^1,2 When compounded by thrombophilia—a broad spectrum of coagulation disorders that increase the risk for venous and arterial thrombosis—the hypercoagulable state of pregnancy may increase the risk of thromboembolism during pregnancy or postpartum.³

Pulmonary embolism is the leading cause of maternal death in the United States.¹ Concern about this lethal sequela has led to numerous recommendations for screening and subsequent prophylaxis and therapy.

Two types

Thrombophilias are inherited or acquired (TABLE 1). The most common inherited disorders during pregnancy are mutations in factor V Leiden, prothrombin gene, and methylenetetrahydrofolate reductase (MTHFR) (TABLE 2). Caucasians have a higher rate of genetic thrombophilias than other racial groups.

Antiphospholipid antibody (APA) syndrome is the most common acquired thrombophilia of pregnancy. It can be diagnosed when the immunoglobulin G or immunoglobulin M level is 20 g per liter or higher, when lupus anticoagulant is present, or both.⁴

TABLE 1

Thrombophilias are inherited or acquired

INHERITED Protein S deficiency Protein C deficiency Protein Z deficiency Antithrombin III Factor V Leiden mutation MTHFR mutation Homozygosity to MTHFR C677T Homozygosity to 4G/4G mutation in PAI-1 gene Prothrombin G20210A mutation Polymorphisms in thrombomodulin gene
ACQUIRED Antiphospholipid antibody syndrome Hyperhomocysteinemia
MTHFR=methylenetetrahydrofolate reductase

TABLE 2

Prevalence of thrombophilias in women with normal pregnancy outcomes

THROMBOPHILIA	PREVALENCE (%)
Factor V Leiden mutation	2–10
MTHFR mutation	8–16
Prothrombin gene mutation	2–6
Protein C and S deficiencies	0.2–1.0*
Anticardiolipin antibodies	1–7
* Combined rate
MTHFR=methylenetetrahydrofolate reductase

Link to adverse pregnancy outcomes

During the past 2 decades, several epidemiologic and case-control studies have explored the association between thrombophilias and adverse pregnancy outcomes,^2-6 which include the following maternal effects:

• Venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and cerebral vein thrombosis
  
• Arterial thrombosis (peripheral, cerebral)
  
• Severe preeclampsia
  

Placental and fetal abnormalities include:

• Thrombosis and infarcts
  
• Abruptio placenta
  
• Recurrent miscarriage
  
• Fetal growth restriction
  
• Death
  
• Stroke
  

Preeclampsia and thrombophilia

The association between preeclampsia and thrombophilia remains somewhat unclear because of inconsistent data. Because of this, we do not recommend routine screening for thrombophilia in women with preeclampsia.

An association between inherited thrombophilias and preeclampsia was reported by Dekker et al in 1995.⁷ Since then, numerous retrospective and case-controlled studies have assessed the incidence of thrombophilia in women with severe preeclampsia.^7-25 Their findings range from:

• Factor V Leiden: 3.7% to 26.5%
  
• Prothrombin gene mutation: 0 to 10.8%
  
• Protein S deficiency: 0.7% to 24.7%
  
• MTHFR variant: 6.7% to 24.0%
  

A meta-analysis of all case-controlled studies suggests that factor V Leiden is the only thrombophilia associated with an increased risk of preeclampsia.⁵ However, almost all studies included in this analysis involved women with severe preeclampsia who were referred to a tertiary-care obstetric center, whereas women in the control groups had a normal term pregnancy. These studies were therefore subject to selection bias because they overestimated the rate of thrombophilias in study groups and underestimated it in control groups.

Other points of contention are the varying levels of severity of preeclampsia and of gestational age at delivery, as well as racial differences. For example, most studies found an association between thrombophilia and severe preeclampsia at less than 34 weeks’ gestation, but not between thrombophilia and mild preeclampsia at term. In addition, a recent prospective observational study at multiple centers involving 5,168 women found a factor V Leiden mutation rate of 6% among white women, 2.3% among Asians, 1.6% in Hispanics, and 0.8% in African Americans.⁸ This large study found no association between thrombophilia and preeclampsia in these women. Therefore, based on available data, we do not recommend routine screening for factor V Leiden in women with severe preeclampsia.

Preeclampsia and APA syndrome

In 1989, Branch et al²⁶ first reported an association between APA syndrome and severe preeclampsia at less than 34 weeks’ gestation. They recommended that women with severe preeclampsia at this gestational age be screened for APA syndrome and treated when the screen is positive. Several later studies supported or refuted the association between APA syndrome and preeclampsia,^26,27 and a recent report concluded that routine testing for APA syndrome in women with early-onset preeclampsia is unwarranted.²⁶ Therefore, we do not recommend routine screening for APA in women with severe preeclampsia.

 

No need to screen women with abruptio placenta

The placental circulation is comparable to venous circulation, with low pressure and low flow velocity rendering it susceptible to thrombotic complications at the maternal–placental interface and consequent premature separation of the placenta.

It is difficult to confirm an association between thrombophilia and abruptio placenta because of confounding variables such as chronic hypertension, cigarette and cocaine use, and advanced maternal age.³ Studies reviewing this association are scarce, and screening for thrombophilia is discouraged in pregnancies marked by abruptio placenta.

Kupferminc et al²⁸ found that 25%, 20%, and 15% of thrombophilia patients with placental abruption had mutations in factor V Leiden, prothrombin gene, and MTHFR, respectively. In contrast, Prochazka et al²⁹ found 15.7% of their cohort of patients with abruptio placenta to have factor V Leiden mutation.

A large prospective, observational study of more than 5,000 asymptomatic pregnant women at multiple centers found no association between abruptio placenta and factor V Leiden mutation.⁸ Nor were there cases of abruptio placenta among 134 women who were heterozygous for factor V Leiden.

And no routine screening in cases of IUGR

Routine screening for thrombophilias in women with intrauterine growth restriction (IUGR) is not recommended. One reason: The prevalence of thrombophilias in these women ranges widely, depending on the study cited: from 2.8% to 35% for factor V Leiden and 2.8% to 15.4% for prothrombin gene mutation (TABLE 3). In addition, in contrast to earlier studies, a large case-control trial by Infante-Rivard et al³⁰ found no increased risk of IUGR in women with thrombophilias, except for a subgroup of women with the MTHFR variant who did not take a prenatal multivitamin.

A recent meta-analysis of case-control studies by Howley et al³¹ found a significant association between factor V Leiden, the prothrombin gene variant, and IUGR, but the investigators cautioned that this strong association may be driven by small, poor-quality studies that yield extreme associations. A multicenter observational study by Dizon-Townson et al⁸ found no association between thrombophilia and IUGR in asymptomatic gravidas.

TABLE 3

Incidence of thrombophilias in women with intrauterine growth restriction

STUDY	FACTOR V LEIDEN (%)		PROTHROMBIN GENE MUTATION (%)
	IUGR	CONTROLS	IUGR	CONTROLS
Kupferminc et al50	5/44 (11.4)	7/110 (6.4)	5/44 (11.4)	3/110 (2.7)
Infante-Rivard et al30	22/488 (4.5)	18/470 (3.8)	12/488 (2.5)	11/470 (2.3)
Verspyck et al51	4/97 (4.1)	1/97 (1)	3/97 (3.1)	1/97 (1)
McCowan et al52	4/145 (2.8)	11/290 (3.8)	4/145 (2.8)	9/290 (3.1)
Dizon-Townson et al*10	6/134 (4.5)	233/4,753 (4.9)	NR	NR
Kupferminc**34	9/26 (35)	2/52 (3.8)	4/26 (15.4)	2/52 (3.8)
*
** Mid-trimester severe intrauterine growth restriction
IUGR=intrauterine growth restriction, NR=not recorded
SOURCE: Adapted from Clin Obstet Gynecol. 2006;49:850–860

Fetal loss is a complication of thrombophilia

One in 10 pregnancies ends in early death of the fetus (before 20 weeks), and 1 in 200 gestations ends in late fetal loss.³² When fetal loss occurs in the second and third trimesters, it is due to excessive thrombosis of the placental vessels, placental infarction, and secondary uteroplacental insufficiency.^2,33 Women who are carriers of factor V or prothrombin gene mutations are at higher risk of late fetal loss than noncarriers are (TABLE 4).

Fetal loss is a well-established complication in women with thrombophilia, but not all thrombophilias are associated with fetal loss, according to a meta-analysis of 31 studies.³³ In women with thrombophilia, first-trimester loss is generally associated with factor V Leiden, prothrombin gene mutation, and activated protein C resistance. Late, nonrecurrent fetal loss is associated with factor V Leiden, prothrombin gene mutation, and protein S deficiency.³³

TABLE 4

Incidence of factor V Leiden mutation in women with recurrent pregnancy loss

STUDY	PATIENT SELECTION	PATIENTS (%)	CONTROLS (%)	ODDS RATIO	95% CONFIDENCE INTERVAL
Grandone et al53	≥2 unexplained fetal losses, other causes excluded	7/43 (16.3)	5/118 (4.2)	4.4	1.3–14.7
Ridker et al54	Recurrent, spontaneous abortion, other causes not excluded	9/113 (8)	16/437 (3.7)	2.3	1.0–5.2
Sarig et al55	≥3 first- or second-trimester losses or ≥1 intrauterine fetal demise, other causes excluded*	96/145 (66)	41/145 (28)	5.0	3.0–8.5
* Excluded chromosomal abnormalities, infections, anatomic alterations, and endocrine dysfunction

History of adverse outcomes? Offer screening

It is well established that women with a history of fetal death, severe preeclampsia, IUGR, abruptio placenta, or recurrent miscarriage have an increased risk of recurrence in subsequent pregnancies.^3,30,34-36 The rate of recurrence of any of these outcomes may be as high as 46% with a history of 2 or more adverse outcomes, even before any thrombophilia is taken into account.³ Although there are few studies describing the rate of recurrence of adverse pregnancy outcomes in women with thrombophilia and a previous adverse outcome (TABLE 5), it appears to range from 66% to 83% in untreated women.^3,37

Based on these findings, some authors recommend screening for thrombophilia in women who have had adverse pregnancy outcomes^3,9,38 and prophylactic therapy in subsequent pregnancies when the test is positive. Therapy includes low-dose aspirin with or without subcutaneous heparin, as well as folic acid and vitamin B₆ supplements, according to the type of thrombophilia present as well as the nature of the previous adverse outcome.

 

TABLE 5

How women with a previous adverse outcome fare on anticoagulation therapy

STUDY	PATIENTS	PREVIOUS ADVERSE PREGNANCY OUTCOME	ANTICOAGULANT	OUTCOME IN CURRENT PREGNANCY
Riyazi et al9	26	Uteroplacental insufficiency	LMWH and low-dose aspirin	Decreased recurrence of preeclampsia (85% to 38%) and IUGR (54% to 15%)
Brenner37	50	≥3 first-trimester recurrent pregnancy losses with thrombophilia	LMWH	Higher live birth rate compared with historical controls (75% vs 20%)
Ogueh et al48	24	Previous adverse pregnancy outcome plus history of thromboembolic disease, family history of thrombophilia	UFH	No significant mprovement
Kupferminc et al38	33	Thrombophilia with history of preeclampsia or IUGR	LMWH and low-dose aspirin	With treatment, 3% recurrence of preeclampsia
Grandone et al53	25	Repeated pregnancy loss, gestational hypertension, HELLP, or IUGR	UFH or LMWH	90.3% treated with LMWH had good obstetric outcome
Paidas et al3	158	Fetal loss, IUGR, placental abruption, or preeclampsia	UFH or LMWH	80% reduction in risk of adverse pregnancy outcome, compared with historical controls (OR, 0.21; 95% CI, 0.11–0.39)
HELLP=hemolysis, elevated liver enzymes, and low platelets; IUGR=intrauterine growth restriction; LMWH=low-molecular-weight heparin; UFH=unfractionated heparin
SOURCE: Adapted from Am J Perinatol. 2006;23:499–506

No randomized trials on prophylaxis

We lack randomized trials evaluating thromboprophylaxis for prevention of recurrent adverse pregnancy outcomes in women with previous severe preeclampsia, IUGR, or abruptio placenta in association with genetic thrombophilia. Therefore, any recommendation to treat such women with low-molecular-weight heparin with or without low-dose aspirin in subsequent pregnancies should remain empiric and/or prescribed after appropriate counseling of the patients regarding risks and benefits.

TABLE 6 summarizes the risk of thromboembolism in women with thrombophilia—both for asymptomatic patients and for those with a history of thromboembolism. These percentages should be used when counseling women about their risk and determining management and therapy.

TABLE 6

Risk of thromboembolism during pregnancy and postpartum in women with thrombophilia

THROMBOPHILIA	RISK (%)
	ASYMPTOMATIC WOMEN	HISTORY OF VENOUS THROMBOEMBOLISM
Factor V Leiden
Heterozygous	0.2	10
Homozygous	1–2	15–20
Prothrombin gene mutation
Heterozygous	0.5	10
Homozygous	2.3	20
Factor V Leiden and prothrombin gene mutation	5	20
Antithrombin deficiency	7	40
Protein C deficiency	0.5	5–15
Protein S deficiency	0.1	Unknown

Prophylaxis for APA syndrome and recurrent pregnancy loss

Several randomized trials have described the use of low-dose aspirin and heparin in women with APA syndrome and a history of recurrent pregnancy loss, although the results are inconsistent (TABLE 7).^39-45 The inconsistency may be due to varying definitions of APA syndrome and gestational age at the time of randomization, as well as the population studied (previous thromboembolism, presence or absence of lupus anticoagulant, level of titer of anticardiolipin antibodies, presence or absence of previous stillbirth). Nevertheless, we recommend that women with true APA syndrome (presence of lupus anticoagulant, high titers of immunoglobulin G, history of thromboembolism or recurrent stillbirth) receive prophylaxis with low-dose aspirin, with subcutaneous heparin added once fetal cardiac activity is documented.⁴⁶

TABLE 7

Live births in women with APA and a history of fetal loss

STUDY	TREATMENT	CONTROL	NO. OF LIVE BIRTHS (%)
			TREATED WOMEN	CONTROL GROUP
Cowchock et al39	Aspirin/heparin	Aspirin/prednisone	9/12 (75)	6/8 (75)
Laskin et al40	Aspirin/prednisone	Placebo	25/42 (60)	24/46 (52)
Kutteh41	Aspirin/heparin	Aspirin only	20/25 (80)	11/25 (44)
Rai et al42	Aspirin/heparin	Aspirin only	32/45 (71)	19/45 (42)
Silver et al43	Aspirin/prednisone	Aspirin only	12/12 (100)	22/22 (100)
Pattison et al44	Aspirin	Placebo	16/20 (80)	17/20 (85)
Farquharson et al45	Aspirin/LMWH	Aspirin only	40/51 (78)	34/47 (72)
LMWH=low-molecular-weight heparin

Genetic thrombophilias

Few published studies describe prophylactic use of low-molecular-weight heparin with or without low-dose aspirin in women with genetic thrombophilia and a history of adverse pregnancy outcomes. All but 1 of these studies are observational, comparing outcome in the treated pregnancy with that of previously untreated gestations in the same woman.^{3,9,38,44,45,47} These studies included a limited number of women and a heterogeneous group of patients with various thrombophilias; they also involved different therapies (TABLE 7).^{3,9,38,41,48,49}

Gris et al⁴⁷ performed a randomized trial in 160 women with at least 1 prior fetal loss after 10 weeks’ gestation who were heterozygous for factor V Leiden or prothrombin G20210A mutation, or had protein S deficiency. Beginning at 8 weeks’ gestation, these women were assigned to treatment with 40 mg of enoxaparin (n=80) or 100 mg of low-dose aspirin (n=80) daily. All women also received 5 mg of folic acid daily.

In the women treated with enoxaparin, 69 (86%) had a live birth, compared with 23 (29%) women treated with low-dose aspirin. The women treated with enoxaparin also had significantly higher median neonatal birth weights and a lower rate of IUGR (10% versus 30%). The authors concluded that women with factor V Leiden, prothrombin gene mutation, or protein S deficiency and a history of fetal loss should receive enoxaparin prophylaxis in subsequent pregnancies.

History of severe preeclampsia, IUGR, or abruptio placenta. No randomized trials have evaluated thromboprophylaxis in women with this history who have genetic thrombophilia. For this reason, any recommendation to treat these women with low-molecular-weight heparin with or without low-dose aspirin in subsequent pregnancies remains empiric. Prophylaxis can be prescribed after an appropriate discussion of risks and benefits with the patient.

Unresolved questions keep management experimental

What is the likelihood that a woman carrying a gene mutation that predisposes her to thrombophilia will have a serious complication during pregnancy? And how safe and effective is prophylaxis?

 

There is a prevailing need for a double-blind placebo-controlled trial to address these questions and evaluate the benefit of heparin in pregnant women with a history of adverse pregnancy outcomes and thrombophilia. Until then, screening and treatment for thrombophilia remain experimental in these women.

The authors report no financial relationships relevant to this article.

Thrombophilia has been widely investigated—and that may be one of the main challenges in detecting and managing it during pregnancy: Numerous studies have yielded different estimates of the incidence of various clotting disorders in pregnancy—itself a hypercoagulable state—and conflicting screening and prevention recommendations. The authors offer whatever recommendations have emerged.

Why thrombophilia matters

During pregnancy, clotting factors I, VII, VIII, IX, and X rise; protein S and fibrinolytic activity diminish; and resistance to activated protein C develops.^1,2 When compounded by thrombophilia—a broad spectrum of coagulation disorders that increase the risk for venous and arterial thrombosis—the hypercoagulable state of pregnancy may increase the risk of thromboembolism during pregnancy or postpartum.³

Pulmonary embolism is the leading cause of maternal death in the United States.¹ Concern about this lethal sequela has led to numerous recommendations for screening and subsequent prophylaxis and therapy.

Two types

Thrombophilias are inherited or acquired (TABLE 1). The most common inherited disorders during pregnancy are mutations in factor V Leiden, prothrombin gene, and methylenetetrahydrofolate reductase (MTHFR) (TABLE 2). Caucasians have a higher rate of genetic thrombophilias than other racial groups.

Antiphospholipid antibody (APA) syndrome is the most common acquired thrombophilia of pregnancy. It can be diagnosed when the immunoglobulin G or immunoglobulin M level is 20 g per liter or higher, when lupus anticoagulant is present, or both.⁴

TABLE 1

Thrombophilias are inherited or acquired

INHERITED Protein S deficiency Protein C deficiency Protein Z deficiency Antithrombin III Factor V Leiden mutation MTHFR mutation Homozygosity to MTHFR C677T Homozygosity to 4G/4G mutation in PAI-1 gene Prothrombin G20210A mutation Polymorphisms in thrombomodulin gene
ACQUIRED Antiphospholipid antibody syndrome Hyperhomocysteinemia
MTHFR=methylenetetrahydrofolate reductase

TABLE 2

Prevalence of thrombophilias in women with normal pregnancy outcomes

THROMBOPHILIA	PREVALENCE (%)
Factor V Leiden mutation	2–10
MTHFR mutation	8–16
Prothrombin gene mutation	2–6
Protein C and S deficiencies	0.2–1.0*
Anticardiolipin antibodies	1–7
* Combined rate
MTHFR=methylenetetrahydrofolate reductase

Link to adverse pregnancy outcomes

During the past 2 decades, several epidemiologic and case-control studies have explored the association between thrombophilias and adverse pregnancy outcomes,^2-6 which include the following maternal effects:

• Venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and cerebral vein thrombosis
  
• Arterial thrombosis (peripheral, cerebral)
  
• Severe preeclampsia
  

Placental and fetal abnormalities include:

• Thrombosis and infarcts
  
• Abruptio placenta
  
• Recurrent miscarriage
  
• Fetal growth restriction
  
• Death
  
• Stroke
  

Preeclampsia and thrombophilia

The association between preeclampsia and thrombophilia remains somewhat unclear because of inconsistent data. Because of this, we do not recommend routine screening for thrombophilia in women with preeclampsia.

An association between inherited thrombophilias and preeclampsia was reported by Dekker et al in 1995.⁷ Since then, numerous retrospective and case-controlled studies have assessed the incidence of thrombophilia in women with severe preeclampsia.^7-25 Their findings range from:

• Factor V Leiden: 3.7% to 26.5%
  
• Prothrombin gene mutation: 0 to 10.8%
  
• Protein S deficiency: 0.7% to 24.7%
  
• MTHFR variant: 6.7% to 24.0%
  

A meta-analysis of all case-controlled studies suggests that factor V Leiden is the only thrombophilia associated with an increased risk of preeclampsia.⁵ However, almost all studies included in this analysis involved women with severe preeclampsia who were referred to a tertiary-care obstetric center, whereas women in the control groups had a normal term pregnancy. These studies were therefore subject to selection bias because they overestimated the rate of thrombophilias in study groups and underestimated it in control groups.

Other points of contention are the varying levels of severity of preeclampsia and of gestational age at delivery, as well as racial differences. For example, most studies found an association between thrombophilia and severe preeclampsia at less than 34 weeks’ gestation, but not between thrombophilia and mild preeclampsia at term. In addition, a recent prospective observational study at multiple centers involving 5,168 women found a factor V Leiden mutation rate of 6% among white women, 2.3% among Asians, 1.6% in Hispanics, and 0.8% in African Americans.⁸ This large study found no association between thrombophilia and preeclampsia in these women. Therefore, based on available data, we do not recommend routine screening for factor V Leiden in women with severe preeclampsia.

Preeclampsia and APA syndrome

In 1989, Branch et al²⁶ first reported an association between APA syndrome and severe preeclampsia at less than 34 weeks’ gestation. They recommended that women with severe preeclampsia at this gestational age be screened for APA syndrome and treated when the screen is positive. Several later studies supported or refuted the association between APA syndrome and preeclampsia,^26,27 and a recent report concluded that routine testing for APA syndrome in women with early-onset preeclampsia is unwarranted.²⁶ Therefore, we do not recommend routine screening for APA in women with severe preeclampsia.

 

No need to screen women with abruptio placenta

The placental circulation is comparable to venous circulation, with low pressure and low flow velocity rendering it susceptible to thrombotic complications at the maternal–placental interface and consequent premature separation of the placenta.

It is difficult to confirm an association between thrombophilia and abruptio placenta because of confounding variables such as chronic hypertension, cigarette and cocaine use, and advanced maternal age.³ Studies reviewing this association are scarce, and screening for thrombophilia is discouraged in pregnancies marked by abruptio placenta.

Kupferminc et al²⁸ found that 25%, 20%, and 15% of thrombophilia patients with placental abruption had mutations in factor V Leiden, prothrombin gene, and MTHFR, respectively. In contrast, Prochazka et al²⁹ found 15.7% of their cohort of patients with abruptio placenta to have factor V Leiden mutation.

A large prospective, observational study of more than 5,000 asymptomatic pregnant women at multiple centers found no association between abruptio placenta and factor V Leiden mutation.⁸ Nor were there cases of abruptio placenta among 134 women who were heterozygous for factor V Leiden.

And no routine screening in cases of IUGR

Routine screening for thrombophilias in women with intrauterine growth restriction (IUGR) is not recommended. One reason: The prevalence of thrombophilias in these women ranges widely, depending on the study cited: from 2.8% to 35% for factor V Leiden and 2.8% to 15.4% for prothrombin gene mutation (TABLE 3). In addition, in contrast to earlier studies, a large case-control trial by Infante-Rivard et al³⁰ found no increased risk of IUGR in women with thrombophilias, except for a subgroup of women with the MTHFR variant who did not take a prenatal multivitamin.

A recent meta-analysis of case-control studies by Howley et al³¹ found a significant association between factor V Leiden, the prothrombin gene variant, and IUGR, but the investigators cautioned that this strong association may be driven by small, poor-quality studies that yield extreme associations. A multicenter observational study by Dizon-Townson et al⁸ found no association between thrombophilia and IUGR in asymptomatic gravidas.

TABLE 3

Incidence of thrombophilias in women with intrauterine growth restriction

STUDY	FACTOR V LEIDEN (%)		PROTHROMBIN GENE MUTATION (%)
	IUGR	CONTROLS	IUGR	CONTROLS
Kupferminc et al50	5/44 (11.4)	7/110 (6.4)	5/44 (11.4)	3/110 (2.7)
Infante-Rivard et al30	22/488 (4.5)	18/470 (3.8)	12/488 (2.5)	11/470 (2.3)
Verspyck et al51	4/97 (4.1)	1/97 (1)	3/97 (3.1)	1/97 (1)
McCowan et al52	4/145 (2.8)	11/290 (3.8)	4/145 (2.8)	9/290 (3.1)
Dizon-Townson et al*10	6/134 (4.5)	233/4,753 (4.9)	NR	NR
Kupferminc**34	9/26 (35)	2/52 (3.8)	4/26 (15.4)	2/52 (3.8)
*
** Mid-trimester severe intrauterine growth restriction
IUGR=intrauterine growth restriction, NR=not recorded
SOURCE: Adapted from Clin Obstet Gynecol. 2006;49:850–860

Fetal loss is a complication of thrombophilia

One in 10 pregnancies ends in early death of the fetus (before 20 weeks), and 1 in 200 gestations ends in late fetal loss.³² When fetal loss occurs in the second and third trimesters, it is due to excessive thrombosis of the placental vessels, placental infarction, and secondary uteroplacental insufficiency.^2,33 Women who are carriers of factor V or prothrombin gene mutations are at higher risk of late fetal loss than noncarriers are (TABLE 4).

Fetal loss is a well-established complication in women with thrombophilia, but not all thrombophilias are associated with fetal loss, according to a meta-analysis of 31 studies.³³ In women with thrombophilia, first-trimester loss is generally associated with factor V Leiden, prothrombin gene mutation, and activated protein C resistance. Late, nonrecurrent fetal loss is associated with factor V Leiden, prothrombin gene mutation, and protein S deficiency.³³

TABLE 4

Incidence of factor V Leiden mutation in women with recurrent pregnancy loss

STUDY	PATIENT SELECTION	PATIENTS (%)	CONTROLS (%)	ODDS RATIO	95% CONFIDENCE INTERVAL
Grandone et al53	≥2 unexplained fetal losses, other causes excluded	7/43 (16.3)	5/118 (4.2)	4.4	1.3–14.7
Ridker et al54	Recurrent, spontaneous abortion, other causes not excluded	9/113 (8)	16/437 (3.7)	2.3	1.0–5.2
Sarig et al55	≥3 first- or second-trimester losses or ≥1 intrauterine fetal demise, other causes excluded*	96/145 (66)	41/145 (28)	5.0	3.0–8.5
* Excluded chromosomal abnormalities, infections, anatomic alterations, and endocrine dysfunction

History of adverse outcomes? Offer screening

It is well established that women with a history of fetal death, severe preeclampsia, IUGR, abruptio placenta, or recurrent miscarriage have an increased risk of recurrence in subsequent pregnancies.^3,30,34-36 The rate of recurrence of any of these outcomes may be as high as 46% with a history of 2 or more adverse outcomes, even before any thrombophilia is taken into account.³ Although there are few studies describing the rate of recurrence of adverse pregnancy outcomes in women with thrombophilia and a previous adverse outcome (TABLE 5), it appears to range from 66% to 83% in untreated women.^3,37

Based on these findings, some authors recommend screening for thrombophilia in women who have had adverse pregnancy outcomes^3,9,38 and prophylactic therapy in subsequent pregnancies when the test is positive. Therapy includes low-dose aspirin with or without subcutaneous heparin, as well as folic acid and vitamin B₆ supplements, according to the type of thrombophilia present as well as the nature of the previous adverse outcome.

 

TABLE 5

How women with a previous adverse outcome fare on anticoagulation therapy

STUDY	PATIENTS	PREVIOUS ADVERSE PREGNANCY OUTCOME	ANTICOAGULANT	OUTCOME IN CURRENT PREGNANCY
Riyazi et al9	26	Uteroplacental insufficiency	LMWH and low-dose aspirin	Decreased recurrence of preeclampsia (85% to 38%) and IUGR (54% to 15%)
Brenner37	50	≥3 first-trimester recurrent pregnancy losses with thrombophilia	LMWH	Higher live birth rate compared with historical controls (75% vs 20%)
Ogueh et al48	24	Previous adverse pregnancy outcome plus history of thromboembolic disease, family history of thrombophilia	UFH	No significant mprovement
Kupferminc et al38	33	Thrombophilia with history of preeclampsia or IUGR	LMWH and low-dose aspirin	With treatment, 3% recurrence of preeclampsia
Grandone et al53	25	Repeated pregnancy loss, gestational hypertension, HELLP, or IUGR	UFH or LMWH	90.3% treated with LMWH had good obstetric outcome
Paidas et al3	158	Fetal loss, IUGR, placental abruption, or preeclampsia	UFH or LMWH	80% reduction in risk of adverse pregnancy outcome, compared with historical controls (OR, 0.21; 95% CI, 0.11–0.39)
HELLP=hemolysis, elevated liver enzymes, and low platelets; IUGR=intrauterine growth restriction; LMWH=low-molecular-weight heparin; UFH=unfractionated heparin
SOURCE: Adapted from Am J Perinatol. 2006;23:499–506

No randomized trials on prophylaxis

We lack randomized trials evaluating thromboprophylaxis for prevention of recurrent adverse pregnancy outcomes in women with previous severe preeclampsia, IUGR, or abruptio placenta in association with genetic thrombophilia. Therefore, any recommendation to treat such women with low-molecular-weight heparin with or without low-dose aspirin in subsequent pregnancies should remain empiric and/or prescribed after appropriate counseling of the patients regarding risks and benefits.

TABLE 6 summarizes the risk of thromboembolism in women with thrombophilia—both for asymptomatic patients and for those with a history of thromboembolism. These percentages should be used when counseling women about their risk and determining management and therapy.

TABLE 6

Risk of thromboembolism during pregnancy and postpartum in women with thrombophilia

THROMBOPHILIA	RISK (%)
	ASYMPTOMATIC WOMEN	HISTORY OF VENOUS THROMBOEMBOLISM
Factor V Leiden
Heterozygous	0.2	10
Homozygous	1–2	15–20
Prothrombin gene mutation
Heterozygous	0.5	10
Homozygous	2.3	20
Factor V Leiden and prothrombin gene mutation	5	20
Antithrombin deficiency	7	40
Protein C deficiency	0.5	5–15
Protein S deficiency	0.1	Unknown

Prophylaxis for APA syndrome and recurrent pregnancy loss

Several randomized trials have described the use of low-dose aspirin and heparin in women with APA syndrome and a history of recurrent pregnancy loss, although the results are inconsistent (TABLE 7).^39-45 The inconsistency may be due to varying definitions of APA syndrome and gestational age at the time of randomization, as well as the population studied (previous thromboembolism, presence or absence of lupus anticoagulant, level of titer of anticardiolipin antibodies, presence or absence of previous stillbirth). Nevertheless, we recommend that women with true APA syndrome (presence of lupus anticoagulant, high titers of immunoglobulin G, history of thromboembolism or recurrent stillbirth) receive prophylaxis with low-dose aspirin, with subcutaneous heparin added once fetal cardiac activity is documented.⁴⁶

TABLE 7

Live births in women with APA and a history of fetal loss

STUDY	TREATMENT	CONTROL	NO. OF LIVE BIRTHS (%)
			TREATED WOMEN	CONTROL GROUP
Cowchock et al39	Aspirin/heparin	Aspirin/prednisone	9/12 (75)	6/8 (75)
Laskin et al40	Aspirin/prednisone	Placebo	25/42 (60)	24/46 (52)
Kutteh41	Aspirin/heparin	Aspirin only	20/25 (80)	11/25 (44)
Rai et al42	Aspirin/heparin	Aspirin only	32/45 (71)	19/45 (42)
Silver et al43	Aspirin/prednisone	Aspirin only	12/12 (100)	22/22 (100)
Pattison et al44	Aspirin	Placebo	16/20 (80)	17/20 (85)
Farquharson et al45	Aspirin/LMWH	Aspirin only	40/51 (78)	34/47 (72)
LMWH=low-molecular-weight heparin

Genetic thrombophilias

Few published studies describe prophylactic use of low-molecular-weight heparin with or without low-dose aspirin in women with genetic thrombophilia and a history of adverse pregnancy outcomes. All but 1 of these studies are observational, comparing outcome in the treated pregnancy with that of previously untreated gestations in the same woman.^{3,9,38,44,45,47} These studies included a limited number of women and a heterogeneous group of patients with various thrombophilias; they also involved different therapies (TABLE 7).^{3,9,38,41,48,49}

Gris et al⁴⁷ performed a randomized trial in 160 women with at least 1 prior fetal loss after 10 weeks’ gestation who were heterozygous for factor V Leiden or prothrombin G20210A mutation, or had protein S deficiency. Beginning at 8 weeks’ gestation, these women were assigned to treatment with 40 mg of enoxaparin (n=80) or 100 mg of low-dose aspirin (n=80) daily. All women also received 5 mg of folic acid daily.

In the women treated with enoxaparin, 69 (86%) had a live birth, compared with 23 (29%) women treated with low-dose aspirin. The women treated with enoxaparin also had significantly higher median neonatal birth weights and a lower rate of IUGR (10% versus 30%). The authors concluded that women with factor V Leiden, prothrombin gene mutation, or protein S deficiency and a history of fetal loss should receive enoxaparin prophylaxis in subsequent pregnancies.

History of severe preeclampsia, IUGR, or abruptio placenta. No randomized trials have evaluated thromboprophylaxis in women with this history who have genetic thrombophilia. For this reason, any recommendation to treat these women with low-molecular-weight heparin with or without low-dose aspirin in subsequent pregnancies remains empiric. Prophylaxis can be prescribed after an appropriate discussion of risks and benefits with the patient.

Unresolved questions keep management experimental

What is the likelihood that a woman carrying a gene mutation that predisposes her to thrombophilia will have a serious complication during pregnancy? And how safe and effective is prophylaxis?

 

There is a prevailing need for a double-blind placebo-controlled trial to address these questions and evaluate the benefit of heparin in pregnant women with a history of adverse pregnancy outcomes and thrombophilia. Until then, screening and treatment for thrombophilia remain experimental in these women.

The authors report no financial relationships relevant to this article.

Thrombophilia has been widely investigated—and that may be one of the main challenges in detecting and managing it during pregnancy: Numerous studies have yielded different estimates of the incidence of various clotting disorders in pregnancy—itself a hypercoagulable state—and conflicting screening and prevention recommendations. The authors offer whatever recommendations have emerged.

Why thrombophilia matters

During pregnancy, clotting factors I, VII, VIII, IX, and X rise; protein S and fibrinolytic activity diminish; and resistance to activated protein C develops.^1,2 When compounded by thrombophilia—a broad spectrum of coagulation disorders that increase the risk for venous and arterial thrombosis—the hypercoagulable state of pregnancy may increase the risk of thromboembolism during pregnancy or postpartum.³

Pulmonary embolism is the leading cause of maternal death in the United States.¹ Concern about this lethal sequela has led to numerous recommendations for screening and subsequent prophylaxis and therapy.

Two types

Thrombophilias are inherited or acquired (TABLE 1). The most common inherited disorders during pregnancy are mutations in factor V Leiden, prothrombin gene, and methylenetetrahydrofolate reductase (MTHFR) (TABLE 2). Caucasians have a higher rate of genetic thrombophilias than other racial groups.

Antiphospholipid antibody (APA) syndrome is the most common acquired thrombophilia of pregnancy. It can be diagnosed when the immunoglobulin G or immunoglobulin M level is 20 g per liter or higher, when lupus anticoagulant is present, or both.⁴

TABLE 1

Thrombophilias are inherited or acquired

INHERITED Protein S deficiency Protein C deficiency Protein Z deficiency Antithrombin III Factor V Leiden mutation MTHFR mutation Homozygosity to MTHFR C677T Homozygosity to 4G/4G mutation in PAI-1 gene Prothrombin G20210A mutation Polymorphisms in thrombomodulin gene
ACQUIRED Antiphospholipid antibody syndrome Hyperhomocysteinemia
MTHFR=methylenetetrahydrofolate reductase

TABLE 2

Prevalence of thrombophilias in women with normal pregnancy outcomes

THROMBOPHILIA	PREVALENCE (%)
Factor V Leiden mutation	2–10
MTHFR mutation	8–16
Prothrombin gene mutation	2–6
Protein C and S deficiencies	0.2–1.0*
Anticardiolipin antibodies	1–7
* Combined rate
MTHFR=methylenetetrahydrofolate reductase

Link to adverse pregnancy outcomes

During the past 2 decades, several epidemiologic and case-control studies have explored the association between thrombophilias and adverse pregnancy outcomes,^2-6 which include the following maternal effects:

• Venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and cerebral vein thrombosis
  
• Arterial thrombosis (peripheral, cerebral)
  
• Severe preeclampsia
  

Placental and fetal abnormalities include:

• Thrombosis and infarcts
  
• Abruptio placenta
  
• Recurrent miscarriage
  
• Fetal growth restriction
  
• Death
  
• Stroke
  

Preeclampsia and thrombophilia

The association between preeclampsia and thrombophilia remains somewhat unclear because of inconsistent data. Because of this, we do not recommend routine screening for thrombophilia in women with preeclampsia.

An association between inherited thrombophilias and preeclampsia was reported by Dekker et al in 1995.⁷ Since then, numerous retrospective and case-controlled studies have assessed the incidence of thrombophilia in women with severe preeclampsia.^7-25 Their findings range from:

• Factor V Leiden: 3.7% to 26.5%
  
• Prothrombin gene mutation: 0 to 10.8%
  
• Protein S deficiency: 0.7% to 24.7%
  
• MTHFR variant: 6.7% to 24.0%
  

A meta-analysis of all case-controlled studies suggests that factor V Leiden is the only thrombophilia associated with an increased risk of preeclampsia.⁵ However, almost all studies included in this analysis involved women with severe preeclampsia who were referred to a tertiary-care obstetric center, whereas women in the control groups had a normal term pregnancy. These studies were therefore subject to selection bias because they overestimated the rate of thrombophilias in study groups and underestimated it in control groups.

Other points of contention are the varying levels of severity of preeclampsia and of gestational age at delivery, as well as racial differences. For example, most studies found an association between thrombophilia and severe preeclampsia at less than 34 weeks’ gestation, but not between thrombophilia and mild preeclampsia at term. In addition, a recent prospective observational study at multiple centers involving 5,168 women found a factor V Leiden mutation rate of 6% among white women, 2.3% among Asians, 1.6% in Hispanics, and 0.8% in African Americans.⁸ This large study found no association between thrombophilia and preeclampsia in these women. Therefore, based on available data, we do not recommend routine screening for factor V Leiden in women with severe preeclampsia.

Preeclampsia and APA syndrome

In 1989, Branch et al²⁶ first reported an association between APA syndrome and severe preeclampsia at less than 34 weeks’ gestation. They recommended that women with severe preeclampsia at this gestational age be screened for APA syndrome and treated when the screen is positive. Several later studies supported or refuted the association between APA syndrome and preeclampsia,^26,27 and a recent report concluded that routine testing for APA syndrome in women with early-onset preeclampsia is unwarranted.²⁶ Therefore, we do not recommend routine screening for APA in women with severe preeclampsia.

 

No need to screen women with abruptio placenta

The placental circulation is comparable to venous circulation, with low pressure and low flow velocity rendering it susceptible to thrombotic complications at the maternal–placental interface and consequent premature separation of the placenta.

It is difficult to confirm an association between thrombophilia and abruptio placenta because of confounding variables such as chronic hypertension, cigarette and cocaine use, and advanced maternal age.³ Studies reviewing this association are scarce, and screening for thrombophilia is discouraged in pregnancies marked by abruptio placenta.

Kupferminc et al²⁸ found that 25%, 20%, and 15% of thrombophilia patients with placental abruption had mutations in factor V Leiden, prothrombin gene, and MTHFR, respectively. In contrast, Prochazka et al²⁹ found 15.7% of their cohort of patients with abruptio placenta to have factor V Leiden mutation.

A large prospective, observational study of more than 5,000 asymptomatic pregnant women at multiple centers found no association between abruptio placenta and factor V Leiden mutation.⁸ Nor were there cases of abruptio placenta among 134 women who were heterozygous for factor V Leiden.

And no routine screening in cases of IUGR

Routine screening for thrombophilias in women with intrauterine growth restriction (IUGR) is not recommended. One reason: The prevalence of thrombophilias in these women ranges widely, depending on the study cited: from 2.8% to 35% for factor V Leiden and 2.8% to 15.4% for prothrombin gene mutation (TABLE 3). In addition, in contrast to earlier studies, a large case-control trial by Infante-Rivard et al³⁰ found no increased risk of IUGR in women with thrombophilias, except for a subgroup of women with the MTHFR variant who did not take a prenatal multivitamin.

A recent meta-analysis of case-control studies by Howley et al³¹ found a significant association between factor V Leiden, the prothrombin gene variant, and IUGR, but the investigators cautioned that this strong association may be driven by small, poor-quality studies that yield extreme associations. A multicenter observational study by Dizon-Townson et al⁸ found no association between thrombophilia and IUGR in asymptomatic gravidas.

TABLE 3

Incidence of thrombophilias in women with intrauterine growth restriction

STUDY	FACTOR V LEIDEN (%)		PROTHROMBIN GENE MUTATION (%)
	IUGR	CONTROLS	IUGR	CONTROLS
Kupferminc et al50	5/44 (11.4)	7/110 (6.4)	5/44 (11.4)	3/110 (2.7)
Infante-Rivard et al30	22/488 (4.5)	18/470 (3.8)	12/488 (2.5)	11/470 (2.3)
Verspyck et al51	4/97 (4.1)	1/97 (1)	3/97 (3.1)	1/97 (1)
McCowan et al52	4/145 (2.8)	11/290 (3.8)	4/145 (2.8)	9/290 (3.1)
Dizon-Townson et al*10	6/134 (4.5)	233/4,753 (4.9)	NR	NR
Kupferminc**34	9/26 (35)	2/52 (3.8)	4/26 (15.4)	2/52 (3.8)
*
** Mid-trimester severe intrauterine growth restriction
IUGR=intrauterine growth restriction, NR=not recorded
SOURCE: Adapted from Clin Obstet Gynecol. 2006;49:850–860

Fetal loss is a complication of thrombophilia

One in 10 pregnancies ends in early death of the fetus (before 20 weeks), and 1 in 200 gestations ends in late fetal loss.³² When fetal loss occurs in the second and third trimesters, it is due to excessive thrombosis of the placental vessels, placental infarction, and secondary uteroplacental insufficiency.^2,33 Women who are carriers of factor V or prothrombin gene mutations are at higher risk of late fetal loss than noncarriers are (TABLE 4).

Fetal loss is a well-established complication in women with thrombophilia, but not all thrombophilias are associated with fetal loss, according to a meta-analysis of 31 studies.³³ In women with thrombophilia, first-trimester loss is generally associated with factor V Leiden, prothrombin gene mutation, and activated protein C resistance. Late, nonrecurrent fetal loss is associated with factor V Leiden, prothrombin gene mutation, and protein S deficiency.³³

TABLE 4

Incidence of factor V Leiden mutation in women with recurrent pregnancy loss

STUDY	PATIENT SELECTION	PATIENTS (%)	CONTROLS (%)	ODDS RATIO	95% CONFIDENCE INTERVAL
Grandone et al53	≥2 unexplained fetal losses, other causes excluded	7/43 (16.3)	5/118 (4.2)	4.4	1.3–14.7
Ridker et al54	Recurrent, spontaneous abortion, other causes not excluded	9/113 (8)	16/437 (3.7)	2.3	1.0–5.2
Sarig et al55	≥3 first- or second-trimester losses or ≥1 intrauterine fetal demise, other causes excluded*	96/145 (66)	41/145 (28)	5.0	3.0–8.5
* Excluded chromosomal abnormalities, infections, anatomic alterations, and endocrine dysfunction

History of adverse outcomes? Offer screening

It is well established that women with a history of fetal death, severe preeclampsia, IUGR, abruptio placenta, or recurrent miscarriage have an increased risk of recurrence in subsequent pregnancies.^3,30,34-36 The rate of recurrence of any of these outcomes may be as high as 46% with a history of 2 or more adverse outcomes, even before any thrombophilia is taken into account.³ Although there are few studies describing the rate of recurrence of adverse pregnancy outcomes in women with thrombophilia and a previous adverse outcome (TABLE 5), it appears to range from 66% to 83% in untreated women.^3,37

Based on these findings, some authors recommend screening for thrombophilia in women who have had adverse pregnancy outcomes^3,9,38 and prophylactic therapy in subsequent pregnancies when the test is positive. Therapy includes low-dose aspirin with or without subcutaneous heparin, as well as folic acid and vitamin B₆ supplements, according to the type of thrombophilia present as well as the nature of the previous adverse outcome.

 

TABLE 5

How women with a previous adverse outcome fare on anticoagulation therapy

STUDY	PATIENTS	PREVIOUS ADVERSE PREGNANCY OUTCOME	ANTICOAGULANT	OUTCOME IN CURRENT PREGNANCY
Riyazi et al9	26	Uteroplacental insufficiency	LMWH and low-dose aspirin	Decreased recurrence of preeclampsia (85% to 38%) and IUGR (54% to 15%)
Brenner37	50	≥3 first-trimester recurrent pregnancy losses with thrombophilia	LMWH	Higher live birth rate compared with historical controls (75% vs 20%)
Ogueh et al48	24	Previous adverse pregnancy outcome plus history of thromboembolic disease, family history of thrombophilia	UFH	No significant mprovement
Kupferminc et al38	33	Thrombophilia with history of preeclampsia or IUGR	LMWH and low-dose aspirin	With treatment, 3% recurrence of preeclampsia
Grandone et al53	25	Repeated pregnancy loss, gestational hypertension, HELLP, or IUGR	UFH or LMWH	90.3% treated with LMWH had good obstetric outcome
Paidas et al3	158	Fetal loss, IUGR, placental abruption, or preeclampsia	UFH or LMWH	80% reduction in risk of adverse pregnancy outcome, compared with historical controls (OR, 0.21; 95% CI, 0.11–0.39)
HELLP=hemolysis, elevated liver enzymes, and low platelets; IUGR=intrauterine growth restriction; LMWH=low-molecular-weight heparin; UFH=unfractionated heparin
SOURCE: Adapted from Am J Perinatol. 2006;23:499–506

No randomized trials on prophylaxis

We lack randomized trials evaluating thromboprophylaxis for prevention of recurrent adverse pregnancy outcomes in women with previous severe preeclampsia, IUGR, or abruptio placenta in association with genetic thrombophilia. Therefore, any recommendation to treat such women with low-molecular-weight heparin with or without low-dose aspirin in subsequent pregnancies should remain empiric and/or prescribed after appropriate counseling of the patients regarding risks and benefits.

TABLE 6 summarizes the risk of thromboembolism in women with thrombophilia—both for asymptomatic patients and for those with a history of thromboembolism. These percentages should be used when counseling women about their risk and determining management and therapy.

TABLE 6

Risk of thromboembolism during pregnancy and postpartum in women with thrombophilia

THROMBOPHILIA	RISK (%)
	ASYMPTOMATIC WOMEN	HISTORY OF VENOUS THROMBOEMBOLISM
Factor V Leiden
Heterozygous	0.2	10
Homozygous	1–2	15–20
Prothrombin gene mutation
Heterozygous	0.5	10
Homozygous	2.3	20
Factor V Leiden and prothrombin gene mutation	5	20
Antithrombin deficiency	7	40
Protein C deficiency	0.5	5–15
Protein S deficiency	0.1	Unknown

Prophylaxis for APA syndrome and recurrent pregnancy loss

Several randomized trials have described the use of low-dose aspirin and heparin in women with APA syndrome and a history of recurrent pregnancy loss, although the results are inconsistent (TABLE 7).^39-45 The inconsistency may be due to varying definitions of APA syndrome and gestational age at the time of randomization, as well as the population studied (previous thromboembolism, presence or absence of lupus anticoagulant, level of titer of anticardiolipin antibodies, presence or absence of previous stillbirth). Nevertheless, we recommend that women with true APA syndrome (presence of lupus anticoagulant, high titers of immunoglobulin G, history of thromboembolism or recurrent stillbirth) receive prophylaxis with low-dose aspirin, with subcutaneous heparin added once fetal cardiac activity is documented.⁴⁶

TABLE 7

Live births in women with APA and a history of fetal loss

STUDY	TREATMENT	CONTROL	NO. OF LIVE BIRTHS (%)
			TREATED WOMEN	CONTROL GROUP
Cowchock et al39	Aspirin/heparin	Aspirin/prednisone	9/12 (75)	6/8 (75)
Laskin et al40	Aspirin/prednisone	Placebo	25/42 (60)	24/46 (52)
Kutteh41	Aspirin/heparin	Aspirin only	20/25 (80)	11/25 (44)
Rai et al42	Aspirin/heparin	Aspirin only	32/45 (71)	19/45 (42)
Silver et al43	Aspirin/prednisone	Aspirin only	12/12 (100)	22/22 (100)
Pattison et al44	Aspirin	Placebo	16/20 (80)	17/20 (85)
Farquharson et al45	Aspirin/LMWH	Aspirin only	40/51 (78)	34/47 (72)
LMWH=low-molecular-weight heparin

Genetic thrombophilias

Few published studies describe prophylactic use of low-molecular-weight heparin with or without low-dose aspirin in women with genetic thrombophilia and a history of adverse pregnancy outcomes. All but 1 of these studies are observational, comparing outcome in the treated pregnancy with that of previously untreated gestations in the same woman.^{3,9,38,44,45,47} These studies included a limited number of women and a heterogeneous group of patients with various thrombophilias; they also involved different therapies (TABLE 7).^{3,9,38,41,48,49}

Gris et al⁴⁷ performed a randomized trial in 160 women with at least 1 prior fetal loss after 10 weeks’ gestation who were heterozygous for factor V Leiden or prothrombin G20210A mutation, or had protein S deficiency. Beginning at 8 weeks’ gestation, these women were assigned to treatment with 40 mg of enoxaparin (n=80) or 100 mg of low-dose aspirin (n=80) daily. All women also received 5 mg of folic acid daily.

In the women treated with enoxaparin, 69 (86%) had a live birth, compared with 23 (29%) women treated with low-dose aspirin. The women treated with enoxaparin also had significantly higher median neonatal birth weights and a lower rate of IUGR (10% versus 30%). The authors concluded that women with factor V Leiden, prothrombin gene mutation, or protein S deficiency and a history of fetal loss should receive enoxaparin prophylaxis in subsequent pregnancies.

History of severe preeclampsia, IUGR, or abruptio placenta. No randomized trials have evaluated thromboprophylaxis in women with this history who have genetic thrombophilia. For this reason, any recommendation to treat these women with low-molecular-weight heparin with or without low-dose aspirin in subsequent pregnancies remains empiric. Prophylaxis can be prescribed after an appropriate discussion of risks and benefits with the patient.

Unresolved questions keep management experimental

What is the likelihood that a woman carrying a gene mutation that predisposes her to thrombophilia will have a serious complication during pregnancy? And how safe and effective is prophylaxis?

 

There is a prevailing need for a double-blind placebo-controlled trial to address these questions and evaluate the benefit of heparin in pregnant women with a history of adverse pregnancy outcomes and thrombophilia. Until then, screening and treatment for thrombophilia remain experimental in these women.

The authors report no financial relationships relevant to this article.